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Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor
Abstract
The term 'learned helplessness' refers to a constellation of behavioral changes that follow exposure to stressors that are not controllable by means of behavioral responses, but that fail to occur if the stressor is controllable. This paper discusses the nature of learned helplessness, as well as the role of the dorsal raphe nucleus, serotonin, and corticotropin-releasing hormone in mediating the behavioral effects of uncontrollable stressors. Recent research indicates that (a) uncontrollable stressors sensitize serotonergic neurons in the dorsal raphe, and that a corticotropin-releasing factor-related ligand, acting at the Type II receptor, is essential to this sensitization process, and (b) the consequent exaggerated release of serotonin in response to subsequent input is at least in part responsible for the behavioral changes that occur. Finally, implications for the general role of corticotropin-releasing hormone in stress-related phenomena and for the learned helplessness paradigm as an animal model of either depression or anxiety are discussed.
... This is particularly interesting because wheel running is naturally rewarding to rodents, as rodents will spontaneously run great distances on wheels (e.g., ∼3-16 km/day), work to obtain access to running wheels, develop a conditioned preference to contexts associated with wheel access, and even run on wheels placed in the wild (Iversen, 1993;Novak et al., 2012;Meijer and Robbers, 2014;Herrera et al., 2016;Medrano et al., 2021). Furthermore, depression-like deficits in rat-motivated behaviors, including preference for sweet substances, food consumption, goaldirected spatial learning, social interaction, and exploration of new contexts recover to non-stressed levels in approximately 72 h post exposure to the uncontrollable tail shock paradigm (Desan et al., 1988;Warren et al., 1991;Will et al., 1998;Maier and Watkins, 2005;Christianson et al., 2008). Tasks requiring rigorous forced locomotor activity, like 15 min of forced swim test and approximately an hour of shuttle box escape testing also recover to non-stressed levels within the same period (Weiss et al., 1981;Desan et al., 1988;Warren et al., 1991;Maier and Watkins, 2005;Strong et al., 2011). ...
... Furthermore, depression-like deficits in rat-motivated behaviors, including preference for sweet substances, food consumption, goaldirected spatial learning, social interaction, and exploration of new contexts recover to non-stressed levels in approximately 72 h post exposure to the uncontrollable tail shock paradigm (Desan et al., 1988;Warren et al., 1991;Will et al., 1998;Maier and Watkins, 2005;Christianson et al., 2008). Tasks requiring rigorous forced locomotor activity, like 15 min of forced swim test and approximately an hour of shuttle box escape testing also recover to non-stressed levels within the same period (Weiss et al., 1981;Desan et al., 1988;Warren et al., 1991;Maier and Watkins, 2005;Strong et al., 2011). Taken together, these data suggest the development of mammalian sedentary behavior following exposure to acute stress may not be just a simple correlate of mood or anxiety disorders, but instead unique to changes within central and/or peripheral biological substrates that chronically deter the willingness to engage in voluntary physically exertive activities. ...
... First, to identify acute stress intensity thresholds that elicit long-term wheel running deficits in rats. A prior study showed that exposing rats to a single episode of 100 uncontrollable tail shocks is sufficient to produce a robust deficit in wheel running behavior that persists months beyond anxiety-and depression-like behaviors (Weiss et al., 1981;Desan et al., 1988;Warren et al., 1991;Moraska and Fleshner, 2001;Maier and Watkins, 2005;Christianson et al., 2008). However, the influence of changes to shock number on physical activity levels is unknown, yet could provide insights into the possible conditions necessary to develop persistent aversions for physical activity. ...
Introduction
Sedentary lifestyles have reached epidemic proportions world-wide. A growing body of literature suggests that exposures to adverse experiences (e.g., psychological traumas) are a significant risk factor for the development of physically inactive lifestyles. However, the biological mechanisms linking prior stress exposure and persistent deficits in physical activity engagement remains poorly understood.
Methods
The purpose of this study was twofold. First, to identify acute stress intensity thresholds that elicit long-term wheel running deficits in rats. To that end, young adult male rats were exposed to a single episode of 0, 50, or 100 uncontrollable tail shocks and then given free access to running wheels for 9 weeks. Second, to identify stress-induced changes to central monoamine neurotransmitters and peripheral muscle physiology that may be maladaptive to exercise output. For this study, rats were either exposed to a single episode of uncontrollable tail shocks (stress) or left undisturbed in home cages (unstressed). Eight days later, monoamine-related neurochemicals were quantified by ultra-high performance liquid chromatography (UHPLC) across brain reward, motor, and emotion structures immediately following a bout of graded treadmill exercise controlled for duration and intensity. Additionally, protein markers of oxidative stress, inflammation, and metabolic activity were assessed in the gastrocnemius muscle by Western blot.
Results
For experiment 1, stress exposure caused a shock number-dependent two to fourfold decrease in wheel running distance across the entire duration of the study. For experiment 2, stress exposure curbed an exercise-induced increase of dopamine (DA) turnover measures in the prefrontal cortex and hippocampus, and augmented serotonin (5HT) turnover in the hypothalamus and remaining cortical area. However, stress exposure also caused several monoaminergic changes independent of exercise that could underlie impaired motivation for physical activity, including a mild dopamine deficiency in the striatal area. Finally, stress potently increased HSP70 and lowered SOD2 protein concentrations in the gastrocnemius muscle, which may indicate prolonged oxidative stress.
Discussion
These data support some of the possible central and peripheral mechanisms by which exposure to adverse experiences may chronically impair physical activity engagement.
... Previous c-Fos studies report that 5-HT neurons in the DRN are more sensitive to uncontrollable versus controllable stressors 9,11,12,31 . Acute swim stress is a well-established inescapable stressor, whereas social defeat is an example of a more controllable stressor. ...
... ; https://doi.org/10.1101/2023.11.25.568634 doi: bioRxiv preprint lower frequencies (1-2 Hz) and 5-HT was preferentially released at the higher frequencies (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Therefore, chemogenetic activation may have preferentially released 5-HT resulting in increased active coping. ...
The majority of midbrain 5-hydroxytryptamine (5-HT) neurons express the vesicular glutamate transporter 3 (VGLUT3) and co-release 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunocytochemistry and conditional gene knock out in mice to test the hypothesis that glutamate co-releasing 5-HT neurons would be activated by stress and involved in stress coping.
Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localised in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN.
To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behaviour, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioural effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition.
We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate released at the 5-HT synapse may impact on stress susceptibility.
... Because the neurocognitive effects of stress likely vary depending on the severity of the stress and the brain region of interest, are undoubtedly mediated by multiple molecular-cellular mechanisms, and are not limited to neurons, no single review can satisfactorily integrate various findings on stress. Thus, we refer the interested reader to the following related topics and references for detailed discussion: time-dependent synaptic plasticity-and glucocorticoid-based stress models of flashbulb/ traumatic memories and amnesia [6,22], cognitive enhancing effects of mild stress [23,24], various candidate neurochemical mediators of stress [6,[25][26][27][28], developmental stress effects [29,30], transcriptomic-translatomic-proteomic changes to stress [31], divergent effects of stress on different brain structures [32,33], and non-neuronal contributions in stress effects [34]. ...
... The sine qua non of stress research has long been rooted in the HPA axis effector hormones, with the harmful effects of stress attributed initially to exhausted corticosteroid activity making the body more susceptible to illnesses [38] and then presently to persistent corticosteroid activity causing illnesses [41][42][43][44]203]. While glucocorticoids and other supposed neurochemical [25][26][27] agents of stress offer a model systems approach to study stress at multiple levels of analysis, whether they accurately reflect the psychophysiological complexity of stress is questionable. For example, corticosteroids serve multifaceted functions, being involved in both aversive and appetitive situations, and thus do not respond uniquely to stress. ...
Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable and unpredictable), can measurably affect subsequent neuronal properties and cognitive functioning of the hippocampus. At the cellular level, stress has been shown to alter hippocampal synaptic plasticity, spike and local field potential activity, dendritic morphology, neurogenesis, and neurodegeneration. At the behavioral level, stress has been found to impair learning and memory for declarative (or explicit) tasks that are based on cognition, such as verbal recall memory in humans and spatial memory in rodents, while facilitating those that are based on emotion, such as differential fear conditioning in humans and contextual fear conditioning in rodents. These vertically related alterations in the hippocampus, procedurally observed after subjects have undergone stress, are generally believed to be mediated by recurrently elevated circulating hypothalamic-pituitary-adrenal (HPA) axis effector hormones, glucocorticoids, directly acting on hippocampal neurons densely populated with corticosteroid receptors. The main purposes of this review are to (i) provide a synopsis of the neurocognitive effects of stress in a historical context that led to the contemporary HPA axis dogma of basic and translational stress research, (ii) critically reappraise the necessity and sufficiency of the glucocorticoid hypothesis of stress, and (iii) suggest an alternative metaparadigm approach to monitor and manipulate the progression of stress effects at the neural coding level. Real-time analyses can reveal neural activity markers of stress in the hippocampus that can be used to extrapolate neurocognitive effects across a range of stress paradigms (i.e., resolve scaling and dichotomous memory effects issues) and understand individual differences, thereby providing a novel neurophysiological scaffold for advancing future stress research.
... However, despite these observations, little work has been completed investigating the possible intestinal physiological underpinnings of GI distress using this model. Moreover, rats display exaggerated physiological and behavioral stress responses (Laudenslager et al., 1988;Fleshner et al., 1995;Maier and Watkins, 2005;Maier and Seligman, 2016) for days following exposure to this stressor in manners that may be relevant for understanding the development of more persistent GI distress symptoms (Greenwood-Van Meerveld and Johnson, 2017). However, to the best of our knowledge, no research has been completed characterizing stress-related monoaminergic responses beyond periods in close proximity to stress exposure (e.g., with a 1-2 h) (Mayer, 2000;Dong et al., 2017;Li et al., 2019bLi et al., , 2022Lyte et al., 2020). ...
