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Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal
Abstract
Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.
Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.
Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists.
Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.
... Decreases in overall locomotor activity in the novel environment were considered indicative of elevated levels of anxiety, which is associated with depressive symptoms. These tests allowed for the assessment of depressive-like behaviors in the rats, including anhedonia, grooming behavior, exploration, and locomotor activity in a novel environment (Fuchikami et al., 2015;Santarelli et al., 2003;Surget et al., 2008). ...
... NSST is a measure of anxiety that is responsive to chronic administration of antidepressants (Fuchikami et al., 2015;Hare et al., 2019;Santarelli et al., 2003;Surget et al., 2008). Decreases in grooming behavior and exploration are indicative of apathy, a symptom of depression. ...
... In the NSST, the PD exercise group spent significantly more time actively exploring the novel arena. Decreased grooming behavior indicates disturbance in self-care routines and demonstrates apathy (Fuchikami et al., 2015;Hare et al., 2019;Surget et al., 2008). ...
Aerobic exercise has been shown to have established benefits on motor function in Parkinson's disease (PD). However, the impact of exercise on depressive symptoms in PD remains unclear. This study aimed to investigate the effects of regular exercise, specifically using a forced running wheel, on both motor performance and the prevalence of depression in a unilateral 6-OHDA-lesioned rat model of PD. The behavioral outcomes of exercise were assessed through the rotarod test (RT), forelimb adjusting step test (FAST), sucrose consumption test (SCT), and novelty sucrose splash test (NSST). Our data revealed evident depressive symptoms in the PD animals, characterized by reduced sucrose consumption in the SCT and diminished exploratory activity in the NSST compared to the naïve control group. Specifically, after 11 weeks of exercise, the PD exercise group demonstrated the most significant improvements in sucrose consumption in the SCT. Additionally, this group exhibited reduced immobility and increased exploratory behavior compared to the PD control group in the NSST. Furthermore, the PD exercise group displayed the greatest improvement in correcting forelimb stepping bias. Our results suggested that a regimen of running wheel exercise enhances motor abilities and mitigates the occurrence of depressive behaviors caused by 6-OHDA dopamine depletion in the PD rat model.
... To fully realise the potential of adult hippocampal neurogenesis as a therapeutic strategy for stress-induced mood disorders, several studies have explored whether and how adult-born neurons in the hippocampus mediate the behavioural and endocrine response to chronic stressors (summarised in Table 2). Most studies using nonspecific ablation strategies such as cranial X-irradiation or cytostatic agents have reported no changes in the susceptibility to stress-induced anxiety-or depression-related behaviours 43,45,78,[84][85][86] . One exception was the study by Bessa and colleagues which showed that treatment with the cytostatic agent MAM during the last two weeks of a 6-week chronic mild stress paradigm exacerbated stress-induced anxiety-like behaviour in the novelty-suppressed feeding test 70 , suggesting the stressbuffering actions of adult hippocampal neurogenesis. ...
... Several factors may contribute to these discrepant results, including the ablation strategy and its efficacy and selectivity, the type of stressor and the timing and duration of both the stressor and ablation. For example, X-irradiation which robustly ablates hippocampal neurogenesis has also been shown to induce inflammation and morphological and synaptic alterations that take a long time to fully recover 52,70,78,90 . Moreover, it has been also shown to impact oligodendrocyte progenitor cells in the brain-a cell population that regulates anxiety and depressive-like behaviours in rodents 91,92 . ...
... blocked the efficacy of fluoxetine in the tail suspension and open field tests. However, it is also worthwhile noting that the actions of antidepressants have been shown to be mediated via both neurogenesis-dependent and -independent mechanisms45,78,[81][82][83] . ...
Adult hippocampal neurogenesis in the developmental process of generating and integrating new neurons in the hippocampus during adulthood and is a unique form of structural plasticity with enormous potential to modulate neural circuit function and behaviour. Dysregulation of this process is strongly linked to stress-related neuropsychiatric conditions such as anxiety and depression, and efforts have focused on unravelling the contribution of adult-born neurons in regulating stress response and recovery. Chronic stress has been shown to impair this process, whereas treatment with clinical antidepressants was found to enhance the production of new neurons in the hippocampus. However, the precise role of adult hippocampal neurogenesis in mediating the behavioural response to chronic stress is not clear and whether these adult-born neurons buffer or increase susceptibility to stress-induced mood-related maladaptation remains one of the controversial issues. In this review, we appraise evidence probing the causal role of adult hippocampal neurogenesis in the regulation of emotional behaviour in rodents. We find that the relationship between adult-born hippocampal neurons and stress-related mood disorders is not linear, and that simple subtraction or addition of these neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects. We propose that future studies examining how stress affects unique properties of adult-born neurons, such as the excitability and the pattern of connectivity during their critical period of maturation will provide a deeper understanding of the mechanisms by which these neurons contribute to functional outcomes in stress-related mood disorders.
... Multiple studies have shown proneurogenic effects of selective serotonin reuptake inhibitors (SSRIs) and fluoxetine both in rodents and clinical populations [11][12][13][14][15][16][17][18]. Moreover, several studies suggest that neurogenesis is required for antidepressants to exert their therapeutic effect in mice [19], although most animal studies show that this effect is limited to particular Downloaded from http://karger.com/dne/article-pdf/doi/10.1159/000531478/3878751/000531478.pdf by guest on 03 July 2023 behavioral or neurobiological endophenotypes [20][21][22]. Cortisol concentrations are typically high in depression and patients frequently exhibit abnormal negative feedback in the dexamethasone suppression test. Thus, when patients take fluoxetine, it is likely that it will be in the presence of high concentrations of cortisol. ...
... If a mouse did not start eating the pellet during the first 10 min in the arena, its latency was recorded as 600 sec. For the splash test [20], mice were sprayed with a 10% sucrose solution and placed in a novel cage for 5 min. Grooming behavior was recorded using Ethovision software and manual scoring method. ...
Antidepressants in general, and fluoxetine in particular, increase adult hippocampal neurogenesis (AHN) in mice. Here we asked how the antidepressant fluoxetine affects behavior and AHN in a corticosterone model of depression. In three groups of adult male C57BL/6j mice we administered either vehicle (VEH), corticosterone (CORT) treatment to induce a depression-like state or corticosterone plus a standard dose of fluoxetine (CORT+FLX). Following treatment, mice performed the open field test, the novelty suppressed feeding (NSF) test and the splash test. Neurogenesis was assessed by means of immunohistochemistry using BrdU and neuronal maturation markers. Unexpectedly, 42% of the CORT+FLX-treated mice exhibited severe weight loss, seizures and sudden death. As expected, the CORT treated group had altered behaviors compared to the VEH group, but the CORT+FLX mice that survived did not show any behavioral improvement compared to the CORT group. Antidepressants generally increase neurogenesis and here we also found that compared to CORT mice, CORT+FLX mice that survived had a significantly greater density of BrdU+, BrdU+DCX+ and BrdU+NeuN+ cells, suggesting increased neurogenesis. Moreover, the density of BrdU+NeuN+ cells was increased in an aberrant location, the hilus, of CORT+FLX mice, similar to previous studies describing aberrant neurogenesis following seizures. In conclusion, fluoxetine could induce considerable adverse effects in wild type mice, including seizure-like activity. Fluoxetine-induced neurogenesis increases could be related to this activity, therefore proneurogenic effects of fluoxetine and other antidepressants, especially in the absence of any behavioral therapeutic effects, should be interpreted with caution.
... However, the neurogenesis hypothesis remains somewhat controversial since depression-like symptoms can occur even when the cell proliferation within the hippocampus is not decreased [72]. Also, antidepressants do not always increase hippocampal neurogenesis in animal models of depression [72][73][74]. In fact, the evidence suggests that depression and the efficacy of antidepressants may be more related to variations in dendritic plasticity and neuronal remodeling than neurogenesis [72,74,75]. ...
... Also, antidepressants do not always increase hippocampal neurogenesis in animal models of depression [72][73][74]. In fact, the evidence suggests that depression and the efficacy of antidepressants may be more related to variations in dendritic plasticity and neuronal remodeling than neurogenesis [72,74,75]. Therefore, the role of neuroplasticity might be more important in the pathophysiology of depression. ...
Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.
... Multiple methods for neurogenesis suppression are available. During adulthood, irradiation, which eliminates neural precursor cells, prevents the decrease in depressive behaviors from antidepressant treatment (Santarelli et al., 2003;Surget et al., 2008;David et al., 2009) but does not typically increase anxiety-like or depressive behaviors on its own (Santarelli et al., 2003;Surget et al., 2008;David et al., 2009;Revest et al., 2009;Snyder et al., 2011). More recently, pharmacogenetic models have been utilized to directly target the generation of new neurons. ...
... Multiple methods for neurogenesis suppression are available. During adulthood, irradiation, which eliminates neural precursor cells, prevents the decrease in depressive behaviors from antidepressant treatment (Santarelli et al., 2003;Surget et al., 2008;David et al., 2009) but does not typically increase anxiety-like or depressive behaviors on its own (Santarelli et al., 2003;Surget et al., 2008;David et al., 2009;Revest et al., 2009;Snyder et al., 2011). More recently, pharmacogenetic models have been utilized to directly target the generation of new neurons. ...
Stressors during the adolescent period can affect development of the brain and have long-lasting impacts on behavior. Specifically, adolescent stress impairs hippocampal neurogenesis and can increase risk for anxiety, depression, and a dysregulated stress response in adulthood. In order to model the functional effects of reduced hippocampal neurogenesis during adolescence, a transgenic neurogenesis ablation rat model was used to suppress neurogenesis during the adolescent period and test anxiodepressive behaviors and stress physiology during adulthood. Wildtype and transgenic (TK) rats were given valganciclovir during the first two weeks of adolescence (4-6 weeks old) to knock down neurogenesis in TK rats. Starting in young adulthood (13 weeks old), blood was sampled for corticosterone at several time points following acute restraint stress to measure negative feedback of the stress response, and rats were tested on a battery of anxiodepressive tests at baseline and following acute restraint stress. Although TK rats had large reductions in both cell proliferation during adolescence, as measured by bromodeoxyuridine (BrdU), and ongoing neurogenesis in adulthood (by doublecortin), resulting in decreased volume of the dentate gyrus, negative feedback of the stress response following acute restraint was similar across all rats. Despite similar stress responses, TK rats showed higher anxiety-like behavior at baseline. In addition, only TK rats had increased depressive-like behavior when tested after acute stress. Together, these results suggest that long-term neurogenesis ablation starting in adolescence produces hippocampal atrophy and increases behavioral caution and despair amid stressful environments.
... Multiple lines of evidence suggest that hippocampal dysfunction is involved in MDD 30 , and the volume of the hippocampus is significantly decreased in patients with MDD 31 . Conventional antidepressants increase adult hippocampal neurogenesis, i.e., development of new granule neurons, possibly reversing the cellular changes induced by depression [32][33][34] , and inhibiting neurogenesis blocks the behavioral effects of these antidepressants in rodent and nonhuman primate models 32,[35][36][37] . It takes several weeks for stem/progenitor cells to generate new granule neurons that integrate into the hippocampal circuitry, and the delay in the onset of action of most antidepressants has been ascribed to the time necessary to generate new neurons [38][39][40] . ...
