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Phenotypic analysis a Confocal image of a newly generated astrocyte in the granule cell layer expressing mature astrocytic marker S100β (blue) and BrdU (red). Emission intensities measured along the lines drawn in the larger image (a) are shown in the bottom and right panels. Furthermore, insets in a show the cell investigated in single channels with separate wavelengths. b Newly generated neuron labeled with BrdU (red) and expressing NeuN-immunoreactivity (green). c BrdU-positive cell (red) expressing neither neuronal marker NeuN (green) nor astrocytic marker S100β (blue). Scale bars in a, b, and c 25 μm
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Glucocorticoid receptor (GR) heterozygous mice (GR+/−
) represent a valuable animal model for major depression. GR+/−
mice show a depression-related phenotype characterized by increased learned helplessness on the behavioral level and neuroendocrine alterations with hypothalamo-pituitary-adrenal (HPA) axis overdrive characteristic of depression. Hi...
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... stress and as an effect of GR ?/2 genotype (detailed results of the ANOVA sta- tistics are presented in Figs. 2a and 3; analysis of 37 ani- mals in total, n = 9-10 animals/group). BrdU-labeled cells were subjected to further phenotypic analysis. The majority of cells showed co-labeling with mature neuronal marker NeuN or astrocytic marker S100b (Figs. 2b and 4) with no further significant effect of either experimental condition or of ...Citations
... Forced downregulation of GR reduced the proliferations of C17.2 NPCs and NSCs, whereas its overexpression increased proliferation. It was revealed in a previous study that GR-heterozygous mice (GR ±), which exhibited ~ 50% reductions in GR protein levels in brain, had significantly fewer BrdU-positive cells in the DG than controls [37]. These observations suggest that GR plays a crucial role in the regulation of cell proliferation, particularly that of NSCs. ...
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.
... Both invasive and non-invasive neuromodulation treatments were able to significantly enhance the expression of proliferation markers in depressed rodents compared to untreated groups. All treatment modalities increased BrdU + DG cells (Bambico et al., 2015;Chen et al., 2015; (Keck et al., 2003;Sah et al., 2012) GR +/-Rodents with heterozygous expression of GR ↑ Behavioral despair ↓ DG neuronal proliferation & differentiation (Kronenberg et al., 2009;Ridder et al., 2005) *CUMS/CUS are often interchanged in literature. Abbreviations: ACTH, adrenocorticotropic hormone; CORT, corticosterone, CRS, chronic restraint stress; CSDS, chronic social defeat stress; CUMS/CUS, chronic unpredictable (mild) stress; DG, dentate gyrus; GR, glucocorticoid receptor; HAB, higher anxiety behavior; OBX, olfactory bulbectomy. ...
The ‘neurogenesis hypothesis of depression’ emphasizes the importance of upregulated hippocampal neurogenesis for the efficacy of antidepressant treatment. Neuromodulation is a promising therapeutic method that stimulates neural circuitries to treat neuropsychiatric illnesses. We conducted a scoping review on the neurogenic and antidepressant outcomes of neuromodulation in animal models of depression. PubMed, Web of Science, and PsycInfo were comprehensively searched for full-text English articles from inception to October 5, 2021. Data screening and extraction were conducted independently by two researchers. Seventeen eligible studies were included in this review. The majority of studies used non-invasive neuromodulation (n = 14) and assessed neurogenesis using neural proliferation (n = 16) and differentiation markers (n = 9). Limited reports (n = 2) used neurogenic inhibitors to evaluate the role of neurogenesis on the depressive-like behavioral outcomes. Overall, neuromodulation substantially effectuated both hippocampal cell proliferation and antidepressant-like behavior in animal models of depression, with some providing evidence for enhanced neuronal differentiation and maturation. The proposed neurogenic-related mechanisms mediating the neuromodulation efficacies included neurotrophic processes, anti-apoptotic pathways, and normalization of HPA axis functions. Further research is warranted to explore the role of neuromodulation-induced neurogenic effects on treatment efficacies and to elucidate the underlying molecular mechanisms.