... Rats were returned to their home cages immediately following the tail shocks. The unpredictable tail shock paradigm is one of the most comprehensively studied models in stress physiology (Maier and Watkins, 2005;Maier and Seligman, 2016). As such, stress responses including, but not limited to, circulating corticosterone responses, glycemic levels, and sterilesystemic inflammation have been exhaustively characterized in past work (for example, see Frank et al., 2007;Maslanik et al., 2012;Beninson et al., 2014;Clark et al., 2014;Cox et al., 2014;Speaker et al., 2014;. ...
Stress-induced abnormalities in gut monoamine levels (e.g., serotonin, dopamine, norepinephrine) have been linked to gastrointestinal (GI) dysfunction, as well as the worsening of symptoms in GI disorders. However, the influence of stress on changes across the entire intestinal monoamine biogeography has not been well-characterized, especially in the days following stress exposure. Therefore, the aim of this study was to comprehensively assess changes to monoamine neurochemical signatures across the entire rat intestinal tract days after exposure to an acute stressor. To the end, adult male F344 rats were subjected to an episode of unpredictable tail shocks (acute stress) or left undisturbed. Forty-eight hours later rats were euthanized either following a 12 h period of fasting or 30 min of food access to evaluate neurochemical profiles during the peri- and early postprandial periods. Monoamine-related neurochemicals were measured via UHPLC in regions of the small intestine (duodenum, jejunum, ileum), large intestine (cecum, proximal colon, distal colon), cecal contents, fecal contents, and liver. The results suggest a relatively wide-spread increase in measures of serotonin activity across intestinal regions can be observed 48 h after exposure to acute stress, however some evidence was found supporting localized differences in serotonin metabolization. Moreover, acute stress exposure reduced catecholamine-related neurochemical concentrations most notably in the ileum, and to a lesser extent in the cecal contents. Next, stress-related fecal serotonin concentrations were consistent with intestinal profiles. However, fecal dopamine was elevated in association with stress, which did not parallel findings in any other intestinal area. Finally, stress exposure and the food access period together only had minor effects on intestinal monoamine profiles. Taken together, these data suggest nuanced differences in monoaminergic profiles exist across intestinal regions the days following exposure to an acute stressor, highlighting the importance of assessments that consider the entire intestinal tract biogeography when investigating stress-related biological outcomes that may be relevant to GI pathophysiology.
... Due to the habituation caused by repeated exposure to acute stress, we gave rats a systemic 4mg/kg dose of a pharmacological stressor known as FG 7142 (henceforth known as stressor or FG stressor). This drug is known to mimic the effects of uncontrollable stress linked to anxiety [45] and increases catecholamine turnover in various limbic associated areas including the BLA and NAc [46][47][48] thought to influence choice behavior in humans and animals [49]. The stressor veered rats' choices towards safety (F(3, 18) = 6.408, p = 0.004; veh vs stressor, p = 0.016; Fig. 3A) and made them slower in their response (F(3, 18) = 25.859, ...
In humans, loss aversion is sensitive to stress, and patients with neurological or psychiatric illnesses are particularly vulnerable to the detrimental effects of stress that lead to suboptimal life-altering choices. The basolateral amygdala (BLA) and nucleus accumbens (NAc) are stress sensitive brain areas that alter extracellular levels of norepinephrine (NE) and dopamine (DA), respectively. However, the dynamics of neurotransmitter release in these brain regions during stress has not been systematically explored. We used pharmacology and fiber photometric analysis to elucidate the impact of stress, DA and NE on brain activity during decision making behavior. Long-Evans rats were trained on an operant touchscreen decision-making task in which they chose between a safe stimulus that delivered a certain 50µl sucrose, or a risky stimulus that delivered either a ‘loss’ (10µl sucrose 75% of the time) or ‘win’ (170µl sucrose 25% of the time). Stress, induced by an inverse GABA A agonist, FG7142, biased rats’ decisions towards safety due to increased loss sensitivity. The aversion to loss was blocked with co-treatment of the α2 A receptor antagonist, yohimbine. We also captured the rapid dynamic properties of stress induced changes in NE and DA release in the BLA and NAc, respectively. We discovered that these dynamics could be modulated with systemic injections of yohimbine by altering stress induced catecholamine release to optimize decision strategy and motivational state.
... The diversity of stressors, their contexts, the time between stress exposure and cognitive tasks, the specific task type, and the individual differences in genetic background, life history, age, and biological sex of the stressed individuals all contribute to a complex matrix of stress effects (Duque et al., 2022;Joëls, 2018;Joëls and Baram, 2009). Factors such as the controllability and predictability of stressors can further modulate the impact of stress' (Maier and Watkins, 2005;Mineka and Hendersen, 1985). At the cellular level, the type of stressor influences the neural populations and mediators involved in adaptive responses. ...
Understanding the impact of stress on cognitive processes, particularly decision-making, is crucial as it underpins behaviors essential for survival. However, research in this domain has yielded disparate results, with inconsistencies evident across stress-induction paradigms and drug administration protocols designed to investigate specific stress pathways or neuromodulators. Building upon empirical studies, this research identifies a multifaceted matrix of variables contributing to the divergent findings. This matrix encompasses factors such as the temporal proximity between stressors and decision tasks, the nature of stressors and decision contexts, individual characteristics including psychobiological profiles and affective states at the time of decision-making and even cultural influences. In response to these complexities, we propose a comprehensive model that integrates these relevant factors and their intricate interplay to elucidate the mechanisms governing decision-making during stressful events. By synthesizing these insights, our model not only refines existing paradigms but also provides a framework for future study designs, offering avenues for theoretical advancements and translational developments in the field of stress's impact on cognitive functions. This research contributes to a deeper understanding of the nuanced relationship between stress and decision-making, ultimately advancing our knowledge of cognitive processes under challenging conditions.
... The design of the study is shown in Figure 1. The prelimbic cortex was selected for analysis due to its role in depression and modulation of the hypothalamic-pituitary axis activity [58][59][60]. In addition, PV changes in maternally separated animals were only observed in the prefrontal cortex, not the hippocampus [17]. ...
Early adversity, the loss of the inhibitory GABAergic interneuron parvalbumin, and elevated neuroinflammation are associated with depression. Individuals with a maltreatment history initiate medicinal cannabis use earlier in life than non-maltreated individuals, suggesting self-medication. Female rats underwent maternal separation (MS) between 2 and 20 days of age to model early adversity or served as colony controls. The prelimbic cortex and behavior were examined to determine whether MS alters the cannabinoid receptor 2 (CB2), which has anti-inflammatory properties. A reduction in the CB2-associated regulatory enzyme MARCH7 leading to increased NLRP3 was observed with Western immunoblots in MS females. Immunohistochemistry with stereology quantified numbers of parvalbumin-immunoreactive cells and CB2 at 25, 40, and 100 days of age, revealing that the CB2 receptor associated with PV neurons initially increases at P25 and subsequently decreases by P40 in MS animals, with no change in controls. Confocal and triple-label microscopy suggest colocalization of these CB2 receptors to microglia wrapped around the parvalbumin neuron. Depressive-like behavior in MS animals was elevated at P40 and reduced with the CB2 agonist HU-308 or a CB2-overexpressing lentivirus microinjected into the prelimbic cortex. These results suggest that increasing CB2 expression by P40 in the prelimbic cortex prevents depressive behavior in MS female rats.
... Second, we addressed whether stable winning buffers against the behavioral and neurochemical outcomes of IS. Robust activation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is necessary and sufficient to elicit the behavioral sequelae of IS (for review, see Maier and Watkins, 2005), such as social avoidance (Christianson et al., 2008), the behavioral endpoint measured here. Thus, we measured extracellular levels of DRN 5-HT during IS and examined subsequent social interaction. ...
Dominance status has extensive effects on physical and mental health, and an individual’s relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. The development of stable dominance was prevented by reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum. Stable winning blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented uncontrollable stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.
... Instead of having no effect, as at present in the model, control might also be necessary for the good avoiders to overcome any possible Pavlovian misbehaviour arising from the opponent. Of course, control might also influence the opponent [48], making for a rich palette of possible interactions. ...
Pavlovian influences notoriously interfere with operant behaviour. Evidence suggests this interference sometimes coincides with the release of the neuromodulator dopamine in the nucleus accumbens. Suppressing such interference is one of the targets of cognitive control. Here, using the examples of active avoidance and omission behaviour, we examine the possibility that direct manipulation of the dopamine signal is an instrument of control itself. In particular, when instrumental and Pavlovian influences come into conflict, dopamine levels might be affected by the controlled deployment of a reframing mechanism that recasts the prospect of possible punishment as an opportunity to approach safety, and the prospect of future reward in terms of a possible loss of that reward. We operationalize this reframing mechanism and fit the resulting model to rodent behaviour from two paradigmatic experiments in which accumbens dopamine release was also measured. We show that in addition to matching animals’ behaviour, the model predicts dopamine transients that capture some key features of observed dopamine release at the time of discriminative cues, supporting the idea that modulation of this neuromodulator is amongst the repertoire of cognitive control strategies.
... In addition to duration of exposure, HCWs in early pandemic hotspots were exposed to stressors that were often new and highly uncontrollable -that is, perceived as hard to prevent or escape. Uncontrollable stress is associated with particularly deleterious health outcomes in animals (Maier & Watkins, 2005) and poorer fear extinction in humans, which may contribute to the development of post-exposure disorders (Hartley, Gorun, Reddan, Ramirez, & Phelps, 2014). In addition to being uncontrollable, stressors may have been appraised by HCWs as hindrances or even threats. ...