... In mammals, adult neurogenesis occurs in the hippocampal dentate gyrus and in the subventricular zone, and substantial evidence links dysfunction of the hippocampal neurogenic niche to major depressive disorder (MDD). Hippocampal neurogenesis decreases with MDD and increases with antidepressant treatment [32][33][34]76 . Increasing neurogenesis can rescue the effects of chronic stress while inhibiting neurogenesis blocks the ameliorative effects of antidepressants 32,[35][36][37] . ...
Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects. Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects. These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine’s side effects while preserving its therapeutic efficacy. Rawat et al. demonstrate that activation of adult-born immature hippocampal neurons is necessary and sufficient for the acute antidepressant effects of low-dose ketamine in mice.
... Moreover, healthy neurogenesis is required for depression treatment [33]. A lack of response to both drug therapy for depression (fluoxetine and imipramine) and alternative therapy (electroconvulsive antidepressant therapy [34], intermittent hypobaric hypoxia [35]) during neurogenesis ablation in animal models has been shown [36,37]. AD treatment (5-HT and NE reverse inhibitors) promotes neurogenesis by increasing cell proliferation, maturation, cell survival, dendritic growth, and neuronal plasticity [38]. ...
Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression.
... Ketamine exerts effects on many regions of the brain, notably in the hippocampus [15,21,[29][30][31][32]. Hippocampal dysfunction and volume loss are known hallmarks of MDD [33,34]. Adult Hippocampal Neurogenesis (AHN) is also disrupted, and conventional antidepressant medications restore AHN [35][36][37]. Inhibiting AHN blocks the effects of antidepressant medications on behavioral phenotypes in Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine’s rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine’s rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained – but not the rapid – behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine’s sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine’s sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine’s dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05121-6.
... Acute or chronic exposure to stress can suppress hippocampal neurogenesis at various stages of the neurogenic processes (Lucassen et al., 2010a;Mirescu and Gould, 2006), affecting the proliferation of hippocampal neural stem cells, neuronal differentiation, or cell survival (Czéh et al., 2002;Gould et al., 1997;Schoenfeld and Gould, 2013). Different types of chronic stress, ranging from unpredictable chronic mild stress (Santarelli et al., 2003;Surget et al., 2008;Surget et al., 2011;Tanti et al., 2013), chronic social defeat (Lehmann et al., 2013), and chronic immobilization (Ramirez et al., 2015) to prenatal (Coe et al., 2003;Lemaire et al., 2000) and early life stress (Mirescu et al., 2004) downregulate neurogenesis in rodents and nonhuman primates (Perera et al., 2007;Perera et al., 2011;Wu et al., 2014). Similar observations were made in depressed patients (Lucassen et al., 2010b), and a reduced hippocampus volume was reported in patients with major depressive disorder (McKinnon et al., 2009). ...
Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders
... Neurogenesis is thought to play an important role in antidepressant action, since antidepressants, including imipramine, increase neurogenesis, and the inhibition of neurogenesis attenuates the effects of antidepressants [43][44][45][46][47]. In contrast, in the present study, imipramine did not increase neurogenesis in ACMS mice, which is consistent with previous results using a repeated ACTH model [48]. ...
The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress.
... The coat state is a reliable metric of depression in a mouse model 34,35 . Seven different body parts were measured, including head, neck, dorsum, ventrum, tail, forepaws and hind paws. ...
Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.
... In contrast, after a 4-week treatment with imipramine, a classic antidepressant, the sucrose preference and coat condition scores of mice subjected to CMS were better than those of the saline group. These results match the findings of previous reports [27,28]. Notwithstanding the above, the effect of imipramine was not long-lasting. ...
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5−HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5−HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α–P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α–P2X2 signaling in DRN5−HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.
... Furthermore, the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) contains multipotent neural stem cells (NSCs), which play a crucial role in hippocampal neurogenesis. Stress potently inhibits neurogenesis in adult animals [19], and unpredictable chronic mild stress, chronic mild stress, and chronic social defeat stress have been shown to induce depressionlike behaviors and reduce the proliferation of neural progenitor cells in the DG [20][21][22]. ...
Dysregulation of the hypothalamic–pituitary–adrenal axis and abnormalities in the glucocorticoid receptor (GR) have been linked to major depressive disorder. Given the critical role of GR in stress response regulation, we investigated the impact of GR changes on neural stem cells (NSCs) proliferation and hippocampal neurogenesis. Stress response was induced using dexamethasone (DEX), a GR agonist, which led to reduced proliferation of neural stem cells and neural progenitor cells, as well as decreased expression of GR. Additionally, a reduction of serum concentration within the culture media resulted in suppressed cell proliferation, accompanied by decreased GR expression. The association between GR expression and cell proliferation was further confirmed through GR siRNA knockdown and overexpression experiments. Furthermore, in vivo studies utilizing young male C57BL/6 mice demonstrated that corticosterone (CORT) (35 μg/ml) administered through drinking water for four weeks induced depression-like behavior, as indicated by increased immobility times in forced swimming and tail suspension tests. CORT exposure led to reduced GR and nestin expression levels, along with diminished numbers of BrdU-positive cells in the hippocampi, indicating impaired hippocampal neurogenesis. Taken together, our findings provide the first evidence that stress-induced downregulation of GR negatively affects neurogenesis by inhibiting NSCs proliferation.
... Novelty suppressed feeding test. Feeding test paradigm elicits competing motivations between hungry up and fear to eat in the center of a brightly lit arena 73 . Briefly, after a food deprivation for 24 h, mice were weighed to control that mice exhibited a similar deprivation-induced weight loss. ...
Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer’s patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.
... Subsequent studies have shown that CUS dramatically impairs hippocampal (HPC) neurogenesis and sucrose consumption in rats [64,65]. Converging lines of evidence have demonstrated that CUS mediates depression-like behavior and that long-term antidepressant treatment reverses depression-like behavior [66]. It is worth noting that CUS suits both criteria (i) and (ii) for developing a TRD animal model [67]. ...
The monoamine hypothesis has significantly improved our understanding of mood disorders and their treatment by linking monoaminergic abnormalities to the pathophysiology of mood disorders. Even 50 years after the monoamine hypothesis was established, some patients do not respond to treatments for depression, including selective serotonin reuptake drugs. Accumulating evidence shows that patients with treatment-resistant depression (TRD) have severe abnormalities in the neuroplasticity and neurotrophic factor pathways, indicating that different treatment approaches may be necessary. Therefore, the glutamate hypothesis is gaining attention as a novel hypothesis that can overcome monoamine restrictions. Glutamate has been linked to structural and maladaptive morphological alterations in several brain areas associated with mood disorders. Recently, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has shown efficacy in TRD treatment and has received the U.S. Food and Drug Administration approval, revitalizing psychiatry research. However, the mechanism by which ketamine improves TRD remains unclear. In this review, we re-examined the glutamate hypothesis, bringing the glutamate system onboard to join the modulation of the monoamine systems, emphasizing the most prominent ketamine antidepressant mechanisms, such as NMDAR inhibition and NMDAR disinhibition in GABAergic interneurons. Furthermore, we discuss the animal models used in preclinical studies and the sex differences in the effects of ketamine.
... Both S group and P group showed a trend for increased NR1 expression (AVOVA, p = 0.17). Previous studies show that chronic fluoxetine confers antidepressant effects via promotion of neurogenesis in the hippocampus 18 . Accordingly, we tested whether the hippocampal neurogenesis was influenced by the experimental conditions, using BrdU as the marker for cell proliferation. ...
Postpartum depression (PPD) affects over 10% of new mothers and adversely impacts the health of offspring. One of the greatest risk factors for PPD is prepregnancy stress but the underlying biological mechanism is unknown. Here we constructed an animal model which recapitulated prepregnancy stress induced PPD and tested the role of Akt-mTOR signaling in the hippocampus. Female virgin Balb/c mice received chronic restraint stress, followed by co-housing with a normal male mouse. We found that the chronic stress led to a transient depressive-like condition that disappeared within two weeks. However, prepregnantly stressed females developed long-term postpartum depressive-like (PPD-like) symptoms as indicated by deficient performance in tests of sucrose preference, forced swim, and novelty-suppressed feeding. Chronic stress induced transient decrease in Akt-mTOR signaling and altered expressions of glutamate receptor subunits NR1 and GluR1, in contrast to long-term deficits in Akt-mTOR signaling, GluR1/NR1 ratio, and hippocampal neurogenesis in PPD-like mice. Acute ketamine improved the molecular signaling abnormality, and reversed the behavioral deficits in PPD-like mice in a rapid and persistent manner, in contrast to ineffectiveness by chronic fluoxetine treatment. Taken together, we find that chronic prepregnancy stress potentiates a long-term PPD, in which Akt-mTOR signaling may play a crucial role. Postpartum depression (PPD) is a serious mental disorder commonly identified as a subtype of major depressive disorder (MDD) which occurs within 4 weeks of childbirth 1 , and affects approximately 10% to 20% of mothers 2. PPD exerts profound adverse effects on mothers and their infants by disturbing maternal behavior and mother-infant interactions. These disturbances can be disabling or life-threatening 3,4. However, the current understanding of the etiology of PPD is incomplete and the mechanisms remain largely unknown. For the last decades, a number of studies have identified multiple risk factors predicting PPD, including a positive family history of depression, past history of depression and other psychiatric illness, and stressful life events. Currently, the genetic factors influencing PPD remained elusive. Some studies support the hypothesis that experiencing depressed mood or anxiety during pregnancy are significant predictors of PPD 5-7. A recent study demonstrated that elevated depressed mood during pregnancy is strongly associated with a history of emotional problems (e.g. anxiety and depression) and having experienced stressful events, e.g. the depressed mothers had a history of previous depression more frequently than the non-depressed mothers 8 , indicating that prepregnancy experience of stress or depression can be a substantial factor contributing to PPD. Moreover, it has consistently
... The CB2R agonist HU308 (Tocris, Bristol, UK; abbreviated nomenclature: HU) or the inverse agonist/antagonist AM630 (Tocris, Bristol, UK; abbreviated nomenclature: AM) were administered for 2 weeks, as follows. Unpredictable chronic mild stress (uCMS) was induced as previously described [46][47][48]. Brie y animals were subjected to an 8-week unpredictable chronic stress paradigm followed by a 2-week milder protocol period during which CB2R ligands were administered in combination with a physical exercise (PE) protocol as previously described [49]. ...
Chronic stress is a major risk factor of neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects upon cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophin levels, we hypothesized that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, and an overall reduction in neuroinflammation. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasizes the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalize on lifestyle interventions complemented with endocannabinoid pharmacomodulation.
... Similar negative effects of the ablation or the suppression of adult neurogenesis were observed in other cognitive tasks [34,47,11,20,43]. Furthermore, adult neurogenesis may reduce anxietylike behaviors [5] as pharmacologically diverse antidepressants promote adult neurogenesis in rodents [42,31,7,17], nonhuman primates [35], human post-mortem brain tissue [10,9], and human hippocampal progenitor cells in vitro [4]. ...