... Signaling mechanisms involving the activation of trkB, MAPK and PI3-kinase pathways, the inhibition of caspase-3induced apoptosis, and downstream variations of transcriptional factors have been implied in the neurogenic effects of BDNF [10,37,40]. The levels of BDNF and neurogenesis are decreased in many neurodegenerative diseases, such as PD, as well as in depressive disorders [37,[144][145][146][147]. Interestingly, BDNF signaling is reported to be necessary for the behavioral effects produced by antidepressant drugs [10,148]. ...
Brain-derived neurotrophic factor (BDNF) is a crucial brain signaling protein that is integral to many signaling pathways. This neurotrophin has shown to be highly involved in brain plastic processes such as neurogenesis, synaptic plasticity, axonal growth, and neurotransmission, among others. In the first part of this review, we revise the role of BDNF in different neuroplastic processes within the central nervous system. On the other hand, its deficiency in key neural circuits is associated with development of psychiatric disorders, including alcohol abuse disorder. Many people begin to drink alcohol during adolescence, and it seems that changes in BDNF are evident after the adolescent engaged regularly in alcohol use. Therefore, the second part of this manuscript addresses
the involvement of BDNF during adolescent brain maturation and how this process can be negatively affected by alcohol abuse. Finally, we propose different BNDF enhancers, both behavioral and pharmacological, which should be considered in the treatment of problematic alcohol consumption initiated during the adolescence.
... More recently, it has been shown that NPCs isolated from the rat ventral hippocampus are more sensitive to the antineurogenic effects of chronic GC treatment compared to the dorsal and the intermediate hippocampus, thus explaining the enhanced susceptibility of NPCs of this hippocampal region to the stress [86]. In the context of stress, heterozygosity for GR was shown to make mice prone to develop depressive-like behavior and impaired neurogenesis after stress [278,279]. Hence, increased sensitivity of NPCs to GCs may influence stress response. This issue has been investigated in ELS models. ...
Newborn neurons in the adult hippocampus are regulated by many intrinsic and extrinsic cues. It is well accepted that elevated glucocorticoid levels lead to downregulation of adult neurogenesis, which this review discusses as one reason why psychiatric diseases, such as major depression, develop after long-term stress exposure. In reverse, adult neurogenesis has been suggested to protect against stress-induced major depression, and hence, could serve as a resilience mechanism. In this review, we will summarize current knowledge about the functional relation of adult neurogenesis and stress in health and disease. A special focus will lie on the mechanisms underlying the cascades of events from prolonged high glucocorticoid concentrations to reduced numbers of newborn neurons. In addition to neurotransmitter and neurotrophic factor dysregulation, these mechanisms include immunomodulatory pathways, as well as microbiota changes influencing the gut-brain axis. Finally, we discuss recent findings delineating the role of adult neurogenesis in stress resilience.
... Intriguingly, glucocorticoid activates TrkB independently of BDNF (Jeanneteau et al. 2008). Transgenic mice in which the glucocorticoid receptor (GR) had been modified with a 50% reduction of the expression showed a down-regulation of hippocampal BDNF expression and AHN (Kronenberg et al. 2009). Although high corticosterone levels resulting from chronic stress create a negative effect on the brain, it has also been suggested that the corticosterone has an inverted U-shaped effect on the hippocampus such as cognitive function (Lupien et al. 2007), synaptic plasticity (Diamond et al. 1992), and AHN (Lucassen et al. 2010;Okamoto et al. 2015). ...
High-intensity intermittent (or interval) training (HIIT) has started to gain popularity as a time-effective approach to providing beneficial effects to the brain and to peripheral organs. However, it still remains uncertain whether HIIT enhances hippocampal functions in terms of neurogenesis and spatial memory due to unconsidered HIIT protocol for rodents. Here, we established the HIIT regimen for rats with reference to human study. Adult male Wistar rats were assigned randomly to Control, moderate-intensity continuous training (MICT; 20 m/min, 30 min/day, 5 times/week), and HIIT (60 m/min, 10 30-s bouts of exercise, interspaced with 2.5 min of recovery, 5 times/week) groups. The ratios of exercise time and volume between MICT and HIIT were set as 6:1 and 2:1–4:1, respectively. After 4 weeks of training, all-out time in the incremental exercise test was prolonged for exercise training. In skeletal muscle, the plantaris citrate synthase activity significantly increased only in the HIIT group. Simultaneously, both HIIT and MICT led to enhanced spatial memory and adult hippocampal neurogenesis (AHN) as well as enhanced protein levels of hippocampal brain-derived neurotrophic factor (BDNF) signaling. Collectively, we suggest that HIIT could be a time-efficient exercise protocol that enhances hippocampal memory and neurogenesis in rats and is associated with hippocampal BDNF signaling.