Background. Healthcare workers (HCWs) in COVID-19 pandemic hotspots were exposed to workplace stressors. Structural occupational factors that prevent stressor exposure from translating into mental health problems (i.e., resilience factors) remain poorly understood. This study identifies resilience factors actionable at the workplace and examines the role of cumulative stressor exposure for developing depressive symptoms.Methods. We prospectively followed a convenience sample of HCWs working in Spain. We used a survey to collect self-reported data on (a) sociodemographic characteristics, (b) workplace and COVID-19-related stressors, (c) potential occupational resilience factors, and (d) depression symptoms, at three time points (2020, 2021 and 2022). We operationalised resilience as low stressor reactivity (SR), quantified as individual deviations from the normative relation between exposure to stressors and depressive symptoms. We performed linear and quadratic multiple regression analyses to examine the prospective association between (a) potential resilience factors and (b) prior stressor exposure, with SR across waves.Results. Our sample consisted of 1,872, 1,560, and 431 participants at time points 1, 2, and 3, respectively (median age 42-43 years, 77-80% female). The occupational factors support from colleagues (SOCwork), trust in the workplace (TRUSTwork), and perceived ability to recover from adversity (REC) were prospectively associated with resilience and thus identified as resilience factors. Stressor exposure at baseline was inversely associated with resilience at follow-ups.Conclusions. Occupational strategies that promote key resilience factors and reduce cumulative or prolonged stressor exposure may enhance resilience in times of crisis. The observational design and the large drop in response rates warrant further studies.
... Eventually, the animal stops trying to avoid the adverse stimulus. This response was first demonstrated in animals experimentally, but has since been identified in some subpopulations of MDD patients (Maier and Watkins, 2005). Repeated administration of the conventional SSRIs is required to elicit an effect on LH (Caldarone et al., 2000;Shanks and Anisman, 1988). ...
Ethnopharmacological relevance: Yueju is a traditional herbal medicine which consists of five herbs and formulated to treat depression-related syndromes 800 years ago. Yueju is still widely prescribed to treat conditions which include digestive dysfunction and depression. Recently, Yueju has been shown to promote a fast-onset antidepressant effect clinically and in preclinical studies. Because conventional antidepressants have a delayed onset in treating depression, the novelty of Yueju's rapid antidepressant effect and its underlying mechanism are of great significance both clinically and scientifically. Aim of the study: To review the use of Yueju for treatment of mood-related syndromes, and particularly its use in depression. To evaluate recent evidence of Yueju rapid antidepressant actions, based on new findings at behavioral and molecular levels. To suggest direction for future studies to address further scientific issues. Materials and methods: Reports regarding to the history and current use of Yueju are summarized. Recent progress on rapid antidepressant effects of Yueju, the crucial constituent, Gardenia jasminoides J.Ellis (GJ) and other herbs, are reviewed. Results: The medical need for rapid antidepressant actions, as well as breakthrough findings using ketamine and its limitations are introduced. Studies with Yueju using a number of acute, subacute and chronic behavioral paradigms are compared with ketamine. Findings from clinical reports also support the rapid action of Yueju. Studies examine the contribution of the constituent herb GJ, in rapid antidepressant effects. Importantly, research into the mechanism of Yueju or GJ's antidepressant response indicate the importance of up-regulation in the neural circuit responsible for antidepressant activity, and highlight common and specific molecular signaling by Yueju that may explain why this herb formula has unique antidepressant activity. Conclusion: Preclinical and clinical studies demonstrate that Yueju confers rapid antidepressant effects. The common mechanisms shared both for ketamine and Yueju, as well as the novel mechanism specific to Yueju are examined. Yueju and GJ may have great clinic applicability and further more detailed studies are warranted.
... Additionally, we addressed whether stable winning buffers against the behavioral and neurochemical outcomes of IS. Robust activation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is necessary and sufficient to elicit the behavioral sequelae of IS (for review, see Maier and Watkins, 2005), was not certified by peer review) is the author/funder. All rights reserved. ...
Dominance status has extensive effects on physical and mental health, and an individual's relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. Reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum led to a long-term reduction in social rank. Stable dominance blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.
... Perceived controllability has been associated with activity in the medial prefrontal cortex (mPFC) and the dorsal anterior cingulate cortex (dACC), linking these regions to LH (11,15,18,19). In line with the learned controllability account, animal studies indicate that low perceived controllability downregulates the mPFC, which, in turn, disinhibits subcortical structures implicated in LH-like behavior (15,18,(20)(21)(22). Further, studies in humans provided evidence that thetaband (4-8 Hz) oscillatory activity recorded above the mPFC/dACC correlates with trial-by-trial fluctuations in subjectively inferred controllability during RL (13). ...
Introduction
Pavlovian bias is an innate motivational tendency to approach rewards and remain passive in the face of punishment. The relative reliance on Pavlovian valuation has been found to increase when the perceived control over environmental reinforcers is compromised, leading to behavior resembling learned helplessness (LH).
Methods
Sixty healthy young adults underwent a Go-NoGo reinforcement learning task and received anodal high-definition transcranial direct current stimulation (HD-tDCS) over the medial prefrontal/dorsal anterior cingulate cortex in our randomized, double-blind, sham- controlled study. Furthermore, we evaluated changes in cue-locked mid-frontal theta power derived from simultaneous electroencephalography (EEG). We hypothesized that active stimulation would reduce Pavlovian bias during manipulation of outcome controllability, and the effect would be accompanied by stronger mid-frontal theta activity, representing arbitration between choice strategies in favor of instrumental relative to Pavlovian valuation.
Results
We found a progressive decrease in Pavlovian bias during and after loss of control over feedback. Active HD-tDCS counteracted this effect while not affecting the mid-frontal theta signal.
Discussion
The results were at odds with our hypotheses but also with previous findings reporting LH-like patterns during and after loss of control without brain stimulation. The discrepancy may be related to different protocols for the controllability manipulation. We argue that the subjective evaluation of task controllability is crucial in mediating the balance between Pavlovian and instrumental valuation during reinforcement learning and that the medial prefrontal/dorsal anterior cingulate cortex is a key region in this respect. These findings have implications for understanding the behavioral and neural underpinnings of LH in humans.
... Some of these are procedurally quite different from each other, so naturally the phenomena produced by one procedure may be distinct from the phenomena produced by another. This is an important point, as apparent discrepancies in the controllability literature may be due to comparisons being made between different phenomena mediated by different neural processes [see discussion in (14)]. For inclusion, a study must compare the effects of physically identical stressors over which the subjects do and do not have behavioral control over one or more of its characteristics (duration, intensity, etc.). ...
“Learned helplessness” refers to debilitating outcomes, such as passivity and increased fear, that follow an uncontrollable adverse event, but do not when that event is controllable. The original explanation argued that when events are uncontrollable the animal learns that outcomes are independent of its behavior, and that this is the active ingredient in producing the effects. Controllable adverse events, in contrast, fail to produce these outcomes because they lack the active uncontrollability element. Recent work on the neural basis of helplessness, however, takes the opposite view. Prolonged exposure to aversive stimulation per se produces the debilitation by potent activation of serotonergic neurons in the brainstem dorsal raphe nucleus. Debilitation is prevented with an instrumental controlling response, which activates prefrontal circuitry detecting control and subsequently blunting the dorsal raphe nucleus response. Furthermore, learning control alters the prefrontal response to future adverse events, thereby preventing debilitation and producing long-term resiliency. The general implications of these neuroscience findings may apply to psychological therapy and prevention, in particular by suggesting the importance of cognitions and control, rather than habits of control.
... Instead of having no effect, as at present in the model, control might also be necessary for the good avoiders to overcome the malign influence of the opponent, depending on the latter's Pavlovian effect. Of course, control might also influence the opponent (Maier & Watkins, 2005), making for a rich palette of possible interactions. ...
Pavlovian influences notoriously interfere with operant behaviour; various such may be associated with the release of the neuromodulator dopamine in the nucleus accumbens. One role for cognitive control is suppressing these influences. Here, using the examples of active avoidance and omission behaviour, we examine the possibility that one instrument of control is direct manipulation of the dopamine signal itself.
... It is known that rodents exhibit stress-related behavioral, neural, and physiological responses in aversive situations that are uncontrollable (e.g., inescapable shocks) but not in aversive situations that are controllable (e.g., escapable shocks) . Prolonged exposure to uncontrollable stressors leads to learned helplessness, often used as an animal model for depression (Bland et al., 2003;Maier and Watkins, 2005). Work from human neuroimaging also indicates that people are averse to uncontrollable situations. ...
Controllability, or the influence one has over their surroundings, is crucial for decision-making and mental health. Traditionally, controllability is operationalized in sensorimotor terms as one's ability to exercise their actions to achieve an intended outcome (also termed "agency"). However, recent social neuroscience research suggests that humans also assess if and how they can exert influence over other people (i.e., their actions, outcomes, beliefs) to achieve desired outcomes ("social controllability"). In this review, we will synthesize empirical findings and neurocomputational frameworks related to social controllability. We first introduce the concepts of contextual and perceived controllability and their respective relevance for decision-making. Then, we outline neurocomputational frameworks that can be used to model social controllability, with a focus on behavioral economic paradigms and reinforcement learning approaches. Finally, we discuss the implications of social controllability for computational psychiatry research, using delusion and obsession-compulsion as examples. Taken together, we propose that social controllability could be a key area of investigation in future social neuroscience and computational psychiatry research.