Evidence suggests that hippocampal adult neurogenesis is critical for discriminating considerably interfering memories. During adult neurogenesis, synaptic competition modifies the weights of synaptic connections non-locally across neurons, thus providing a different form of unsupervised learning from Hebb’s local plasticity rule. However, how synaptic competition achieves separating similar memories largely remains unknown. Here, we aim to link synaptic competition with such pattern separation. In synaptic competition, adult-born neurons are integrated into the existing neuronal pool by competing with mature neurons for synaptic connections from the entorhinal cortex. We show that synaptic competition and neuronal maturation play distinct roles in separating interfering memory patterns. Furthermore, we demonstrate that a feed-forward neural network trained by a competition-based learning rule can outperform a multi-layer perceptron trained by the backpropagation algorithm when only a small number of samples are available. Our results unveil the functional implications and potential applications of synaptic competition in neural computation.
... 155 Additional animal model studies have shown that antagonism of the V 1b receptor attenuates depressive-like and anxiety-like behaviors. 6,[19][20][21][22]146,153,[156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171] Consistent effects of V 1b receptor antagonism were not observed in 2 studies; although the reason for this discrepancy is unknown, the researchers speculated that methodological differences in the behavior assays used may have been a contributing factor. 6,161,167 In humans, the V 1b receptor antagonist ABT-436 has demonstrated reduction of HPA axis parameters such as plasma ACTH, serum and urine cortisol, and urine total glucocorticoids in healthy adults. ...
A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body’s response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body’s stress response equilibrium to a “new normal” underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.
... It is not clear whether the decrease in hippocampal volume is associated with inhibition of neurogenesis, but impaired neurogenesis may be one of the causes of the observed atrophy. Reduced hippocampal neurogenesis is not a cause of stress-related behavioral deficits in animals [275], but behavioral effects of chronic antidepressants treatment may be mediated by the stimulation of neurogenesis in the hippocampus [276]. Chronic antidepressant treatment induces neurogenesis in adult rat hippocampus increasing the proliferation of cells in the dentate gyrus [277]. ...
Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body’s systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.
... The mice were intraperitoneally administered saline, ASD (20,40 or 80 mg/kg/day), or imipramine (10 mg/kg/day; Sigma-Aldrich) once daily (at 16:00 h) for 3 weeks. Based on the antidepressant effects of imipramine involved in hippocampal neurogenesis, 34 imipramine was used as a positive control in this study. The doses of ASD and imipramine were chosen based on previous studies. ...
Background
Using drugs to modulate microglial function may be an effective way to treat disorders, such as depression, that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood–brain barrier and exert anti‐inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression.
Methods
We exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. The potential role of the peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) or BDNF–TrkB pathway in the pro‐neurogenesis and anti‐depressant of ASD was identified using there inhibitors GW9662 and K252a, respectively. The neurogenic effects of ASD‐treated microglia were evaluated using conditioned culture methods.
Results
We found that CMS upregulated pro‐inflammatory factors and inhibited hippocampal neurogenesis in dentate gyrus of mice, while inducing depressive‐like behaviors. Dramatically, ASD (40 mg/kg) treatment reprogrammed an arginase (Arg)‐1⁺ microglial phenotype in dentate gyrus, which increased brain‐derived neurotrophic factor (BDNF) expression and restored the hippocampal neurogenesis, and partially ameliorated the depressive‐like behaviors of the CMS‐exposed mice. K252a or neurogenesis inhibitor blocked the pro‐neurogenic, anti‐depressant effects of ASD. Furthermore, ASD activated PPAR‐γ in dentate gyrus of CMS mice as well as in primary microglial cultures treated with lipopolysaccharide. Blocking the PPAR‐γ using GW9962 suppressed the ASD‐reprogrammed Arg‐1⁺ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD‐treated microglia on NSPC proliferation, survival, and neurogenesis. The pro‐neurogenic and anti‐depressant effects of ASD were blocked by GW9962.
Conclusion
These results suggested that ASD acts via the PPAR‐γ pathway to induce a pro‐neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis.
... In this study, the NAC antioxidant mechanism of action is linked with its cysteine component which is a rate-limiting component in the production of glutathione in the brain (Pallanti et al., 2014;Yin et al., 2016). Fluoxetine neuroprotective action in this study is linked with neuron proliferation, differentiation, and survival of neuron cells (Surget et al., 2008;David et al., 2009). ...
Introduction:
The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.
Methods:
Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).
Results:
Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.
Conclusion:
NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.
... However, few studies have investigated how the brain is specifically regulated by the gut microbiota. Monoamine oxidase is responsible for converting 5-HT to 5-HIAA [77]. Conversely, Parabacteroides has been reported to produce the tryptophan catabolite indoleacetic acid [72]. ...
Background
The microbiota–gut–brain axis plays an important role in the development of depression. The aim of this study was to investigate the effects of 5-HT on cognitive function, learning and memory induced by chronic unforeseeable mild stress stimulation (CUMS) in female mice. CUMS mice and TPH2 KO mice were used in the study. Lactococcus lactis E001-B-8 fungus powder was orally administered to mice with CUMS.
Methods
We used the open field test, Morris water maze, tail suspension test and sucrose preference test to examine learning-related behaviours. In addition, AB-PAS staining, immunofluorescence, ELISA, qPCR, Western blotting and microbial sequencing were employed to address our hypotheses.
Results
The effect of CUMS was more obvious in female mice than in male mice. Compared with female CUMS mice, extracellular serotonin levels in TPH2 KO CUMS mice were significantly reduced, and cognitive dysfunction was aggravated. Increased hippocampal autophagy levels, decreased neurotransmitter levels, reduced oxidative stress damage, increased neuroinflammatory responses and disrupted gut flora were observed. Moreover, L. lactis E001-B-8 significantly improved the cognitive behaviour of mice.
Conclusions
These results strongly suggest that L. lactis E001-B-8 but not FLX can alleviate rodent depressive and anxiety-like behaviours in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition.
... The mechanism of conduct during the CMUS procedure involves chronic exposure of examined rodents to various social and/or environmental stressors. The used stress stimuli are mild in character, and the frequency of their application each week is changed regularly in order to achieve their maximum differentiation in the performed examinations [26]. The stressors used in the CMUS model include, among others: limited access to food/water, swimming in cold or hot water, changes in temperature, wet litter or a lack of it, squeezing the tail, tilting the cage by 45 • , disturbing the day/night cycle, putting rat excreta into mouse cages [27]. ...
Nowadays, stressful situations are an unavoidable element of everyday life. Stressors activate a number of complex mental and physiological reactions in the organism, thus affecting the state of health of an individual. Stress is the main risk factor in the development of mental disorders, such as depression and other disorders developing as a result of addiction. Studies indicate that women are twice as likely as men to develop anxiety, depression and therefore addiction, e.g., to nicotine. Even though the data presented is indicative of significant differences between the sexes in the prevalence of these disorders, the majority of preclinical animal models for investigating stress-induced disorders use predominantly male subjects. However, the recent data indicates that this type of studies has also been launched in female rodents. Therefore, conducting research on both sexes allows for a more accurate understanding and assessment of the impact of stress on stress-induced behavioral, peripheral and molecular changes in the body and brain. In this manuscript we have gathered the data from 41 years (from 1981–2022) on the influence of stress on the development of depression and nicotine addiction in both sexes.
... Neurodegenerative effects in HIP include atrophy of dendrites, loss of granule cells, and suppression of neurogenesis, and in PFC include microglial activation, atrophy of pyramidal neurons, dendritic retraction, suppression of cell proliferation, and reduction of synaptic proteins; and chronic treatment with antidepressant drugs repairs all of this functional and structural damage in both structures (Willner et al., 2013;Duman, 2014;Dusi et al., 2015;Liu et al., 2017). However, recovery from stress-induced behavioural impairments is dependent on a restoration of neurogenesis in the HIP (Santarelli et al., 2003;Surget et al., 2008Surget et al., , 2011Mateus-Pinheiro et al., 2013), suggesting a primacy of antidepressant effects in HIP for functional recovery. In people, a decrease in hippocampal volume, reflecting changes in hippocampal morphology and loss of dendrites, is a reliable correlate of major depression (Campbell et al., 2004;Videbech and Ravnkilde, 2004;Czeh and Lucassen, 2007), and is associated with resistance to antidepressant treatment. ...
Background:
Our earlier study demonstrated that repeated optogenetic stimulation of afferents from ventral hippocampus (vHIP) to the prelimbic region of medial prefrontal cortex (mPFC) overcame resistance to antidepressant treatment in Wistar-Kyoto (WKY) rats. These results suggested that antidepressant resistance may result from an insufficiency of transmission from vHIP to mPFC. Here we examined whether similar effects can be elicited from major output of mPFC; the pathway from to nucleus accumbens core (NAc).
Method:
WKY rats were subjected to Chronic Mild Stress and were used in two sets of experiments: 1) they were treated acutely with optogenetic stimulation of afferents to NAc core originating from the mPFC, and 2) they were treated with chronic (5 weeks) venlafaxine (10 mg/kg) and/or repeated (once weekly) optogenetic stimulation of afferents to NAc originating from either mPFC or vHIP.
Results:
Chronic mild stress procedure decreased sucrose intake, open arm entries on elevated plus maze, and novel object recognition test. Acute optogenetic stimulation of the mPFC-NAc and vHIP-NAc pathways had no effect in sucrose or plus maze tests, but increased object recognition. Neither venlafaxine nor mPFC-NAc optogenetic stimulation alone was effective in reversing the effects of CMS, but the combination of chronic antidepressant and repeated optogenetic stimulation improved behaviour on all three measures.
Conclusions:
The synergism between venlafaxine and mPFC-NAc optogenetic stimulation supports the hypothesis that the mechanisms of non-responsiveness of WKY rats involves a failure of antidepressant treatment to restore transmission in the mPFC-NAc pathway. Together with earlier results, this implicates insufficiency in a vHIP-mPFC-NAc circuit in non-responsiveness to antidepressant drugs.
... We also found higher DCX expression in adolescent males compared to adolescent females, similar to findings of greater hippocampal neurogenesis in naïve pre-pubertal males compared to females [65,66]. Intriguingly, reduced hippocampal neurogenesis was associated with increased negative cognitive bias in young adult males only which may be consistent with findings of increased hippocampal neurogenesis being associated reduced depressivelike behavior, found after antidepressant treatment or voluntary exercise in both males and females [24,27,31,32,67]. It is difficult to understand why we saw this association in males but not in females in the present study. ...
Background
Cognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias in rats that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of male and female rats across the lifespan.
Results
After cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Adolescent male rats had higher hippocampal neurogenesis than adolescent females after cognitive bias testing and young rats that underwent cognitive bias testing had higher levels of hippocampal neurogenesis than controls. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males.
Conclusions
Overall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.
... A score of either 0 for a coat in a good state or a score of 1 for a dirty and unkempt coat were given for each of these areas. The total score for an individual mouse was obtained from the sum of the score of each of its body parts [20]. ...
Nitrous oxide (N2O) has shown promise as a putative rapid acting antidepressant but little is known about the underlying mechanisms. We have here performed transcriptomics and electrophysiological studies to dissect shared signatures acutely induced by 1-hour inhalation of 50% N2O and single subanesthetic dose of ketamine, a well-established antidepressant, in the adult mouse medial prefrontal cortex. Unbiased quantitative RNA sequencing demonstrated that several transcripts belonging to the mitogen-activated protein kinase (MAPK) pathway are similarly regulated by N2O and ketamine. In particular, both treatments increased the expression of the dual specificity phosphatases (DUSPs), negative regulators of MAPKs. N2O also rapidly reduced saccharine preference and induced expression of Dusp1 and Dusp6 in animals subjected to chronic treatment with stress hormone corticosterone. Interestingly, overall, the effects of N2O on the mRNA expression were more prominent and widespread compared to
ketamine. Ketamine and to lesser extent nitrous oxide caused elevation of gamma-activity (30-100 Hz) of cortical local field potential, however firing rate and phase locking of spike-to-LFPs of neurons of this brain area showed no uniform changes across the treatments. These findings provide support for the antidepressant properties of N2O and further highlight the involvement of MAPK regulation in the mechanism of action of rapid-acting antidepressants.