... Indeed, only hippocampal GR (and not hypothalamus GR) mediates the chronic stress induced hyperactivity of the HPA axis [73]. Moreover, GR-deficient heterozygous mice (GR +/− ) have a predisposition for depressive-like symptoms and exhibit an alteration in corticosterone secretion associated with a decrease in the expression of BDNF in the hippocampus and reduced hippocampal neurogenesis [74,75]. In parallel, increasing GR activity in the hippocampus controls BDNF production and thus improves contextual fear memory [76]. ...
Introduction:
Several studies have suggested that diet, especially one enriched in microbiota-fermented fibers or fat, regulates behavior. The underlying mechanisms are currently unknown. We previously reported that certain macronutrients (fermentable fiber and protein) regulate energy homeostasis via the activation of intestinal gluconeogenesis (IGN), which generates a neural signal to the brain. We hypothesized that these nutriments might control behavior using the same gut-brain circuit.
Methods:
Wild-type and IGN-deficient mice were fed chow or diets enriched in protein or fiber. Changes in their behavior were assessed using suited tests. Hippocampal neurogenesis, extracellular levels of serotonin and protein expression levels were assessed by immunofluorescence, in vivo dialysis or western-blotting respectively. Rescue of IGN was performed by infusing glucose in the portal vein of IGN-deficient mice.
Results:
We show here that both fiber- and protein-enriched diets exert beneficial actions on anxiety-like and depressive-like behaviors. These benefits do not occur in mice lacking IGN. Consistently, IGN-deficient mice display hallmarks of depressive-like disorders, including decreased hippocampal neurogenesis, basal hyperactivity and deregulation of the hypothalamic-pituitary-adrenal axis, which are associated with increased expression of the precursor of corticotropin releasing hormone in the hypothalamus and decreased expression of the glucocorticoid receptor in the hippocampus. These neurobiological alterations are corrected by portal glucose infusion mimicking IGN.
Conclusion:
IGN translates nutritional information allowing the brain to finely coordinate energy metabolism and behavior.
... It is known that neurogenesis is reduced in major depression in both animal models and in humans (Kronenberg et al. 2009;Deyama and Duman 2020;Planchez et al. 2020). ProBDNF and p75 NTR signalling plays a critical role in the regulation of neurogenesis and synaptic plasticity (Hempstead 2015). ...
Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4–8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a time-dependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity.
... Some authors consider that nucleus dentatus of hippocampus is related closely with olfactory system (31). While hippocampal atrophy was reported in people studies (32), decreased neurogenesis at the level of hippocampus was demonstrated in the animal model of depression (33). Neurogenesis in the formation of the hippocampus is suppressed in individuals who tend to MDD such as prolonged stress, and this process is reversed wit antidepressant treatment (34). ...
Introduction:
Loss in sense of smell and taste is a condition that can occur without an organic pathology and it is noteworthy in patients diagnosed with Major Depressive Disorder (MDD). Few studies have shown that Repetitive Transcranial Magnetic Stimulation (tTMS) can correct losses in sense of smell and taste. In this study, we aimed to examine the effects of tTMS treatment applied to patients diagnosed with MDD on the sense of smell and taste in this patient group.
Methods:
The sense of smell of 56 patients who were diagnosed with MDD and had tTMS indication was examined with the "Sniffin' Sticks" smell test and the sense of taste with the "Taste Strips" taste test. MDD patients who lost at least one sense of smell and taste were included in the study, but a total of 30 patients were able to complete the study. Hamilton Depression Scale (HAM-D) was applied to the patients before tTMS treatment, and this scale was repeated after 15 sessions of tTMS treatment. Taste and smell senses were re-evaluated after the last tTMS session.