... FG-7142, in males, at similar and even lower doses than that used in this work induces pronounced anxiogenic effects on standardized tests such as the open field (Stephens et al., 1987;Dawson et al., 2006), the elevated plus maze (Pellow and File, 1986;Rodgers et al., 1995;Atack et al., 2005;Dawson et al., 2006), or the darkness-light test (Bueno et al., 2005). FG-7142 also alters the ability to regulate and inhibit emotional responses, potentiates fear behaviors, and induces avoidance deficits (Thiébot et al., 1991;Harris and Westbrook, 1998;Jelen et al., 2003;Kim and Richardson, 2007;Willadsen et al., 2018) and learned helplessness (Weiss et al., 1981;Drugan et al., 1985;Short and Maier, 1993;Maier and Watkins, 2005). ...
Introduction
Depression and anxiety are highly comorbid mental disorders with marked sex differences. Both disorders show altered activity in the amygdala, hippocampus, and prefrontal cortex. Infralimbic deep brain stimulation (DBS-IL) has anxiolytic and antidepressant effects, but the underlying mechanisms remain unclear. We aimed to contribute to understanding sex differences in the neurobiology of these disorders.
Methods
In male and female rats, we recorded neural oscillations along the dorsoventral axis of the hippocampus and the amygdala in response to an anxiogenic drug, FG-7142. Following this, we applied DBS-IL.
Results
Surprisingly, in females, the anxiogenic drug failed to induce most of the changes observed in males. We found sex differences in slow, delta, theta, and beta oscillations, and the amygdalo-hippocampal communication in response to FG-7142, with modest changes in females. Females had a more prominent basal gamma, and the drug altered this band only in males. We also analyzed c-Fos expression in both sexes in stress-related structures in response to FG-7142, DBS-IL, and combined interventions. With the anxiogenic drug, females showed reduced expression in the nucleus incertus, amygdala, septohippocampal network, and neocortical levels. In both experiments, the DBS-IL reversed FG-7142-induced effects, with a more substantial effect in males than females.
Discussion
Here, we show a reduced response in female rats which contrasts with the higher prevalence of anxiety in women but is consistent with other studies in rodents. Our results open compelling questions about sex differences in the neurobiology of anxiety and depression and their study in animal models.
... Indeed, correlations have been reported between changes in DR 5-HT neuron activity and different cognitive processes, such as working memory [58], cognitive flexibility [59], response inhibition [60], and exploration-exploitation balance [61]. Furthermore, the raphe 5-HT system is also involved in the modulation of mood, emotion, perception, stress, reward, aggression, and social interactions, among others [62][63][64][65][66]. It is difficult to find a human behavior that is not regulated by a 5-HT response. ...
In patients affected by Parkinson’s disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein (α-Syn). Much of PD research has focused on the role of α-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of α-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of α-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to α-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach.
... A first limitation is that mood is assumed to depend entirely on rewards (i.e., on whether the agent perceives their availability as increasing or decreasing). This fits well with the notion of anhedonia or lack of interest that indeed relates to perception of reward (Der-Avakian and Markou, 2012;Husain and Roiser, 2018;Kieslich et al., 2022;Treadway and Zald, 2011), but misses the notion of helplessness (i.e., the inability to cope with a situation) that relates to perception of self-efficacy (Kavanagh and Bower, 1985;Maier and Watkins, 2005;Miller and Seligman, 1975;Weems and Silverman, 2006). Yet patients with depression typically report self-depreciative assessments: they complain that they are worthless, or unable to achieve anything, and not just that gratifications are scarce in their environment. ...
A stable and neutral mood (euthymia) is commended by both economic and clinical perspectives, because it enables rational decisions and avoids mental illnesses. Here we suggest, on the contrary, that a flexible mood responsive to life events may be more adaptive for natural selection, because it can help adjust the behavior to fluctuations in the environment. In our model (dubbed MAGNETO), mood represents a global expected value that biases decisions to forage for a particular reward. When flexible, mood is updated every time an action is taken, by aggregating incurred costs and obtained rewards. Model simulations show that, across a large range of parameters, flexible agents outperform cold agents (with stable neutral mood), particularly when rewards and costs are correlated in time, as naturally occurring across seasons. However, with more extreme parameters, simulations generate short manic episodes marked by incessant foraging and lasting depressive episodes marked by total inaction. The MAGNETO model therefore accounts for both the function of mood fluctuations and the emergence of mood disorders.
... Pojedini autori u mehanizme naučene bespomoćnosti uključuju i neurofiziološke i biokemijske procese koji se u organizmu događaju pri izlaganju stresnom događaju. Maier i Watkins (2005) navode da, pri djelovanju nekontrolabilnih stresora, dolazi do podraživanja serotonergičkih neurona u području tzv. dorsalnih rapha jezgri. ...
Knjiga predstavlja jedinstven uspjeli pokušaj objedinjavanja različitih koncepata koji se bave kontrolom kako vlastitoga ponašanja i osjećanja, tako i doživljaja izvora i mogućnosti kontrole događaja koji se zbivaju oko nas. Budući da se koncepti kontrole javljaju u najrazličitijim granama psihologije kao što su psihologija ličnosti, kognitivna psihologija, psihologija emocija, motivacije i učenja, razvojna psihologija, psihologija rada, pa i klinička psihologija, ovaj poduhvat autora zaista je hvalevrijedan znanstveni poduhvat. Premda nam se može činiti kako je o konceptu mjesta ili lokusa kontrole sve već davno poznato i istraženo, autor nam pokazuje koliko smo u krivu i koliki su još brojni metodološki problemi vezani uz taj koncept.
... Symptoms of MDD include memory deficits, attention impairment [16][17][18], alterations in the speed of mental processing and motor performance and executive dysfunction [19][20][21]. Evidence suggests that 5-HT plays an important role in the control of anxiety and fear responses [22][23][24][25][26][27]. Serotonin is a major neurotransmitter in the central nervous system (CNS), and its role in psychiatric disorders is well-documented. ...
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.
... Perceived controllability has been associated with activity in the medial prefrontal cortex (mPFC) and the dorsal anterior cingulate cortex (dACC), linking these regions to LH (11,15,18,19). In line with the learned controllability account, animal studies indicate that low perceived controllability downregulates the mPFC, which, in turn, disinhibits subcortical structures implicated in LH-like behavior (15,18,(20)(21)(22). Further, studies in humans provided evidence that thetaband (4-8 Hz) oscillatory activity recorded above the mPFC/dACC correlates with trial-by-trial fluctuations in subjectively inferred controllability during RL (13). ...
Pavlovian bias is an innate motivational tendency to approach rewards and remain passive in the face of punishment. The relative reliance on Pavlovian valuation has been found to increase when the perceived control over environmental reinforcers is compromised, leading to behavior resembling learned helplessness (LH). In our study, we used a version of an orthogonalized Go-NoGo reinforcement learning task to examine the relative reliance on Pavlovian and instrumental valuation during and after an intermittent loss of control over rewards and losses. Sixty healthy young adults underwent the task and received anodal high-definition transcranial direct current stimulation (HD-tDCS) over the medial prefrontal/ dorsal anterior cingulate cortex in a randomized, double-blind, sham-controlled study. Furthermore, we evaluated changes in cue-locked mid-frontal theta power derived from electroencephalography. We hypothesized that active stimulation would reduce Pavlovian bias during manipulation of outcome controllability, and the effect would be accompanied by stronger mid-frontal theta activity, representing arbitration between choice strategies in favor of instrumental relative to Pavlovian valuation. We found a progressive decrease in Pavlovian bias during and after the loss of control over feedback. Active HD-tDCS counteracted this effect while not affecting the mid-frontal theta signal. The results were at odds with our hypotheses but also with previous findings reporting LH-like patterns during and after the loss of control without brain stimulation. The discrepancy may be related to different protocols for the controllability manipulation. We argue that the subjective evaluation of task controllability is crucial in mediating the balance between Pavlovian and instrumental valuation during reinforcement learning and that the medial prefrontal/dorsal anterior cingulate cortex is a key region in this respect. These findings have implications for understanding the behavioral and neural underpinnings of LH in humans.
... However, a difference in perceived level of control could also influence the experience since participants in the smartphone condition were asked to press a button that stopped the movement of the spider when it reached the 50 cm mark, as opposed to the spider stopping automatically in the HoloLens 2 application. Experiencing control over stressful situations can diminish distress, although studies manipulating level of control during exposure experience have not been able to replicate this finding (Maier & Watkins, 2005;Healey et al., 2017). Nevertheless, participants with greater control during a computerized exposure task were able to approach closer towards a spider (Healey et al., 2017). ...
Exposure therapy is an effective treatment for specific phobia that could be further enhanced through Augmented Reality, a novel technology that can facilitate implementation of gradual exposure and promote treatment acceptability. Effective exposure interventions require stimuli evoking high levels of anxiety. Therefore, it is important to ascertain whether animals can induce anxiety in distinct Augmented Reality modalities, such as Head-Mounted Displays and smartphones, which can differ in user experience and technological embodiment. This study compared the anxiety inducing potential and experienced realism of a spider within the HoloLens 2 Augmented Reality headset and an Augmented Reality smartphone application. Sixty-five participants were exposed to a virtual spider in a 5-step Behavioral Approach Task through both the HoloLens 2 head-mounted display and the PHOBOS Augmented Reality smartphone application. Participants reported Subjective Units of Distress at each step and physiological arousal was measured using heart rate and Skin Conductance. Results show that both technological modalities induced self-reported anxiety for spiders in a Behavioral Approach Task task in a non-clinical sample. The Hololens 2 modality was also related to an skin conductance (SC) increase. Perceived realism did not differ between modalities but was associated with increased anxiety in the HoloLens 2 modality. Findings demonstrate that both implemented modalities have potential for enabling Augmented Reality Exposure Therapy, although the role of experienced realism merits additional investigation. Future research should assess the effectiveness of Augmented Reality Exposure Therapy in clinical samples and assess whether new extended reality modalities, such as passthrough virtual reality, could accommodate observed limitations and improve Augmented Reality Exposure Therapy experiences and outcomes.