... We also found higher DCX expression in adolescent males compared to adolescent females, similar to findings of greater hippocampal neurogenesis in naïve pre-pubertal males compared to females [65,66]. Intriguingly, reduced hippocampal neurogenesis was associated with increased negative cognitive bias in young adult males only which may be consistent with findings of increased hippocampal neurogenesis being associated reduced depressivelike behavior, found after antidepressant treatment or voluntary exercise in both males and females [24,27,31,32,67]. It is difficult to understand why we saw this association in males but not in females in the present study. ...
Background: Cognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of males and females across the lifespan. Results: After cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males. Conclusions: Overall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.
... Decreased hippocampal volumes are reported also in other neuropsychiatric disorders (Kempermann et al., 2008;Navarro-Sanchis et al., 2017), suggesting that neurogenesis might be an important mediating factor in the pathogenesis. Moreover, chronic antidepressant treatments seem to increase adult hippocampal neurogenesis, and blocking neurogenesis in mice abolished the beneficial impact of the antidepressant treatment (Navarro-Sanchis et al., 2017; Santarelli et al., 2003;Surget et al., 2008), this would explain the delayed onset of their therapeutic action. Indeed, changes in neurotransmitters balance could have long-term effects on the neuronal organization of the brain. ...
We summarize here the progress in identifying the neuronal network as well as the function of paradoxical sleep and the gaps of knowledge that should be filled in priority. The core system generating paradoxical sleep localized in the brainstem is now well identified, and the next step is to clarify the role of the forebrain in particular that of the hypothalamus including the melanin‐concentrating hormone neurons and of the basolateral amygdala. We discuss these two options, and also the discovery that cortical activation during paradoxical sleep is restricted to a few limbic cortices activated by the lateral supramammillary nucleus and the claustrum. Such activation nicely supports the findings recently obtained showing that neuronal reactivation occurs during paradoxical sleep in these structures, and induces both memory consolidation of important memory and forgetting of less relevant ones. The question that still remains to be answered is whether paradoxical sleep is playing more crucial roles in processing emotional and procedural than other types of memories. One attractive hypothesis is that paradoxical sleep is responsible for erasing negative emotional memories, and that this function is not properly functioning in depressed patients. On the other hand, the presence of a muscle atonia during paradoxical sleep is in favour of a role in procedural memory as new types of motor behaviours can be tried without harm during the state. In a way, it also fits with the proposed role of paradoxical sleep in setting up the sensorimotor system during development.
... These results are consistent with previous studies of the effects of chronic stress exposure in various animal models of depression [42,43]. We did not observe an increased latency to eat in the novelty-suppressed feeding test, even though this test is sensitive to chronic stress [44]. Our findings show that chronic LCGA-17 administration ameliorated anxietyand depressive-related behaviors following CUS in rats in all behavioral paradigms utilized. ...
We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.
... The NSFT was used to measure anxiety-induced hyponeophagia, which is the inhibition of ingestion and approach to food pellets when exposed to an anxiety-provoking novel environment. The testing apparatus consisted of a square, transparent methacrylate cage 40 × 40 × 50 cm, with a food pellet on the white platform in the center of the cage [44,98]. Before the experiment, mice were deprived of food for 24 h, and then each mouse was placed in the corner of the apparatus. ...
The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.
... However, a direct relationship between adult hippocampal neurogenesis and affective disorders has been challenged. Whilst earlier studies highlighted that neurogenesis integrity is a requirement for the behavioral effects of antidepressants (Santarelli et al., 2003;Surget et al., 2008), recent reports have rejected this possibility (Bessa et al., 2009) or depicted a more nuanced picture by suggesting the existence of neurogenesis-dependent and -independent mechanisms of antidepressant action (David et al., 2009). Thus, although other studies are necessary to determine whether adult neurogenesis is critical for the behavioral effects of antimanic agents, it is noteworthy that any increase in cell proliferation may not be sufficient to produce antimanic effects. ...
... Generally, by presenting mice with food in a new environment such as an unfamiliar cage, anxiety is produced and hyponeophagia is evaluated by measuring the latency to feed and the total food consumed. The point is that in experimental animal, while acute treatment with anxiolytic drugs is effective, only chronic treatment with SSRIs and TCA is effective in decreasing latency period until feeding (30,31). BCG as a chronic model of depression clearly increased the latency to feed and the food intake was lower than normal animals in NSFT. ...
Objective: Bacillus-Calmette-Guerin (BCG) inoculation in mice produces an acute period of illness followed by a chronic depressive-like behavior period that lasts for few weeks. The aim was to evaluate vitamin B6 antidepressant effect in comparison with common antidepressants.
Method: BCG (0.2 ml/mouse) single dose was intraperitoneally inoculated in male mice. Vitamin B6 (100 mg/kg), fluoxetine, imipramine, or venlafaxine (10 mg/kg each) were intraperitoneally injected for 14 consecutive days following BCG administration. Illness was evaluated following inoculation and depressive-like behaviors were assessed on days 7 and 14.
Results: Illness was induced by BCG since mice lost weight and locomotor activity was reduced. Illness was prevented by vitamin B6 similar to antidepressant drugs. Despair was measured by immobility time during the forced swim test and BCG increased it compared to control (193 ± 3s vs 151 ± 7s, P < 0.01) on day 7, and (200 ± 5s vs 147 ± 6s, P < 0.001) on day 14. Vitamin B6, like antidepressants, reduced despair. BCG clearly induced anhedonia evaluated by sucrose preference test (47.5%), and it was soothed by B6 and the antidepressants. Novelty-suppressed feeding test evaluated long term depressive behavior after 14 days. BCG increased the latency to first feeding (222 ± 41s vs control 87 ± 2.6s, P < 0.001) and reduced food consumption per body weight (13 ± 1 mg/g vs control 19 ± 2 mg/g, P < 0.001) while B6 like antidepressants reduced latency and improved food consumption.
Conclusion: Vitamin B6 efficiently prevented BCG sickness and depression that was comparable to common antidepressant drugs. Therefore, B6 supplement for preventing depression in high-risk individuals is suggested for further clinical research.
... The contrasting effect of stress on BDNF in the basolateral amygdala and dentate gyrus has been previously reported using a different stress paradigm (Lakshminarasimhan and Chattarji 2012). Fluoxetine (Gumuslu et al. 2013;Nollet et al. 2012;Surget et al. 2008;Zavvari et al. 2020) and thymoquinone (Alam et al. 2018) compensated the chronic stress-induced changes, which is in accordance with previous studies. Increased BDNF and NeuN expression observed in our study may be explained by the increased volume and activity of the amygdala in stressed human subjects reported elsewhere (Muscatell et al. 2015). ...
Rationale
Major depressive disorder is the leading cause of disability worldwide. The corticolimbic system plays a critical role in the emotional and cognitive aspects of major depressive disorder. Owing to the unsatisfactory efficacy of conventional antidepressants, there is a need to explore novel therapies.
Objectives
The current study aimed to explore the antidepressant potential of thymoquinone, a natural compound with anti-inflammatory activity, and propose its underlying mechanism of action in the unpredictable chronic mild stress (UCMS) mouse model.
Methods
Coat state, forced swim test, elevated plus maze test, novelty suppressed feeding test and social interaction test were performed to quantify the behavioural shift induced by UCMS and the effect of thymoquinone and fluoxetine treatment. In addition, messenger RNA (mRNA) expression levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and BDNF and NeuN were analysed by a quantitative real-time polymerase chain reaction in the hippocampus and amygdala of experimental and control groups.
Results
UCMS significantly deteriorated coat state. Thymoquinone reinstated the resignation behaviour and latency to feed affected by UCMS. UCMS induced an increase in inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the hippocampus and amygdala, which was decreased by thymoquinone. UCMS caused an increase in BDNF and NeuN mRNA levels in the amygdala while a decrease in the hippocampus. This opposite effect on BDNF was also compensated by thymoquinone; however, thymoquinone did not significantly change Ki67 and NeuN mRNA levels in the hippocampus.
Conclusions
Thymoquinone restored the behavioural changes induced by UCMS. In addition, the antidepressant effect of thymoquinone is in line with changes in inflammatory parameters and changes in BDNF in the hippocampus and amygdala.
... It has been suggested that the anti-depressant effect of orexin-A may be related to increased hippocampal cell proliferation in the DG region of the hippocampus, induced by orexinergic activation (Ito et al., 2008). Another study showed that blocking the orexinergic system reduced cell proliferation and neurogenesis, especially in the ventral hippocampus, but it did not induce depressive-like behaviors (Surget et al., 2008(Surget et al., , 2011. Conflicting results are reported as well (Snyder et al., 2011). ...
In this review study, we aimed to introduce the orexinergic system as an important signaling pathway involved in a variety of cognitive functions such as memory, motivation, and reward-related behaviors. This study focused on the role of orexinergic system in modulating reward-related behavior, with or without the presence of stressors. Cross-talk between the reward system and orexinergic signaling was also investigated, especially orexinergic signaling in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the hippocampus. Furthermore, we discussed the role of the orexinergic system in modulating mood states and mental illnesses such as depression, anxiety, panic, and posttraumatic stress disorder (PTSD). Here, we narrowed down our focus on the orexinergic signaling in three brain regions: the VTA, NAc, and the hippocampus (CA1 region and dentate gyrus) for their prominent role in reward-related behaviors and memory. It was concluded that the orexinergic system is critically involved in reward-related behavior and significantly alters stress responses and stress-related psychiatric and mood disorders.
... 27 Furthermore, evidence also shows that blockage of hippocampal neurogenesis diminishes the antidepressant-like effects of fluoxetine, suggesting involvement of BDNF in antidepressant actions. 28 In our previous study we also found increased serum BDNF concentration in patients with VaD treated with fluoxetine. 14 A preclinical study also showed that vascular endothelial growth factor (VEGF) was identified as a key mediator of both the cytogenetic and behavioral actions of antidepressants. ...
Purpose
Selective serotonin reuptake inhibitors (SSRIs) enhance angiogenesis and neurogenesis. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) play an important role in neurogenesis and angiogenesis. However, the effect of SSRIs on cognition and serum BDNF and VEGF in patients with vascular cognitive impairment no dementia (VCIND) is largely unknown.
Patients and Methods
It was an open label study. Fifty VCIND patients were randomly allocated to receive fluoxetine (20 mg/d; n = 25) or no fluoxetine (control group; n = 25) for 12 weeks. VCIND patients received fluoxetine 20 mg/d and secondary prevention of stroke for 12 weeks in the fluoxetine group, whereas the control group received only secondary prevention of stroke for 12 weeks. The primary outcome and secondary outcome were of assessment of Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) score, Ten Point Clock drawing test score (TPC), Verbal Fluency Test (VFT), Trail Making Test form a (TMTa), Trail Making Test form b (TMTb) and Digit Span Test score at baseline and week 12 in the both groups. And serum concentration of BDNF and VEGF was also tested at baseline and week 12 in both groups.