Results:
According to the Sniffin Stick Smell test, 15 of 29 patients with hyposmia had normosmia after tTMS, and 16 of 18 patients who were found to have hypogeusia according to Taste Strips Taste test had Normogeusia after tTMS. There was a positive improvement in both the smell and taste scores of all patients who were treated, compared to before tTMS. The positive improvement in the smell tests of the patients who responded to the treatment according to the HAM-D scores was found to be significantly different than the patients who did not respond.
Conclusion:
The positive effect of tTMS treatment on the sense of smell and taste has been demonstrated even in patients whose HAM-D scores could not be sufficiently decreased. In patients diagnosed with depression, using tTMS alone or adding it to the current treatment suggests that it may have a positive effect on the sense of smell and taste as well as depression treatment.
... Thus, GR in neuron plays key roles in the stress system by maintaining molecular, cellular and systemic homeostasis in neurons via the HPA (hypothalamic-pituitary-adrenal) axis [17]. Dysfunctions in the GR had been implicated in the pathogenesis of depression [18]. Chronic high concentrations of GC, associated with down-regulated BDNF expression in hippocampus, can cause anxiety and depression-like behavior, which in turn affects neuronal plasticity, learning and memory, and severe neuronal injury [19][20][21][22]. ...
Chronic corticosterone (CORT) stress is an anxiety and depression inducing factor that involves the dysfunction of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF), and neuronal plasticity. However, the regulation of proteomic profiles in neurons suffering CORT stress is remaining elusive. Thus, the proteomic profiles of mouse neuronal C17.2 stem cells were comprehensively investigated by TMT (tandem mass tag)-labeling quantitative proteomics. The quantitative proteomics conjugated gene ontology analysis revealed the inhibitory effect of CORT on the expression of mitochondrial oxidative phosphorylation-related proteins, which can be antagonized by berberine (BBR) treatment. In addition, animal studies showed that changes in mitochondria by CORT can affect neuropsychiatric activities and disturb the physiological functions of neurons via disordering mitochondrial oxidative phosphorylation. Thus, the mitochondrial energy metabolism can be considered as one of the major mechanism underlying CORT-mediated depression. Since CORT is important for depression after traumatic stress disorder, our study will shed light on the prevention and treatment of depression as well as posttraumatic stress disorder (PTSD).
... 1. [64][65][66][67][68]. ...
Stress während der pränatalen Periode hat verschiedene Auswirkungen auf das soziale und sexuelle Verhalten bei den Nachkommen von Mensch und Tier. Die vorliegende Studie untersucht die Auswirkungen von chronischem „restraint“ Stress im zweiten versus dritten Trimenon der Schwangerschaft auf die Produktion von Ultraschallvokalisationen männlicher C57BL/6N Mäuse im Erwachsenenalter. Hierfür wurde eine neuartige Cluster Analyse entwickelt und genutzt. Außerdem wurde der Einfluss einer heterozygoten Mutation des Glukokortikoid-Rezeptors (GR) auf die Vokalisation analysiert. Schließlich wurden auch Kortikosteron- und Testosteronspiegel gemessen. Pränataler Stress im dritten, nicht aber im zweiten Trimenon führt zu einer signifikanten qualitativen Veränderung der Ultraschallvokalisationen der Mäuse, unabhängig von ihrem GR-Genotyp. Der Kortikosteron-Serumspiegel bei pränatal im 3. Trimenon gestressten Tieren ist signifikant erhöht. Der Testosteron-Serumspiegel bei GR +/- Männchen ist im Vergleich zu Wildtypen tendenziell erhöht, während pränataler Stress hierauf keinen Einfluss zeigt. Pränatale Stress-Exposition im dritten Trimenon ändert die "mating songs“ erwachsener Männchen qualitativ und signifikant. Zuletzt zeigen wir erstmals erhöhte basale Kortikosteronspiegel in GR +/- Männchen nach pränatalem Stress, was darauf hindeutet, dass das GR +/- Mausmodell der Depression auch als Modell für pränatalen Stress bei männlichen Nachkommen dienen könnte.