... Given the evidence of multiple behavioral and physiological measurements coupled with genetic variants, it is hard to argue that the WKY rat is NOT a model of depression. In contrast, others argue that the FST is not a measure of depression-like behavior but, rather, of stress coping strategy [22,211,212] and that the learned helplessness test measures the same [213]. Thus, WKY is a strain showing either depressive or passive coping behavior. ...
There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair-like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may compare characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.
... A consistent finding is that the impact of behavioral control is sex-specific. In males, numerous neurochemical and behavioral consequences that typically follow IS (social avoidance, enhanced freezing, impaired shuttle box escape, etc.) do not develop following physically identical ES (for review see [6]). Furthermore, an initial experience with ES buffers males against the behavioral outcomes of future IS and other uncontrollable stressors, such as social defeat [7,8]. ...
Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data demonstrate that ventral tegmental area (VTA) neurons expressing the vesicular glutamate transporter 2 (VGluT2) signal and causally contribute to behaviors that involve aversive or threatening stimuli. However, it is unknown whether VTA VGluT2 neurons regulate transsituational outcomes of stress and whether these neurons are sensitive to stressor controllability. This work adapted an operant mouse paradigm to examine the impact of stressor controllability on VTA VGluT2 neuron function as well as the role of VTA VGluT2 neurons in mediating transsituational stressor outcomes. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance and exaggerated fear in male mice. Uncontrollable stress in females led to exploratory avoidance of a novel brightly lit environment. Both controllable and uncontrollable stressors increased VTA VGluT2 neuronal activity, and chemogenetic silencing of VTA VGluT2 neurons prevented the behavioral sequelae of uncontrollable stress in male and female mice. Further, we show that stress activates multiple genetically-distinct subtypes of VTA VGluT2 neurons, especially those that are VGluT2+VGaT+, as well as lateral habenula neurons receiving synaptic input from VTA VGluT2 neurons. Our results provide causal evidence that mice can be used for identifying stressor controllability circuitry and that VTA VGluT2 neurons contribute to transsituational stressor outcomes, such as social avoidance, exaggerated fear, or anxiety-like behavior that are observed within trauma-related disorders.
Neuroscientific research on emotion has developed dramatically over the past decade. The cognitive neuroscience of human emotion, which has emerged as the new and thriving area of 'affective neuroscience', is rapidly rendering existing overviews of the field obsolete. This handbook provides a comprehensive, up-to-date and authoritative survey of knowledge and topics investigated in this cutting-edge field. It covers a range of topics, from face and voice perception to pain and music, as well as social behaviors and decision making. The book considers and interrogates multiple research methods, among them brain imaging and physiology measurements, as well as methods used to evaluate behavior and genetics. Editors Jorge Armony and Patrik Vuilleumier have enlisted well-known and active researchers from more than twenty institutions across three continents, bringing geographic as well as methodological breadth to the collection. This timely volume will become a key reference work for researchers and students in the growing field of neuroscience.
Neuroscientific research on emotion has developed dramatically over the past decade. The cognitive neuroscience of human emotion, which has emerged as the new and thriving area of 'affective neuroscience', is rapidly rendering existing overviews of the field obsolete. This handbook provides a comprehensive, up-to-date and authoritative survey of knowledge and topics investigated in this cutting-edge field. It covers a range of topics, from face and voice perception to pain and music, as well as social behaviors and decision making. The book considers and interrogates multiple research methods, among them brain imaging and physiology measurements, as well as methods used to evaluate behavior and genetics. Editors Jorge Armony and Patrik Vuilleumier have enlisted well-known and active researchers from more than twenty institutions across three continents, bringing geographic as well as methodological breadth to the collection. This timely volume will become a key reference work for researchers and students in the growing field of neuroscience.
Neuroscientific research on emotion has developed dramatically over the past decade. The cognitive neuroscience of human emotion, which has emerged as the new and thriving area of 'affective neuroscience', is rapidly rendering existing overviews of the field obsolete. This handbook provides a comprehensive, up-to-date and authoritative survey of knowledge and topics investigated in this cutting-edge field. It covers a range of topics, from face and voice perception to pain and music, as well as social behaviors and decision making. The book considers and interrogates multiple research methods, among them brain imaging and physiology measurements, as well as methods used to evaluate behavior and genetics. Editors Jorge Armony and Patrik Vuilleumier have enlisted well-known and active researchers from more than twenty institutions across three continents, bringing geographic as well as methodological breadth to the collection. This timely volume will become a key reference work for researchers and students in the growing field of neuroscience.
Over one-third of patients with epilepsy will develop refractory epilepsy and continue to experience seizures despite medical treatment. These patients are at the greatest risk for sudden unexpected death in epilepsy. The precise mechanisms underlying sudden unexpected death in epilepsy are unknown, but cardiorespiratory dysfunction and arousal impairment have been implicated. Substantial circumstantial evidence suggests serotonin is relevant to sudden unexpected death in epilepsy as it modulates sleep/wake regulation, breathing and arousal. The dorsal raphe nucleus is a major serotonergic center and a component of the ascending arousal system. Seizures disrupt the firing of dorsal raphe neurons, which may contribute to reduced responsiveness. However, the relevance of the dorsal raphe nucleus and its subnuclei to sudden unexpected death in epilepsy remains unclear. The dorsomedial dorsal raphe may be a salient target due to its role in stress and its connections with structures implicated in sudden unexpected death in epilepsy. We hypothesized that optogenetic activation of dorsomedial dorsal raphe serotonin neurons in TPH2-ChR2-YFP (n = 26) mice and wild-type (n = 27) littermates before induction of a maximal electroshock seizure would reduce mortality. In this study, pre-seizure activation of dorsal raphe nucleus serotonin neurons reduced mortality in TPH2-ChR2-YFP mice with implants aimed at the dorsomedial dorsal raphe. These results implicate the dorsomedial dorsal raphe in this novel circuit influencing seizure-induced mortality. It is our hope that these results and future experiments will define circuit mechanisms that could ultimately reduce sudden unexpected death in epilepsy.
A major subpopulation of midbrain 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) and co-releases 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunohistochemistry and conditional gene knockout mice to test the hypothesis that glutamate co-releasing 5-HT neurons are activated by stress and involved in stress coping. Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localized in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN. To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behavior, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioral effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition. We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate co-released at the 5-HT synapse may impact stress susceptibility.
Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5‐HT:5‐hydroxytryptamine) neurons and decreased 5‐HT activity was classically thought to increase aggression. However, recent studies challenge this 5‐HT deficiency model, revealing a more complex role for the DRN 5‐HT system in aggression. Furthermore, emerging evidence has shown that non‐5‐HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5‐HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5‐HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN‐mediated aggression modulation.
Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10 mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.
Stress is a construct that may be nearly universally understood, discussed at length among scientists and in casual conversation. Stressors, which produce a state of stress in the body, can take many forms, including being psychological in nature. The stress response is an adaptive reaction of the brain and body, which is necessary for proper energy utilization and behavioral responses to ensure that our survival is not threatened. However, stress can also be maladaptive for many reasons. This chapter addresses both adaptive and maladaptive constructs relevant to stress and stress-related processes in the central and peripheral nervous systems that influence cardiovascular function. Two examples of psychological stress—emotional stress and social stress—are discussed in the context of interactions between stress and the cardiovascular system. Several mechanisms underlying the associations of stress, psychological states, and cardiovascular dysfunction are addressed, including specific evidence from research with animal models of stress. The chapter concludes with recommendations for advancing our understanding of the interactions among stress, psychology, and the cardiovascular system.
Common stress-related mental health disorders affect women more than men. Physical activity can provide protection against the development of future stress-related mental health disorders (i.e. stress resistance) in both sexes, but whether there are sex differences in exercise-induced stress resistance is unknown. We have previously observed that voluntary wheel running (VWR) protects both female and male rats against the anxiety- and exaggerated fear-like behavioral effects of inescapable stress, but the time-course and magnitude of VWR-induced stress resilience has not been compared between sexes. The goal of the current study was to determine whether there are sex differences in the time-course and magnitude of exercise-induced stress resistance. In adult female and male Sprague Dawley rats, 6 weeks of VWR produced robust protection against stress-induced social avoidance and exaggerated fear. The magnitude of stress protection was similar between the sexes and was independent of reactivity to shock, general locomotor activity, and circulating corticosterone. Interestingly, 3 weeks of VWR prevented both stress-induced social avoidance and exaggerated fear in females but only prevented stress-induced social avoidance in males. Ovariectomy altered wheel-running behavior in females such that it resembled that of males, however; 3 weeks of VWR still protected females against behavioral consequences of stress regardless of the absence of ovaries. These data indicate that female Sprague Dawley rats are more responsive to exercise-induced stress resistance than are males.
Translational neuroscience for anxiety has had limited success despite great progress in understanding the neurobiology of Pavlovian fear conditioning and extinction. This chapter explores the idea that conditioning paradigms have had a modest impact on translation because studies in animals and humans are misaligned in important ways. For instance, animal conditioning studies typically use imminent threats to assess short-duration fear states with single behavioral measures (e.g., freezing), whereas human studies typically assess weaker or more prolonged anxiety states with physiological (e.g., skin conductance) and self-report measures. A path forward may be more animal research on conditioned anxiety phenomena measuring dynamic behavioral and physiological responses in more complex environments. Exploring transitions between defensive brain states during extinction, looming threats, and post-threat recovery may be particularly informative. If care is taken to align paradigms, threat levels, and measures, this strategy may reveal stable patterns of non-conscious defense in animals and humans that correlate better with conscious anxiety. This shift in focus is also warranted because anxiety is a bigger problem than fear, even in disorders defined by dysfunctional fear or panic reactions.KeywordsFearAnxietyTranslationThreatExtinctionFreezing
Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.
Posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder that is a source of significant societal and economic costs. Although it is not possible to fully model human psychiatric disorders using animal models, physiological responses to trauma and stressors, including hypothalamic-pituitary-adrenal (HPA) axis responses, autonomic nervous system responses, and immune responses, are highly conserved across mammalian species. Each of these physiological response systems, in turn, has been implicated in determining risk of development of PTSD symptoms, or contributing to PTSD severity, in humans, suggesting that understanding mechanisms underlying these responses may lead to novel therapeutic strategies for the prevention or treatment of PTSD. Furthermore, individual variability in physiological responses to trauma and stressors is thought to be an important determinant of stress vulnerability or stress resilience; therefore, understanding mechanisms underlying individual variability in physiological responses to trauma or stressor exposure has promise to increase our understanding of mechanisms underlying vulnerability to development of PTSD and persistence of PTSD symptoms. Here we describe a model of inescapable stress exposure in rats that has contributed to our understanding of the mechanisms underlying stress vulnerability and stress resilience. Given that PTSD is more common in females than males, we also highlight the need for increased focus on inclusion of both males in females in future studies.Key wordsAnxietyImmunoregulationInflammasomeInflammationMicrobiomeOld FriendsPTSDResilienceStressTrauma
Stress has a strong influence on mental health around the world. Decades of research has sought to identify mechanisms through which stress contributes to psychiatric disorders such as depression, to potentially guide the development of therapeutics targeting stress systems. The hypothalamic pituitary adrenal (HPA) axis is the key endocrine system that is responsible for coordinating body-wide changes that are necessary for survival under stress, and much of the research aimed at understanding the mechanisms by which stress contributes to depression has focussed on HPA axis dysfunction. Corticotrophin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) sit at the apex of the HPA axis, integrating signals relevant to stress and external threats, to ensure HPA axis activity is appropriate for the given context. In addition to this, emerging research has demonstrated that neural activity in PVNCRH neurons regulates stress related behaviours via modulation of downstream synaptic targets. This review will summarize convergent evidence from preclinical studies on chronic stress and clinical research in mood disorders demonstrating changes in PVNCRH neural function, consider how this may influence synaptic targets of PVNCRH neurons, and discuss the potential role of these PVNCRH synaptic pathways in the development of maladaptive behaviours following chronic stress that are relevant to depression. We will also highlight important questions for future research aimed at precisely dissecting endocrine and synaptic roles of PVNCRH neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders.
Serotonin (5‐HT) is a major neurotransmitter broadly involved in many aspects of feeling and behavior. Although its electro‐active feature renders the electrochemical sensor promising, the persistent generation of fouling layers on electrode by its oxidation products presents a hurdle for reliable sensing. Here, we present a fouling‐free 5‐HT sensor based on galvanic redox potentiometry. The sensor efficiently minimizes electrode fouling as revealed by in situ Raman spectroscopy, ensuring a less than 3% signal change in a 2‐hour continuous experiment, whereas amperometric sensors losing 90% within 30 min. Most importantly, the sensor is highly amenable for in vivo studies, permitting real‐time 5‐HT monitoring, and supporting the mechanism associated with serotonin release in brain. Our system offers an effective way to sensing different neurochemicals having significant fouling issues, thus facilitating the molecular‐level understanding of brain function.
Serotonin (5‐HT) is a major neurotransmitter broadly involved in many aspects of feeling and behavior. Although its electro‐activity makes it a promising candidate for electrochemical sensing, the persistent generation of fouling layers on the electrode by its oxidation products presents a hurdle for reliable sensing. Here, we present a fouling‐free 5‐HT sensor based on galvanic redox potentiometry. The sensor efficiently minimizes electrode fouling as revealed by in situ Raman spectroscopy, ensuring a less than 3 % signal change in a 2 hour continuous experiment, whereas amperometric sensors losing 90 % within 30 min. Most importantly, the sensor is highly amenable for in vivo studies, permitting real‐time 5‐HT monitoring, and supporting the mechanism associated with serotonin release in brain. Our system offers an effective way for sensing different neurochemicals having significant fouling issues, thus facilitating the molecular‐level understanding of brain function.
By means of an expansive innervation, the serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) are positioned to enact coordinated modulation of circuits distributed across the entire brain in order to adaptively regulate behavior. Yet the network computations that emerge from the excitability and connectivity features of the DRN are still poorly understood. To gain insight into these computations, we began by carrying out a detailed electrophysiological characterization of genetically-identified mouse 5-HT and somatostatin (SOM) neurons. We next developed a single-neuron modeling framework that combines the realism of Hodgkin-Huxley models with the simplicity and predictive power of generalized integrate-and-fire (GIF) models. We found that feedforward inhibition of 5-HT neurons by heterogeneous SOM neurons implemented divisive inhibition, while endocannabinoid-mediated modulation of excitatory drive to the DRN increased the gain of 5-HT output. Our most striking finding was that the output of the DRN encodes a mixture of the intensity and temporal derivative of its input, and that the temporal derivative component dominates this mixture precisely when the input is increasing rapidly. This network computation primarily emerged from prominent adaptation mechanisms found in 5-HT neurons, including a previously undescribed dynamic threshold. By applying a bottom-up neural network modeling approach, our results suggest that the DRN is particularly apt to encode input changes over short timescales, reflecting one of the salient emerging computations that dominate its output to regulate behavior.
Exposure to various stressors potentiates nociceptive and nonnociceptive responses to morphine. These phenomena have received little study despite their seeming generality and importance for understanding analgesia and opiate action. The present experiments characterize inescapable shock (IS)-induced potentiation of morphine analgesia. Rats were exposed to IS, equal escapable shocks (ESs), or restraint (control). Potentiation of analgesia (tail-flick [TF] test and hotplate test) was observed only in rats given IS 24 or 48 hr earlier, in agreement with previously reported learned-helplessness effects. Finally, no change in tail temperature or motor function was found that could be inaccurately interpreted as analgesia. The relevance of these findings to stressor-induced enhancement of morphine analgesia and potential substrates of IS effects are discussed.
Corticotropin-releasing factor (CRF) is the primary factor involved in controlling the release of ACTH from the anterior pituitary and also acts as a neurotransmitter in a variety of brain systems. The actions of CRF are mediated by G-protein coupled membrane bound receptors and a high affinity CRF receptor, CRF1, has been previously cloned and functionally characterized. We have recently isolated a cDNA encoding a second member of the CRF receptor family, designated CRF2, which displays approximately 70% homology at the nucleotide level to the CRF1 receptor and exhibits a distinctive pharmacological profile. The present study utilized in situ hybridization histochemistry to localize the distribution of CRF2 receptor mRNA in rat brain and pituitary gland and compared this with the distribution of CRF1, receptor expression. While CRF1 receptor expression was very high in neocortical, cerebellar, and sensory relay structures, CRF2 receptor expression was generally confined to subcortical structures. The highest levels of CRF2 receptor mRNA in brain were evident within the lateral septal nucleus, the ventromedial hypothalamic nucleus and the choroid plexus. Moderate levels of CRF2 receptor expression were evident in the olfactory bulb, amygdaloid nuclei, the paraventricular and suraoptic nuclei of the hypothalamus, the inferior colliculus and 5-HT-associated raphe nuclei of the midbrain. CRF2-expressing cells were also evident in the bed nucleus of the stria terminalis, the hippocampal formation and anterior and lateral hypothalmic areas. In addition, CRF2 receptor mRNA was also found in cerebral arterioles throughout the brain. Within the pituitary gland, CRF2 receptor mRNA was detectable only at very low levels in scattered cells while CRF1 receptor mRNA was readily detectable in anterior and intermediate lobes. This heterogeneous distribution of CRF1 and CRF2 receptor mRNA suggests distinctive functional roles for each receptor in CRF-related systems. The CRF1 receptor may be regarded as the primary neuroendocrine pituitary CRF receptor and important in cortical, cerebellar and sensory roles of CRF. The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF.
Systemic administration of benzodiazepines before exposure to inescapable shock (IS) blocks the enhanced fear conditioning and escape learning deficits that follow exposure to IS, whereas administration before the subsequent behavioral testing eliminates the enhanced fear but not the interference with escape. The failure of benzodiazepines to reduce the IS-produced escape learning deficit when given before testing is inconsistent with a recent proposal that interference with escape is mediated by an IS-induced sensitization of dorsal raphe nucleus (DRN) activity. The present experiments demonstrate that chlordiazepoxide will block both the enhancement of fear and interference with escape responding when given before either IS or testing if microinjected in the region of the DRN. This suggests that systemic benzodiazepines fail to block escape deficits when given before testing because action at a site distant from the DRN counters the effect of the drug at the DRN.