Results
After 12 weeks, TPC scores increased more significantly in the fluoxetine group than in the control group, while TMTa score and TMTb score were decreased more significantly in the fluoxetine group than in the control group. We also found that the serum concentration of BDNF and VEGF in the fluoxetine group increased more significantly than in the control group. However, we found no significant differences in mean change from baseline between fluoxetine and control group in ADAS-Cog score, Digit Span Test score and VFT score.
Conclusion
Fluoxetine may enhance cognition in certain cognitive domains and serum concentration of BDNF and VEGF in patients with VCIND.
... Because antidepressants promote neurogenesis in the adult hippocampus [12][13][14][15][16][17][18][19], the delay in therapeutic response could reflect the time necessary for newborn neurons to mature and incorporate into the hippocampal circuitry. Multiple classes of antidepressants, including tricyclic antidepressants [20], monoamine oxidase inhibitors [21], selective serotonin reuptake inhibitors (SSRIs) [22], and serotonin-noradrenaline reuptake inhibitors (SNRIs) [23,24] increase neurogenesis, and the antidepressant effects of these drugs in experimental models of depression are dependent upon newborn neurons [13,22,[25][26][27][28]. Further, we recently demonstrated that the most widely used SSRI, fluoxetine (Prozac), not only increases the number of newborn neurons in the hippocampal dentate gyrus (DG) but also increases their excitability [25]. ...
The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.
Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.
Major depressive disorder (MDD) is characterized by persistent depressed mood, loss of interest or pleasure in previously enjoyable activities, recurrent thoughts of death, and physical and cognitive symptoms. People with MDD can have reduced quality of life owing to the disorder itself as well as related medical comorbidities, social factors, and impaired functional outcomes. MDD is a complex disorder that cannot be fully explained by any one single established biological or environmental pathway. Instead, MDD seems to be caused by a combination of genetic, environmental, psychological and biological factors. Treatment for MDD commonly involves pharmacological therapy with antidepressant medications, psychotherapy or a combination of both. In people with severe and/or treatment-resistant MDD, other biological therapies, such as electroconvulsive therapy, may also be offered.
There is an urgent need to develop more effective treatments for stress-related illnesses, which include depression, post-traumatic stress disorder, and anxiety. We view animal models as playing an essential role in this effort, but to date, such approaches have generally not succeeded in developing therapeutics with new mechanisms of action. This is partly due to the complexity of the brain and its disorders, but also to inherent difficulties in modeling human disorders in rodents and to the incorrect use of animal models: namely, trying to recapitulate a human syndrome in a rodent which is likely not possible as opposed to using animals to understand underlying mechanisms and evaluating potential therapeutic paths. Recent transcriptomic research has established the ability of several different chronic stress procedures in rodents to recapitulate large portions of the molecular pathology seen in postmortem brain tissue of individuals with depression. These findings provide crucial validation for the clear relevance of rodent stress models to better understand the pathophysiology of human stress disorders and help guide therapeutic discovery. In this review, we first discuss the current limitations of preclinical chronic stress models as well as traditional behavioral phenotyping approaches. We then explore opportunities to dramatically enhance the translational use of rodent stress models through the application of new experimental technologies. The goal of this review is to promote the synthesis of these novel approaches in rodents with human cell-based approaches and ultimately with early-phase proof-of-concept studies in humans to develop more effective treatments for human stress disorders.
Depression is a mood disorder coursing with several behavioral, cellular, and neurochemical alterations. The negative impact of chronic stress may precipitate this neuropsychiatric disorder. Interestingly, downregulation of oligodendrocyte-related genes, abnormal myelin structure, and reduced numbers and density of oligodendrocytes in the limbic system have been identified in patients diagnosed with depression, but also in rodents exposed to chronic mild stress (CMS). Several reports have emphasized the importance of pharmacological or stimulation-related strategies in influencing oligodendrocytes in the hippocampal neurogenic niche. Repetitive transcranial magnetic stimulation (rTMS) has gained attention as an intervention to revert depression. Here, we hypothesized that 5 Hz (Hz) of rTMS or Fluoxetine (Flx) would revert depressive-like behaviors by influencing oligodendrocytes and revert neurogenic alterations caused by CMS in female Swiss Webster mice. Our results showed that 5 Hz rTMS or Flx revert depressive-like behavior. Only rTMS influenced oligodendrocytes by increasing the number of Olig2-positive cells in the hilus of the dentate gyrus and the prefrontal cortex. However, both strategies exerted effects on some events of the hippocampal neurogenic processes, such as cell proliferation (Ki67-positive cells), survival (CldU-positive cells), and intermediate stages (doublecortin-positive cells) along the dorsal-ventral axis of this region. Interestingly, the combination of rTMS-Flx exerted antidepressant-like effects, but the increased number of Olig2-positive cells observed in mice treated only with rTMS was canceled. However, rTMS-Flx exerted a synergistic effect by increasing the number of Ki67-positive cells. It also increased the number of CldU- and doublecortin-positive cells in the dentate gyrus. Our results demonstrate that 5 Hz rTMS has beneficial effects, as it reverted depressive-like behavior by increasing the number of Olig2-positive cells and reverting the decrement in hippocampal neurogenesis in CMS-exposed mice. Nevertheless, the effects of rTMS on other glial cells require further investigation.
Background:
Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice.
Methods:
Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze).
Results:
UCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA.
Conclusions:
DHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.
Dentate gyrus (DG), a “gate” that control the information flow into the hippocampus, is critical for learning, memory, spatial navigation, and mood regulations. Several lines of evidence have demonstrated that deficits in dentate granule cells (DGCs) (e.g., loss of DGCs or genetic mutations in DGCs) contribute to the development of various psychiatric disorders, such as depression and anxiety disorders. Whereas ventral DGCs are believed to be critical for mood regulations, the functions of dorsal DGCs (dDGCs) in this aspect remain elusive. Here, we will review DGCs, in particular the dDGCs, in regulating mood, and their functional relationships with DGC development, and dysfunctional DGCs’ contributions to mental disorders.
Transcranial magnetic stimulation (TMS) induces electric fields that depolarize or hyperpolarize neurons. Intermittent theta burst stimulation (iTBS), a patterned form of TMS that is delivered at the theta frequency (~5 Hz), induces neuroplasticity in the hippocampus, a brain region that is implicated in memory and learning. One form of plasticity that is unique to the hippocampus is adult neurogenesis, however little is known about whether TMS, or iTBS in particular, affects newborn neurons. Here we therefore applied repeated sessions of iTBS to male and female mice and measured the extent of adult neurogenesis and the morphological features of immature neurons. We found that repeated sessions of iTBS did not significantly increase the amount of neurogenesis or affect the gross dendritic morphology of new neurons, and there were no sex differences in neurogenesis rates or aspects of afferent morphology. In contrast, efferent properties of newborn neurons varied as a function of sex and stimulation. Chronic iTBS increased the size of mossy fiber terminals, which synapse onto CA3 pyramidal neurons, but only in males. iTBS also increased the number of terminal-associated filopodia, putative synapses onto inhibitory interneurons, but only in male mice. This efferent plasticity could be result from a general trophic effect or it could reflect accelerated maturation of immature neurons. Given the important role of mossy fiber synapses in hippocampal learning, our results identify a neurobiological effect of iTBS that might be associated with sex-specific changes in cognition.
Objective:
To evaluate the effect of compound Gaoziban tablet (, CGZBT) on depression, and to investigate the underlying mechanism.
Methods:
The components of CGZBT were analysed by high-performance liquid chromatography. Then, we assessed the effects of varying doses of CGZBT on an established chronic unpredictable mild stress (CUMS) model in rats. Whether animals were depressed was evaluated by sucrose preference test, open field test and forced swimming test. Neurotransmitters of hippocampus were detected by liquid chromatography-mass spec-trometry. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-4, and IL-10 were measured by enzyme-linked immunosorbent assay. Expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phospho-nuclear factor-kappa B (p-NF-κB), cyclooxygenase-2 (COX-2), ionized calcium binding adapter molecule-1 (IBA-1) were assessed by immunohistochemical staining and western blotting.
Results:
Eight compounds were identified from CGZBT, moreover, our results showed that CGZBT effectively reversed the CUMS-induced decrease in sucrose preference, shortened the movement distance and prolonged immobility time. CGZBT significantly increased levels of 5-hydroxytryptamine, dopamine, norepinephrine, 5-hydroxyindoleacetic acid levels, and reduced the expression of TNF-α, IL-1β, IL-6, yet increased IL-4 and IL-10. Furthermore, the expressions of TLR4, MyD88, COX-2, p-NF-κB and IBA-1 in hippocampus were effectively reversed after treatment with CGZBT.
Conclusions:
These results indicated that CGZBT could, at least in part, alleviate depression induced by CUMS the TLR4/MyD88/NF-κB pathway, suggesting its potential as an antidepressant drug.
Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
Hippocampal neurogenesis persists across the lifespan in many species, including rodents and humans, and is associated with cognitive performance and the pathogenesis of neurodegenerative disease and psychiatric disorders. Neurogenesis is modulated by steroid hormones that change across development and differ between the sexes in rodents and humans. Here, we discuss the effects of stress and glucocorticoid exposure from gestation to adulthood as well as the effects of androgens and estrogens in adulthood on neurogenesis in the hippocampus. Throughout the review we highlight sex differences in the effects of steroid hormones on neurogenesis and how they may relate to hippocampal function and disease. These data highlight the importance of examining age and sex when evaluating the effects of steroid hormones on hippocampal neurogenesis.
Ethnopharmacological relevance
Xiaoyaosan (XYS), a representative and classic traditional Chinese medicine (TCM) prescription with function of dispersing stagnated liver and strengthening spleen, has been used for thousands of years to treat depression. XYS’ anti-depression effect has been demonstrated both clinically and experimentally; however, the material basis for this effect has yet to be elucidated.
Aim of the study
This study aimed to evaluate the impact and underlying action mechanism of XYS’ antidepressant active component (Xiaoyaosan ethyl acetate fraction, XYSEF) against chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice.
Materials and methods
First, we established a behavioral despair depression mouse model to preliminarily determine the effective antidepressant dose of XYSEF. Then, we created a CUMS mouse model and used various classic behavioral tests, including SPT, ST, NFST, and TST, to assess XYSEF's antidepressant properties. IGF-1 levels in mouse serum and hippocampus were quantified using ELISA. The average optical density of Nissl bodies in the mouse hippocampal CA3 region was determined utilizing toluidine blue staining. Brdu and DCX expression in the hippocampal dentate gyrus (DG) was assayed using the immunofluorescence method. IGF-1Rβ, PI3K, p-PI3K, Akt, p-Akt, Caspase-3, and cleaved Caspase-3 protein levels in the hippocampus were determined with Western blot.
Results
The behavioral despair mouse model findings showed that 9.1 and 40 g/kg of XYSEF both significantly shortened the immobility time of mice, suggesting that the effective dose range was 9.1–40 g/kg. Compared to the CUMS mouse model, XYSEF at 20 and 40 g/kg markedly increased the sucrose preference percentage in the SPT and grooming time in the ST, shortened the immobility time in the TST and the feeding latency in the NSFT, and reversed the downregulated IGF-1 content in mouse serum and hippocampus. In addition, XYSEF amplified the average optical density of Nissl bodies in the hippocampal CA3 region, promoted Brdu and DCX expression in DG, and diminished IGF-1Rβ, p-PI3K/PI3K, p-Akt/Akt, and cleaved Caspase-3/Caspase-3 protein levels in the hippocampi of CUMS mice.
Conclusion
XYSEF acted as an antidepressant in mice exhibiting CUMS-induced depression-like behaviors, possibly by promoting hippocampal neurogenesis, reducing neuronal apoptosis, and inhibiting the over-activation of the IGF-1Rβ/PI3K/Akt pathway.
Major depression is a disease having high lifetime prevalence, characterized by alterations in the affective and cognitive spheres. It is related to a complex aetiology, as both stress sensitivity and genetic factor contribute to vulnerability and is associated with cerebral, endocrine and neurotransmission alterations, such as decreased hippocampal functioning, modifications of the monoaminergic level or an hyperactivity of the hypothalamus-pituitary-adrenal axis. Chronic antidepressants enable to decrease the depression-related symptoms, but many drawbacks of such treatments made the discovery of new therapeutic targets urgent. Progress in this area needs valid animal models. Here, we review data on one of these models, the unpredictable chronic mild stress in mice. Data show that this protocol is associated with several behavioural and neurobiological alterations, suggesting that it induces features that are isomorphic to the human disease. Further, these alterations are induced by factors involved in the aetiology of major depression in humans. Finally, these modifications are sensitive only to chronic, but not acute, antidepressants used in the clinic. This review therefore suggests that the unpredictable chronic mild stress has an excellent predictive, etiologic and face validity and that it thus might be an excellent model of major depression.
OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.
Although granule cells continue to be added to the dentate gyrus of adult rats and tree shrews, this phenomenon has not been demonstrated in the dentate gyrus of adult primates. To determine whether neurons are produced in the dentate gyrus of adult primates, adult marmoset monkeys (Callithrix jacchus) were injected with BrdU and perfused 2 hr or 3 weeks later. BrdU is a thymidine analog that is incorporated into proliferating cells during S phase. A substantial number of cells in the dentate gyrus of adult monkeys incorporated BrdU and approximately 80% of these cells had morphological characteristics of granule neurons and expressed a neuronal marker by the 3-week time point. Previous studies suggest that the proliferation of granule cell precursors in the adult dentate gyrus can be inhibited by stress in rats and tree shrews. To test whether an aversive experience has a similar effect on cell proliferation in the primate brain, adult marmoset monkeys were exposed to a resident-intruder model of stress. After 1 hr in this condition, the intruder monkeys were injected with BrdU and perfused 2 hr later. The number of proliferating cells in the dentate gyrus of the intruder monkeys was compared with that of unstressed control monkeys. We found that a single exposure to this stressful experience resulted in a significant reduction in the number of these proliferating cells. Our results suggest that neurons are produced in the dentate gyrus of adult monkeys and that the rate of precursor cell proliferation can be affected by a stressful experience.
Expression of mRNAs coding for the ACTH secretagogues corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) was examined in the hypothalamic paraventricular nucleus (PVN) of rats bearing hippocampal lesions. Either total hippocampectomy (HPX) or extirpation of the dorsal hippocampus (DHPX) precipitated a 4-fold increase in CRF mRNA expression relative to sham-operated controls (SHAM), as determined by semiquantitative in situ hybridization histochemistry. AVP mRNA was localized to individual parvocellular neurons of the medial parvocellular division of the PVN in only the HPX and DHPX groups, consistent with enhanced production of AVP message in this neuronal population subsequent to hippocampal damage. HPX did not affect AVP mRNA content in magnocellular divisions of PVN. Plasma beta-endorphin levels were significantly elevated in the HPX and DHPX groups relative to SHAM animals, indicating a chronic increase in release of proopiomelanocortin peptides from the anterior pituitary gland in response to hippocampal lesion. Circulating corticosterone levels were elevated in HPX rats as well. To control for effects of lesion size and location, additional animals received large ablations of cerebral cortex or cerebellum. In neither case was CRF or AVP mRNA significantly altered in the PVN. The results suggest that the hippocampus exercises a tonic inhibitory role on ACTH secretagogue production in neuroendocrine neurons promoting ACTH release.
Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.
These studies were designed to determine whether adult neurogenesis occurs in the dentate gyrus of the tree shrew, an animal phylogenetically between insectivores and primates, and to explore the possibility that this process is regulated by stressful experiences and NMDA receptor activation. We performed immunohistochemistry for cell-specific markers and the thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny, on the brains of adult tree shrews subjected to psychosocial stress or NMDA receptor antagonist treatment. Cells that incorporated BrdU in the dentate gyrus of adult tree shrews were primarily located in the subgranular zone, had morphological characteristics of granule neuron precursors, and appeared to divide within 24 hr after BrdU injection. Three weeks after BrdU injection, BrdU-labeled cells had neuronal morphology, expressed the neuronal marker neuron specific enolase, and were incorporated into the granule cell layer. Vimentin-immunoreactive radial glia were observed in the dentate gyrus with cell bodies in the subgranular zone and processes extending into the granule cell layer.
Exposure to acute psychosocial stress resulted in a rapid decrease in the number of BrdU-labeled cells in the dentate gyrus. In contrast, blockade of NMDA receptors, with the NMDA receptor antagonist MK-801, resulted in an increase in the number of BrdU-labeled cells in the dentate gyrus. These results indicate that adult neurogenesis occurs in the tree shrew dentate gyrus and is regulated by a stressful experience and NMDA receptor activation. Furthermore, we suggest that these characteristics may be common to most mammalian species.
Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-13%), creatine and phosphocreatine (-15%), and choline-containing compounds (-13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.
(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), the first selective, nonpeptide vasopressin V1b receptor antagonist yet described, has been characterized in vitro and in vivo. SSR149415 showed competitive nanomolar affinity for animal and human V1b receptors and exhibited much lower affinity for rat and human V1a, V2, and oxytocin receptors. Moreover, this compound did not interact with a large number of other receptors, enzymes, or ion channels. In vitro, SSR149415 behaved as a full antagonist and potently inhibited arginine vasopressin (AVP)-induced Ca2+ increase in Chinese hamster ovary cells expressing rat or human V1b receptors. The in vivo activity of SSR149415 has been studied in several models of elevated corticotropin secretion in conscious rats. SSR149415 inhibited exogenous AVP-induced increase in plasma corticotropin, from 3 mg/kg i.p. and 10 mg/kg p.o. upwards. Similarly, this compound antagonized AVP-potentiated corticotropin release provoked by exogenous corticoliberin at 3 mg/kg p.o. The effect lasted for more than 4 h at 10 mg/kg p.o. showing a long-lasting oral effect. SSR149415 (10 mg/kg p.o.) also blocked corticotropin secretion induced by endogenous AVP increase subsequent to body water loss. Moreover, 10 mg/kg i.p SSR149415 inhibited plasma corticotropin elevation after restraint-stress in rats by 50%. In the four-plate test, a mouse model of anxiety, SSR149415 (3 mg/kg p.o. upwards) displayed anxiolytic-like activity after acute and 7-day repeated administrations. Thus, SSR149415 is a potent, selective, and orally active V1b receptor antagonist. It represents a unique tool for exploring the functional role of V1b receptors and deserves to be clinically investigated in the field of stress and anxiety.
The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.
4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.
The limbic localization of the arginine vasopressin V(1b) receptor has prompted speculation as to a potential role of this receptor in the control of emotional processes. To investigate this possibility, we have studied the behavioral effects of SSR149415, the first selective and orally active non-peptide antagonist of vasopressin V(1b) receptors, in a variety of classical (punished drinking, elevated plus-maze, and light/dark tests) and atypical (fear/anxiety defense test battery and social defeat-induced anxiety) rodent models of anxiety, and in two models of depression [forced swimming and chronic mild stress (CMS)]. When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like activity at doses that ranged from 1 to 30 mg/kg (i.p. or p.o.), but the magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam, which was used as a positive control. In contrast, SSR149415 produced clear-cut anxiolytic-like activity in models involving traumatic stress exposure, such as the social defeat paradigm and the defense test battery (1-30 mg/kg, p.o.). In the forced swimming test, SSR149415 (10-30 mg/kg, p.o.) produced antidepressant-like effects in both normal and hypophysectomized rats. Moreover, in the CMS model in mice, repeated administration of SSR149415 (10 and 30 mg/kg, i.p.) for 39 days improved the degradation of the physical state, anxiety, despair, and the loss of coping behavior produced by stress. These findings point to a role for vasopressin in the modulation of emotional processes via the V(1b) receptor, and suggest that its blockade may represent a novel avenue for the treatment of affective disorders.
The neuropeptide substance P and its receptor, the neurokinin 1 receptor (NK(1)R) have been proposed as possible targets for new antidepressant therapies. The present study investigated the effect of the NK(1)R antagonist L-760,735 and the tricyclic antidepressant clomipramine in the chronic psychosocial stress paradigm of adult male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of L-760,735 (10 mg kg(-1) day(-1)) or clomipramine (50 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Cell proliferation in the dentate gyrus and hippocampal volume were measured post mortem. Stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-14%), creatine and phosphocreatine (-15%) and choline-containing compounds (-15%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-45%), and hippocampal volume was decreased (-14%). The stress-induced changes of brain metabolites, hippocampal volume and dentate cytogenesis rate were prevented by concomitant drug administration. Elevated myo-inositol concentrations after both treatments hint to an astrocytic enhancement. These results suggest that-despite a different pharmacological profile-the NK(1)R antagonist L-760,735, a member of a novel class of antidepressant drugs, has comparable neurobiological efficacy to tricyclic antidepressants such as clomipramine.
Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.
Adult hippocampal neurogenesis has been demonstrated in several species and is regulated by both environmental and pharmacological stimuli. The present study seeks to determine whether hippocampal proliferation and neurogenesis are altered in adult animals exposed to inescapable shock (IS) in the learned helplessness model of depression. We report that exposure to avoidance testing, regardless of pre-exposure to IS, decreases cell proliferation in the hippocampus, extending previous studies demonstrating downregulation of neurogenesis by exposure to acute stressors. In addition, when the analysis was conducted 9 days after exposure to IS we observed a significant decrease in cell proliferation compared to nonshocked animals. Administration of fluoxetine, a serotonin selective reuptake inhibitor, from days 2-8 blocked the downregulation of cell proliferation resulting from IS. Fluoxetine treatment also reversed the deficit in escape latency observed in animals exposed to IS. Finally, at the 9 day time point, there was no significant difference in blood levels of corticosterone between nonshocked and IS exposed animals, indicating that the decreased cell proliferation that is observed is not due to increased levels of this adrenal steroid. These findings demonstrate that exposure to IS, which results in a state of behavioral despair, decreases hippocampal cell proliferation and that this effect can be reversed by fluoxetine treatment.
In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression
in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene
was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short
allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in
relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides
evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by
his or her genetic makeup.
Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon
remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis
blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral
effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing
the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest
that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
The adult nervous system is not static, but instead can change, can be reshaped by experience. Such plasticity has been demonstrated from the most reductive to the most integrated levels, and understanding the bases of this plasticity is a major challenge. It is apparent that stress can alter plasticity in the nervous system, particularly in the limbic system. This paper reviews that subject, concentrating on: a) the ability of severe and/or prolonged stress to impair hippocampal-dependent explicit learning and the plasticity that underlies it; b) the ability of mild and transient stress to facilitate such plasticity; c) the ability of a range of stressors to enhance implicit fear conditioning, and to enhance the amygdaloid plasticity that underlies it.
The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.
The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animal models. Presently, SSR149415 and SSR125543 were evaluated in a differential reinforcement of low-rate 72 s (DRL-72 s) schedule, a procedure known to respond differentially to antidepressants and anxiolytics. Male Wistar rats were trained to lever-press for food reinforcement, but only lever-presses occurring after a 72 s delay were reinforced; otherwise, presses were not rewarded, and the timer was reset to 0 s. The selective serotonin reuptake inhibitor, fluoxetine, and the benzodiazepine anxiolytic, diazepam, were tested in parallel. SSR149415 (10-30 mg/kg, i.p.) and SSR125543 (30 mg/kg, i.p.) increased the percentage of responses emitted in the inter-response time (IRT) bin (49-96 s), which resulted in a greater number of reinforced presses. Both compounds shifted the frequency distribution of responses toward longer IRT durations, with a preservation of the bell shape of the IRT distribution curve. Fluoxetine (10 mg/kg, i.p.) had an effect on DRL-72 s similar to that of SSR149415 and SSR125543. By contrast, diazepam increased the number of responses in IRT bin (0-12 s), and the IRT distribution curve was shifted toward shorter IRT durations and flattened. In summary, these results show that SSR149415 and SSR125543 displayed antidepressant-like activity in a DRL-72 s schedule in rat, confirming their therapeutic potential for the treatment of pathological states induced by chronic frustration such as depression.
Substance P (NK1 receptor) antagonists (SPAs) are currently the best validated and clinically most advanced novel approach to treating major depressive disorder (MDD), and several compounds are in advanced clinical development. Three years since the discovery of the antidepressant efficacy of MK-869 (Merck & Co Inc), the first in a new class of drugs that act by selectively blocking the actions of substance P, the principle that blocking the NK1 receptor can alleviate major depression has recently been replicated in a placebo-controlled, blinded study. SPAs are active in a range of preclinical assays that detect clinically used antidepressant drugs, but they have a pharmacological profile that is distinct from established drugs. There is preliminary evidence that substance P and NK1 receptor density may be altered in MDD, suggesting a possible link between substance P and depressive pathophysiology. Studies in animals indicate that the psychotherapeutic effects of SPAs may be mediated at least partly through stimulation of hippocampal neurogenesis, by direct blockade of NK1 receptors in the amygdala and its associated output projections, and also via interactions with monoamines. Additional studies are needed to explore these hypotheses further.
Various minor tranquilizers (benzodiazepines, barbiturates and meprobamate) induced an increase in the food intake of rats or mice. Drugs were injected i.p. 30 min before testing and the amount of food consumed during 30 min was recorded. The enhanced food consumption occurred when the animals were in a novel situation, in a situation which they had previously experienced, or in their home cage, in which they were used to eating in the daytime within 30 min. Studies with two benzodiazepines showed this effect to be maximal between 10 to 30 min after injection and to disappear 4 hrs after injection. Moreover, minor tranquilizers reduce the latency before eating of rats and mice tested in a new situation. These results and the observation of anti-anxiety drugs-induced hyperphagia in satiated animals suggest that:1.
The enhanced food consumption of a non familiar food in a novel situation induced by the minor tranquilizers could hardly be related only to their anti-anxiety action.
2.
The existence of some inhibitory controls (endogenous satiety in daytime or satiety after recent absorption) is not essential for the action of the minor tranquilizers.
3.
An increased motivation and a disruption in the food related behavior could possibly be an explanation for all the observed effects.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Various minor tranquilizers (benzodiazepines, barbiturates and meprobamate) induced an increase in the food intake of rats or mice. Drugs were injected i.p. 30 min before testing and the amount of food consumed during 30 min was recorded. The enhanced food consumption occurred when the animals were in a novel situation, in a situation which they had previously experienced, or in their home cage, in which they were used to eating in the daytime within 30 min. Studies with two benzodiazepines showed this effect to be maximal between 10 to 30 min after injection and to disappear 4 hrs after injection. Moreover, minor tranquilizers reduce the latency before eating of rats and mice tested in a new situation. These results and the observation of anti-anxiety drugs-induced hyperphagia in satiated animals suggest that: 1. The enhanced food consumption of a non familiar food in a novel situation induced by the minor tranquilizers could hardly be related only to their anti-anxiety action. 2. The existence of some inhibitory controls (endogenous satiety in daytime or satiety after recent absorption) is not essential for the action of the minor tranquilizers. 3. An increased motivation and a disruption in the food related behavior could possibly be an explanation for all the observed effects.
In water-deprived rats and mice, animals trained to the test situation spent more time in drinking than naive animals (first exposure to the test situation). The time spent in drinking, either during 5 min or during 10 min was recorded. As compared to controls, benzodiazepines, phenobarbital, meprobamate, and mecloqualone increased drinking time whether the experiments were run on naive or on experienced animals [5 or 10 (in mice) and 9 (in rats) exposures in the test situation]. All drugs were injected i.p. 30 min before testing. This release of the drinking behavior was more pronounced during the last 5 min than during the first 5 min of the 10 min test session. These results suggest that: 1. The inhibition of water intake of naive animals as compared to trained rats and mice, could be related to some emotional factors elicited by the first exposure to an unknown situation. 2. The increase in drinking time induced by the antianxiety drugs in a novel and in a familiar situation seems difficult to correlate only with the antianxiety action of these compounds. 3. Antianxiety drugs could interfere with the regulatory mechanism of thirst.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Plasma ACTH, cortisol, and GH concentrations were measured at 15-min intervals for 24 h in 11 men suffering from major depressive illness during an acute episode of depression and during clinical remission following antidepressant treatment with either electroconvulsive therapy or amitriptyline. Seven age-matched normal men also were studied. During the acute phase of the illness, the patients had abnormally short rapid eye movement sleep latencies, hypercortisolism, early timing of the nadirs of the ACTH-cortisol rhythms, and shorter nocturnal periods of quiescent cortisol secretion. GH was hypersecreted during wakefulness, and a major pulse occurred before, rather than after, sleep onset. After treatment, rapid eye movement sleep latencies were lengthened, and cortisol levels returned to normal due to a decrease in the magnitude of episodic pulses. Moreover, the timing of the circadian rhythms of ACTH and cortisol as well as the duration of the quiescent period of cortisol secretion were normalized. The amount of GH secreted during wakefulness decreased to normal values, with fewer significant GH pulses. The major elevation of GH secretion in the early part of the night occurred later than that during the depressive episode. These results demonstrate that a disorder of circadian rhythmicity characterizes acute episodes of major depressive illness and that this chronobiological abnormality as well as the hypersecretion of ACTH, cortisol, and GH are state rather than trait dependent.
Patients with depression frequently have symptom clusters which point strongly to involvement of the hypothalamic-pituitary-adrenal (HPA) system as a relay station between neurocircuitries in the brain and peripheral hormone and autonomic nervous function. It has been proposed that this increased, state-dependent hyperactivity of the HPA-system in depression is probably initiated and/or maintained by the combination of enhanced central production of CRH and desensitization of the binary, glucocorticoid receptor binding system in the hippocampus, which is the central regulator of HPA system activity. In a first series of studies a refined neuroendocrine test to probe the integrity of HPA system status--the combined dexamethasone suppression/CRH challenge (DEX/CRH) test--was developed and the differential effects of aging and depressed psychopathology on DEX/CRH test outcome were described. In a second set of studies, the chronological relationship between improvement of psychopathology in depressed patients treated with antidepressants and normalization of the disturbed HPA system function in these patients was further elucidated. Given the evidence from animal studies, we conclude that antidepressants induce an up-regulation of hippocampal glucocorticoid receptor mRNA concentration, thus amplifying the negative feedback effect of glucocorticoids. This then results in the normalization of DEX/CRH test results observed in the depressed patients in our study. We further conclude that dampening of HPA system hyperactivity in depression by means of antidepressants is a conditio sine qua non for successful improvement of psychopathology.
Adaptations at the cellular and molecular levels in response to stress and antidepressant treatment could represent a form of neural plasticity that contributes to the pathophysiology and treatment of depression. At the cellular level, atrophy and death of stress-vulnerable neurons in the hippocampus, as well as decreased neurogenesis of hippocampal neurons, has been reported in preclinical studies. Clinical studies also provide evidence for atrophy and cell death in the hippocampus, as well as the prefrontal cortex. It is possible that antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function. The molecular mechanisms underlying these effects are discussed, including the role of the cAMP signal transduction cascade and neurotrophic factors.
Clinical and preclinical data suggest that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS produces several signs and symptoms of depression and anxiety disorders through continuous activation of CRH(1) receptors. This led to the development of drugs that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior in rats and also in monkey models of anxiety. These findings led to a clinical development program exploring the antidepressive potential of R121919, a water-soluble pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and is well absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its endocrine mode of action compromises the stress-hormone system or whether other safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n=10) where the dose range increased from 5-40 mg and another group (n=10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients dropped out because of withdrawal of consent to participate (three cases) or worsening of depressive symptomatoloy in one case. We found that R121919 was safe and well tolerated by the patients during the observation period. Moreover, the data suggested that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores using both, patient and clinician ratings. These findings, along with the observed worsening of affective symptomatology after drug discontinuation, suggests that the pharmacological principle of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment and the prevention of diseases where exaggerated central CRH activity is present at baseline or following stress exposure.
An extensive literature stretching back decades has shown that prolonged stress or prolonged exposure to glucocorticoids-the adrenal steroids secreted during stress-can have adverse effects on the rodent hippocampus. More recent findings suggest a similar phenomenon in the human hippocampus associated with many neuropsychiatric disorders. This review examines the evidence for hippocampal atrophy in (1) Cushing syndrome, which is characterized by a pathologic oversecretion of glucocorticoids; (2) episodes of repeated and severe major depression, which is often associated with hypersecretion of glucocorticoids; and (3) posttraumatic stress disorder. Key questions that will be examined include whether the hippocampal atrophy arises from the neuropsychiatric disorder, or precedes and predisposes toward it; whether glucocorticoids really are plausible candidates for contributing to the atrophy; and what cellular mechanisms underlie the overall decreases in hippocampal volume. Explicit memory deficits have been demonstrated in Cushing syndrome, depression, and posttraumatic stress disorder; an extensive literature suggests that hippocampal atrophy of the magnitude found in these disorders can give rise to such cognitive deficits.
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.