Reviews the literature which examined the effects of exposing organisms to aversive events which they cannot control. Motivational, cognitive, and emotional effects of uncontrollability are examined. It is hypothesized that when events are uncontrollable the organism learns that its behavior and outcomes are independent, and this learning produces the motivational, cognitive, and emotional effects of uncontrollability. Research which supports this learned helplessness hypothesis is described along with alternative hypotheses which have been offered as explanations of the learned helplessness effect. The application of this hypothesis to rats and man is examined. (114 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hrs after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The effects of application of five different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the striatum and hippocampus were compared using in vivo microdialysis. Forced swimming for 30 min elevated extracellular 5-hydroxytryptamine to 90% above basal levels and reduced 5-hydroxyindoleacetic acid to 45% of basal levels in the striatum during the swim session. In contrast, hippocampal 5-hydroxytryptamine was not altered significantly by forced swimming but 5-hydroxyindoleacetic acid levels were reduced to 60% of basal levels. Tail pinch for 5 min elevated 5-hydroxytryptamine to 55% above basal levels in striatum and to 35% above basal levels in hippocampus. Tail pinch had no effect on 5-hydroxyindoleacetic acid in either brain region. In contrast to forced swimming and the tail pinch, the other three stressors, immobilization stress for 100 min, exposure to a cold environment (4°C) for 2 h, and forced motor activity on a rotarod for 30 min, failed to alter extracellular 5-hydroxytryptamine in either the striatum or the hippocampus. All five stressors increased plasma corticosterone levels: tail pinch, 246%; cold stress, 432%; immobilization, 870%; forced motor activity, 1030%; and forced swimming, 1530%. These results suggest that individual stressors produce different effects on extracellular 5-hydroxytryptamine in different brain regions. In addition, there does not appear to be a relationship between the effects of stressors on the 5-hydroxytryptamine system and the magnitude of their ability to activate the hypothalamic-pituitary-adrenal axis.
The disturbances observed in animals subjected to unpredictable and uncontrollable aversive events resemble post-traumatic stress disorder (PTSD) symptoms and thus may constitute an animal model of this disorder. It is argued that the similarity between animals' symptoms and those of trauma victims may reflect common etiological factors. Relevant experiments in which animals exhibit generalized fear and arousal, discrete fear of a conditioned stimulus (CS), analgesia, and avoidance are reviewed with the view that these manifestations may be analogous to the PTSD symptom clusters of persistent arousal, reexperiencing, numbing, and avoidance, respectively. Finally, animal paradigms are suggested to test the validity of the model and specific hypotheses are derived from the animal literature regarding trauma variables that are predictive of particular PTSD symptom clusters.
The relation between the shuttlebox escape deficit produced by prior inescapable shock (IS) and fear during shuttlebox testing as assessed by freezing was investigated in rats. IS rats learned to escape poorly and were more fearful than either escapably shocked subjects or controls, both before and after receiving shock in the shuttlebox. However, fear and poor escape performance did not covary with the manipulation of variables designed to modulate the amount of fear and the occurrence of the escape deficit. A 72-hr interval between IS and testing eliminated the escape deficit but did not reduce preshock freezing. Diazepam before testing reduced both preshock and postshock fear in the shuttlebox but had no effect on the escape deficit. Naltrexone had no effect on fear but eliminated the escape deficit. This independence of outcomes suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects.
The 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone or TVXQ 7821 (ipsapirone) but not the 5-HT1B agonist RU 24969, attenuated the hyperphagic response to 8-OH-DPAT administered on the next day. Attenuation was still apparent on the fifth day after either 8-OH-DPAT or buspirone but not on the tenth day after 8-OH-DPAT administration. The ability of 8-OH-DPAT to reduce raphe 5-HIAA levels was also impaired by previous 8-OH-DPAT treatment. However, the 8-OH-DPAT or 5-methoxy-N,N-dimethyltryptamine-induced 5-HT syndromes were unaltered. The results indicate that a single pretreatment with 5-HT1A agonists rapidly desensitises 5-HT1A presynaptic receptor-mediated responses. This effect may mediate the antidepressant-like action of the drugs in an animal model of depression.
Stressor controllability can alter both behavior and pituitary-adrenal activity. Potential mediation of these behavioral effects by differential pituitary-adrenal output requires that the precise conditions that lead to differential behavioral consequences also produce differential pituitary-adrenal activity. Both plasma ACTH and corticosterone levels were measured at various times following escapable and yoked inescapable electric shock conditions known to produce differential behavioral outcomes. The escapable and inescapable shock procedures did not produce a detectable differential effect. Both shock conditions produced equivalent elevation of ACTH and corticosterone. Neither decay rates nor the ACTH and corticosterone response to shock reexposure differed among shocked groups.
MALE, SPRAGUE-DAWLEY, 90-DAY-OLD ALBINO RATS WHICH COULD PERFORM A COPING RESPONSE TO AVOID OR ESCAPE ELECTRIC SHOCK DEVELOPED LESS SEVERE PHYSIOLOGICAL SYMPTOMS OF STRESS THAN YOKED SS WHICH RECEIVED THE SAME SHOCKS BUT COULD NOT PERFORM SUCH A COPING RESPONSE. YOKED SS SHOWED A GREATER DECREASE IN BODY WEIGHT AND MORE EXTENSIVE GASTRIC LESIONS THAN AVOIDANCE AND NONSHOCK SS. SINCE AVOIDANCE AND YOKED SS RECEIVED THE SAME AMOUNT OF SHOCK THROUGH FIXED TAIL ELECTRODES WIRED IN SERIES, DIFFERENCES BETWEEN GROUPS ARE ATTRIBUTABLE TO PSYCHOLOGICAL FACTORS PRODUCED BECAUSE 1 S COULD "COPE WITH" THE STRESS SITUATION WHEREAS THE OTHER S COULD NOT. (20 REF.)
Exposed 35 dogs to inescapable traumatic shock. Either 24, 48, 72, or 144 hr. later, they were given instrumental avoidance training using a technique which eliminated all escape contingencies. Short time intervals between inescapable shock and avoidance training produced severe interference with the acquisition of avoidance responding as compared with a control group. But at longer intervals the amount of interference decreased. Results imply that the interference phenomenon is not mediated by the concurrent presence of shock.
EXPOSURE OF DOGS TO INESCAPABLE SHOCKS UNDER A VARIETY OF CONDITIONS RELIABLY INTERFERED WITH SUBSEQUENT INSTRUMENTAL ESCAPE-AVOIDANCE RESPONDING IN A NEW SITUATION. USE OF A HIGHER LEVEL OF SHOCK DURING INSTRUMENTAL AVOIDANCE TRAINING DID NOT ATTENUATE INTERFERENCE; THIS WAS TAKEN AS EVIDENCE AGAINST AN EXPLANATION BASED UPON ADAPTATION TO SHOCK. SS CURARIZED DURING THEIR EXPOSURE TO INESCAPABLE SHOCKS ALSO SHOWED PROACTIVE INTERFERENCE WITH ESCAPE-AVOIDANCE RESPONDING, INDICATING THAT INTERFERENCE IS NOT DUE TO ACQUISITION, DURING THE PERIOD OF EXPOSURE TO INESCAPABLE SHOCKS, OF INAPPROPRIATE, COMPETING INSTRUMENTAL RESPONSES. MAGNITUDE OF INTERFERENCE WAS FOUND TO DISSIPATE RAPIDLY IN TIME, LEAVING AN APPARENTLY NORMAL S AFTER ONLY 48 HR.
DOGS WHICH HAD 1ST LEARNED TO PANEL PRESS IN A HARNESS IN ORDER TO ESCAPE SHOCK SUBSEQUENTLY SHOWED NORMAL ACQUISITION OF ESCAPE/AVOIDANCE BEHAVIOR IN A SHUTTLE BOX. IN CONTRAST, YOKED, INESCAPABLE SHOCK IN THE HARNESS PRODUCED PROFOUND INTERFERENCE WITH SUBSEQUENT ESCAPE RESPONDING IN THE SHUTTLE BOX. INITIAL EXPERIENCE WITH ESCAPE IN THE SHUTTLE BOX LED TO ENHANCED PANEL PRESSING DURING INESCAPABLE SHOCK IN THE HARNESS AND PREVENTED INTERFERENCE WITH LATER RESPONDING IN THE SHUTTLE BOX. INESCAPABLE SHOCK IN THE HARNESS AND FAILURE TO ESCAPE IN THE SHUTTLE BOX PRODUCED INTERFERENCE WITH ESCAPE RESPONDING AFTER A 7-DAY REST. THESE RESULTS ARE INTERPRETED AS SUPPORTING A LEARNED "HELPLESSNESS" EXPLANATION OF INTERFERENCE WITH ESCAPE RESPONDING: SS FAILED TO ESCAPE SHOCK IN THE SHUTTLE BOX FOLLOWING INESCAPABLE SHOCK IN THE HARNESS BECAUSE THEY HAD LEARNED THAT SHOCK TERMINATION WAS INDEPENDENT OF RESPONDING.
Benzodiazepines probably exert their anxiolytic, hypnotic, and anticonvulsant effects by interacting with brain-specific high-affinity benzodiazepine receptors. In searching for possible endogenous ligands for these receptors we have purified a compound 10(7)-fold from human urine by extractions, treatment with hot ethanol, and column chromatography. The compound was identified as beta-carboline-3-carboxylic acid ethyl ester (IIc) by mass spectrometry, NMR spectrometry, and synthesis; IIc was also isolated from brain tissues (20 ng/g) by similar procedures. Very small concentrations of IIc displaced [3H]diazepam completely from specific cerebral receptors, but not from liver and kidney binding sites; the concentration causing 50% inhibition of specific [3H]diazepam binding (IC50) was 4-7 nM compared to ca. 5 nM for the potent benzodiazepine lorazepam. Specific binding sites for quinuclidinyl benzilate, naloxone, spiroperidol, serotonin, muscimol, and WB 4101 were not affected by IIc. In contrast to benzodiazepines, IIc exhibits "mixed type" competitive inhibition of forebrain benzodiazepine receptors (negative cooperativity). We surmise that an endogenous ligand for benzodiazepine receptors may be a derivative of beta-carboline-3-carboxylic acid.