To determine whether exposure to fox odor alters granule neuron production, we examined proliferating cells and their progeny in the dentate gyrus of adult male rats exposed to trimethyl thiazoline, a component of fox feces. Additionally, to determine whether this effect is adrenal hormone-mediated, we examined animals exposed to fox odor after bilateral adrenalectomy and replacement with low levels of the endogenous glucocorticoid corticosterone. Stereologic analyses of the number of 5-bromo-2'deoxyuridine (BrdU) -labeled cells revealed that exposure to fox odor but not other, nonthreatening, odors (mint or orange) rapidly decreased the number of proliferating cells in the dentate gyrus. This effect is dependent on a stress-induced rise in adrenal hormones; exposure to fox odor resulted in an increase in circulating corticosterone levels and prevention of this increase (by means of adrenalectomy plus low-dose corticosterone replacement) eliminated the suppression of cell proliferation. Examination at longer survival times revealed that the decrease in the number of new granule cells in fox odor-exposed animals was transient; a difference was still detectable at 1 week after BrdU labeling but not at 3 weeks. In both fox and sham odor-exposed animals, many new cells acquired morphologic and biochemical characteristics of mature granule neurons. The majority of these cells expressed a marker of immature granule neurons (TuJ1) by 1 week after BrdU labeling and markers of mature granule neurons (calbindin, NeuN) by 3 weeks after labeling. These findings suggest that stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, resulting in a transient decrease in the number of adult-generated immature granule neurons.
The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain. The hippocampal formation is vulnerable to damage from seizures, ischemia, and head trauma and is particularly sensitive to the effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress. Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis. The damaging actions of glucocorticoids under such conditions have been termed "allostatic load", referring to the cost to the body of adaptation to adverse conditions. Adrenal steroids display both protective and damaging effects in the hippocampus. They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner. The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region. In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones. Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus. They also potentiate the damage produced by ischemia and seizures. Moreover, the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress. Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved. It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception.
Substance P (NK1 receptor) antagonists (SPAs) are currently the best validated and clinically most advanced novel approach to treating major depressive disorder (MDD), and several compounds are in advanced clinical development. Three years since the discovery of the antidepressant efficacy of MK-869 (Merck & Co Inc), the first in a new class of drugs that act by selectively blocking the actions of substance P, the principle that blocking the NK1 receptor can alleviate major depression has recently been replicated in a placebo-controlled, blinded study. SPAs are active in a range of preclinical assays that detect clinically used antidepressant drugs, but they have a pharmacological profile that is distinct from established drugs. There is preliminary evidence that substance P and NK1 receptor density may be altered in MDD, suggesting a possible link between substance P and depressive pathophysiology. Studies in animals indicate that the psychotherapeutic effects of SPAs may be mediated at least partly through stimulation of hippocampal neurogenesis, by direct blockade of NK1 receptors in the amygdala and its associated output projections, and also via interactions with monoamines. Additional studies are needed to explore these hypothesesfurther.
CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines.
The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP).
DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined.
DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency.
These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.
Chronic restraint stress has been shown to induce structural remodelling throughout the interconnected dentate gyrus-CA3 fields. To find out how this stressor affects the rate of adult hippocampal neurogenesis, we subjected rats to acute or chronic restraint stress and assessed the proliferation, survival and differentiation of newly born cells in the dentate gyrus. We also examined polysialylated neural cell adhesion molecule expression, a molecule normally expressed in immature neurons and important for morphological plasticity. The results show that acute restraint stress did not change either the proliferation of dentate gyrus precursor cells or the expression of polysialylated neural cell adhesion molecule, whereas 3 weeks of chronic restraint stress suppressed proliferation by 24% and increased polysialylated neural cell adhesion molecule expression by 40%. The study was extended for an additional 3 weeks to trace the survival and development of the cells born after the initial 3 weeks of restraint. Rats subjected to 6 weeks of daily restraint stress exhibited suppressed cell proliferation and attenuated survival of the recently born cells after the extended time course, resulting in a 47% reduction of granule cell neurogenesis. Furthermore, 6 weeks of chronic stress significantly reduced the total number of granule cells by 13% and the granule cell layer volume by 5%. Expression of polysialylated neural cell adhesion molecule followed a biphasic time course, displaying a significant up-regulation after 3 weeks of daily restraint stress that was lost after 6 weeks of stress. These studies may help us understand the basis for hippocampal shrinkage and raise questions about the ultimate reversibility of the effects of chronic stress.
Disruption of the glucocorticoid negative feedback system is observed in approximate one half of human depressives, and a similar condition is induced in animals by chronic stress. This disruption is thought to involve down-regulation of glucocorticoid receptors (GRs) in the feedback sites of the brain. However, the responsible site of the brain has not been well elucidated. Here we examined the effects of chronic stress induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days on the GR levels in the prefrontal cortex (PFC), hippocampus, and hypothalamus of rats using a Western immunoblot technique. In the PFC, the cytosolic GR levels were decreased, but the nuclear GR levels were not changed. In the hippocampus, the levels of cytosolic and nuclear GRs were increased. However, there were no marked changes in the GR levels in the hypothalamus. The changes in the cytosolic GR levels were confirmed at the mRNA level by an in situ hybridization technique. We next examined the suppressive effects of dexamethasone (DEX) infusions into these regions on the circulating corticosterone levels. When DEX was infused into the PFC or hippocampus of the chronically stressed rats, the suppressive response to DEX was abolished, but the response was normal in the hypothalamus. In addition, when DEX was injected systemically to the chronically stressed rats, the suppressive response to DEX was significantly attenuated. These results suggest that the abnormal changes in GRs in the higher centers of the hypothalamo-pituitary-adrenal axis are involved in the chronic stress-induced attenuation of the feedback. Since dysfunction of the PFC or hippocampus is implicated in the pathogenesis of depression, the present findings would help to understand the mechanisms underlying the disrupted feedback system and its relation to brain dysfunction in depression.
Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF(1) and V(1b) receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF(1) receptor antagonist SSR125543A, the V(1b) receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF(1) and V(1b) receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants.
We have previously reported that MGS0039, a novel antagonist of group II metabotropic glutamate receptors (mGluRs), exerts antidepressant-like effects in experimental animal models. Recent studies suggest that the behavioral effects of chronic antidepressant treatment are mediated by the stimulation of neurogenesis in the hippocampus. In the present study, we examined the effects of MGS0039 on cell proliferation in the adult mouse hippocampus. MGS0039 (5 or 10mg/kg) or fluvoxamine was administered chronically to male ICR mice over a period of 14 days. Multiple bromodeoxyuridine (BrdU) administrations were performed after the last drug injection to label dividing cells. Immunohistochemical analyses after BrdU injections revealed that chronic MGS0039 treatment enhanced BrdU-positive cells in the dentate gyrus ( approximately 62% increase) in the same manner as chronic fluvoxamine treatment. This is the first in vivo study to demonstrate an increase in cell proliferation following a blockade of group II mGluRs. These findings raise the possibility that MGS0039 may exert antidepressant-like effects by modulating cell proliferation in the hippocampus.
Although the hippocampus has been found to be smaller in patients with depression, prospective longitudinal in vivo studies are necessary to investigate whether depression can result in a further diminution of hippocampal volumes or whether a smaller hippocampal volume predisposes an individual to the development of depression.
Thirty patients with DSM-IV major depressive disorder as well as 30 healthy control subjects matched for age, gender, and handedness were examined at admission to the hospital and 1 year later using a documentation of the medical history and high-resolution magnetic resonance imaging (MRI) for the presence of depression and to determine changes in hippocampal as well as amygdala volumes. Patients were enrolled from March 2000 to August 2002.
No significant hippocampal and amygdala volume changes were observed in patients or controls between baseline and 1-year follow-up investigations. However, the subgroup of patients who were nonremitted at the time of the follow-up investigation showed significantly reduced left and right hippocampal volumes at both baseline and the 1-year follow-up compared with remitted patients. Moreover, the right hippocampal volumes of nonremitted patients were significantly smaller compared with matched healthy controls.
These results do not support the hypothesis that hippocampal volumes diminish during the 1-year follow-up period. However, smaller hippocampal volumes may be related to a poor clinical outcome after 1 year.
The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.
Depression is a widespread and serious disorder that afflicts an estimated 13.1 to 14.2 million adults in the United States each year. Even more compellingly, the lifetime prevalence rate of depression in the US has recently been estimated to include 16.2% of adults (21% women, 13% men), or >32.6 million people. There are multiple putative "causes" of depression, with approximately one-third of an individual's propensity for unipolar depression due to genetic vulnerability, while the remaining two-thirds is due to environmental factors. Although the selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to mainly act by selectively binding to the serotonin (5-HT) transporter to block reuptake of 5-HT from the synapse into the presynaptic nerve terminal, thereby increasing synaptic serotonin concentrations, some of the SSRIs also exhibit other neuropharmacologic effects. One such example is the high affinity for paroxetine in blocking norepinephrine reuptake. Another is the inhibition of dopamine reuptake by sertraline. In depression, hyperactivity of corticotropin-releasing factor (CRF)--producing neurons contribute to the well-characterized hypothalamic-pituitary-adrenal axis hyperactivity of depression. Increased activity of extrahypothalamic CRF circuits are believed to contribute to several depressive symptoms. Treatment and certain SSRIs have been shown to reduce the activity of CRF neurons and may contribute to their therapeutic action. Each SSRI apparently has its own unique pharmacologic properties that likely underlie their observed differences in clinical use.
This study aimed at investigating the relationship between anxiety-like and depressive-like behaviour in mice. Therefore, we assessed the behaviour of mice from eight different strains (FVB/NA, BALB/c, C57BL/6, DBA/2, 129/Sv, C3H/He, CBA and BA) confronted first to anxiety models (the elevated plus-maze and the free exploratory test) and then to tests of depressive-like behaviours (forced swim test and unpredictable subchronic mild stress). In the forced swim test, mice from the DBA/2, the BA and the C3H/He strains displayed higher immobility than mice from the 129/Sv, the BALB/c, the C57BL/6 and the CBA strains. In the subchronic mild stress, mice from the C57BL/6 and the CBA strains displayed low sensitivity when compared with mice from all the others strains. A stepwise multiple regression analysis suggests that behaviour in the elevated plus-maze is associated with the time of immobility in the forced swim test (20%) and with the susceptibility to the unpredictable subchronic stress procedure (31%). The behaviour in the free exploratory paradigm is slightly associated with behaviours in the two tests of depression. These results suggest that anxiety may be a factor contributing, among others, to the susceptibility to depressive-like behaviours.
Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF(1) antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines.
The present study evaluated the similarity of DS effects of a CRF(1) antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration.
Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity.
In chlordiazepoxide-trained rats, DMP696 (1.0-100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT(1A) partial agonist buspirone (0.3-10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10-60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals.
Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines.
Animal models exhibiting sensitivity to chronic, but not acute, antidepressant treatment are greatly needed for studying the neural mechanisms of the antidepressant response. Although several models of acute antidepressant effects provide excellent tools for antidepressant discovery, they do not permit investigation into their therapeutic effects, which require several weeks of treatment to emerge. The inhibition of feeding produced by novelty, termed 'hyponeophagia', provides an anxiety-related measure that is sensitive to the effects of chronic, but not acute or subchronic, antidepressant treatment. This review evaluates the value of hyponeophagia-based tests as tools for investigating the neurobiology of the therapeutic response to antidepressant treatment. Criteria for the development and validation of animal models used to study neurobiological mechanisms of the antidepressant response are presented. Methodological considerations affecting the reliability, specificity, and ease of use of hyponeophagia-based models are also discussed. Lastly, we present a newly revised hyponeophagia paradigm, called the novelty-induced hypophagia (NIH) test, which attempts to maximize the predictive validity and practicality of the test. The NIH paradigm provides a promising new model for investigations into the neurobiology underlying the antidepressant response.
This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (alpha2-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen. The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.
Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.