Exposure of rats to a series of inescapable shocks produced in sequence both an early naltrexone-insensitive and a late naltrexone-reversible analgesic reaction. Activation of the opiate system was necessary and sufficient to produce an analgesic reaction 24 hours later on exposure to a small amount of shock. The amount of inescapable shock which induced naltrexone-reversible analgesia also produced hyperreactivity to morphine 24 hours later.
Systemic administration of benzodiazepine receptor inverse agonists leads to behavioral changes similar to those produced by inescapable shock (IS). The dorsal raphe nucleus (DRN) is a critical structure mediating IS effects. The present experiments determined whether the DRN is a site mediating the behavioral changes produced by benzodiazepine receptor inverse agonists. Microinjection of the inverse agonist Methyl 6,7-Dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the region of the DRN produced enhancement of fear conditioning as assessed by the amount of freezing in the presence of shock cues as well as interference with shuttlebox escape learning assessed 24 hr later. Furthermore, lesion of the DRN blocked the effects of systemic DMCM on fear conditioning and escape learning. These data suggest that the DRN is indeed critical in mediating these behavioral consequences of DMCM and further support a role for the DRN in producing the behavioral changes induced by IS.
Prior work suggests that inhibition of the dorsal raphe nucleus (DRN) either during exposure to inescapable electric shock (IS) or during later behavioral testing might block the usual behavioral consequences of IS. The 5-HT1A agonist 8-OH-DPAT was microinjected into the region of the DRN either before exposure to IS or before testing for fear conditioning and escape learning conducted 24 hr later. IS potentiated fear conditioning and interfered with escape performance. These effects were completely prevented by intra-DRN administration of 8-OH-DPAT at either point. Low but not high systemic doses of 8-OH-DPAT had a similar effect, supporting the idea that the effective site of action is presynaptic. The relation between these data and other effects of 8-OH-DPAT is discussed.
Many stressors elicit changes in corticotrophin (CRH), enkephalin (ENK), and neurotensin (NT) mRNA levels within the medial parvocellular region of the paraventricular nucleus of the hypothalamus (mpPVN), and the pattern of changes in mRNA levels appears to depend on the physical characteristics of the stressor. We questioned whether psychologically distinct stressors would cause different patterns of neuropeptide mRNA expression within the PVN. Psychologically distinct stressors were created by employing a paradigm of escapable (controllable) vs non-escapable (yoked) tail shock. An adult male rats could terminate the stress stimulus by performing wheel-turning behaviour; his behaviour also terminated the stress for his yoked partner, who had no control over the termination of the shock. Four h post-stress, brains were collected and processed for in-situ hybridization histochemistry. Tail-shock stress stimulated a significant increase in CRH, ENK, and NT mRNA levels within the mpPVN. The number of CRH identified neurones coexpressing AVP mRNA was also significantly elevated in both stress groups. Moreover, the pattern and magnitude of the stress-induced increases in mRNA was similar ire both stress groups. Additionally, no stress-induced changes in CRH mRNA levels were observed in the central nucleus of the amygdala. In sum, two psychologically distinct stressors, escapable vs yoked tail shock stress, stimulated similar increases in CRH, NT, ENK, and AVP mRNA levels within the mpPVN. These results suggest that physical attributes of a stress, rather than psychological, may be the more important factors in determining the PVN mRNA response.
The nonpeptide CRH antagonist antalarmin has been shown to block both behavioral and endocrine responses to CRH. However, it’s potential activity in blunting behavioral and endocrine sequelae of stressor exposure has not been assessed. Because antagonism of central CRH by α-helical CRH attenuates conditioned fear responses, we sought to test antalarmin in this regard. In addition, it remains unclear as to whether this is a result of receptor blockade during conditioning or during testing. Thus, we explored whether CRH mediates the induction or expression of conditioned fear (freezing in a context previously associated with 2 footshocks; 1.0 mA, 5 sec each). Furthermore, because rats previously exposed to inescapable shock (IS; 100 shocks, 1.6 mA, 5 sec each), demonstrate enhanced fear conditioning, we investigated whether this effect would be blocked by antalarmin. Antalarmin (20 mg/kg·2 ml ip) impaired both the induction and expression of conditioned fear. In addition, antalarmin blocked the enhancement of fear conditioning produced by prior exposure to IS. Despite the marked behavioral effects observed in antalarmin-treated rats, antalarmin had no effect on IS-induced rises in ACTH or corticosterone. However, antalarmin did block the ACTH response produced by exposure to 2 footshocks.
It is argued that exposure to stressors cansensitize the neural machinery that mediates fear for aperiod of time, and that during this time period fearconditioning is potentiated and responses to ambiguous or mildly fearful stimuli are exaggerated. Thecontrollability of the stressor is a key characteristicof the stressor which determines whether thissensitization occurs. That is, sensitization follows exposure to uncontrollable, but not tocontrollable, stressors. It is argued that thissensitization of the neural structures that mediate fearmay be similar to what is meant by anxiety, and thatbrain serotonin systems are a key component of thissensitization process. The implications of this point ofview for a variety of phenomena including learnedhelplessness and reactivity to drugs of abuse are discussed.
Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids1. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh (ref. 2). Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues3,
4,
5,
6. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.
Corticotropin-releasing factor (CRF), when administered directly into the CNS, can have activating properties on behaviour and can enhance behavioural responses to stress. CRF injected intraventricularly produces a dose-dependent increase in locomotor activity and increased responsiveness to an acoustic startle stimulus. However, this profile of activation changes to enhanced suppression of behaviour in stressful situations and includes increased freezing, increased conditioned suppression, increased conflict, decreased feeding and decreased behaviour in a novel open field. These effects of CRF are independent of the pituitary–adrenal axis and can be reversed by the CRF antagonist α-helical CRF(9–41). More importantly, the CRF antagonist can also reverse many behavioural responses to stressors. α-Helical CRF(9–41) reverses stress-induced fighting behaviour, stress-induced freezing, stress-induced suppression of feeding, stress-induced decreases in exploration of an elevated plus maze, fear-potentiated startle and the development of conditioned suppression. Intracerebral microinjections suggest that the amygdala may be an important site for the anti-stress effects of α-helical CRF(9–41). These results suggest that endogenous CRF systems in the CNS may have a role in mediating behavioural responses to stress and further suggest that CRF in the brain may function as a fundamental behavioural activating system. This CRF system may be particularly important in situations where an organism must mobilize not only the pituitary–adrenal system but also the CNS in response to environmental challenge.
Strategies used to explore the role of stressors in drug addiction include measuring stressor’s effects on drug’s rewarding properties. The current investigation explored the effect of an acute stressor on morphine conditioned place preference. Twenty-four hours following either inescapable tail shock or home-cage control treatment, all subjects were conditioned with morphine (0, 1, 2, and 3 mg/kg SC) over 2 days, and later tested for conditioned place preference. Inescapably shocked subjects demonstrated a potentiated place preference compared to controls. The inescapable shock-induced potentiated place preference developed even when conditioning was delayed until 6 and 7 days following the stressor, while no longer occurring after a 14- and 15-day interval. The potentiation was not a result of reduced locomotion in the inescapably shocked subjects, as activity in inescapably shocked and home-cage control subjects was the same following “mock” saline conditioning. Furthermore, the anxiogenic methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg/kg IP), which produces effects similar to those produced by inescapable shock, also potentiated morphine place preference. In addition, the potentiation in inescapably shocked subjects was dependent upon the stressor’s uncontrollability, as identical escapable shock did not potentiate place preference above control subjects. Finally, the inescapable shock-induced potentiated place preference was drug specific, as amphetamine place preference was not affected.
Interference with shuttle-box escape learning following exposure to inescapable shock is often difficult to obtain in rats. The first experiment investigated the role of shock intensity during escape training in the apparent fragility of the effect. Experiment 1A demonstrated that the magnitude of the interference effect was systematically related to shock intensity during shuttle-box testing. At .6 mA, a robust effect was obtained, whereas at .8 mA and 1.0, little or no deficit in the escape performance of inescapably shocked rats was observed. Experiment 1B demonstrated that the deficit observed in Experiment 1A depended upon whether or not rats could control shock offset. Experiment 2 suggested that preshock may suppress activity and that higher shock levels may overcome this deficit. Experiment 3 tested this as the sole cause of the escape deficit by requiring an escape response which exceeded the level of activity readily elicited by a 1.0-mA shock in both restrained and preshocked rats. In such a task, preshocked rats performed more poorly than did restrained controls. These results are consistent with the possibility that inescapable shock may, in addition to reducing activity, produce an associative deficit. Experiment 4 more clearly demonstrated that inescapable shock produces deficits in performance which cannot be expleined by activity deficits and which appear to be associative in nature. It was shown that inescapable shock interfered with the acquisition of signaled punishment suppression but not CER suppression. The theoretical implications of these data for explanations of the manner in which prior exposure to inescapable shock interferes with escape learning were discussed.
This paper presents two experiments that continue efforts to determine the neurochemical changes responsible for stress-induced behavioral depression. These expriments measured active motor behavior in a swim tank as well as levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in various brain regions of rats after the animals had (a) been exposed to electric shocks they could control (Avoidance-escape condition), or (b) received the same shocks with no control over them (Yoked condition), or (c) received no shock (No-shock condition). In the first experiment, measures were taken 90 min after the shock session ended. In the swim test, Yoked animals showed a depression of active behavior relative to the other groups. From measures of monoamine levels, the change found to be most closely related to this post-stress behavioral depression was in NE in the locus coeruleus (LC), where Yoked animals showed a considerable depletion of NE. In the second study, the same measures were taken 48 h and 72–96 h after the stress session. Yoked animals tested at 48 h post-stress showed motor depression, but those tested after 72–96 h did not. NE in the LC was significantly depleted in Yoked animals tested at 48 h post-stress but showed only slight (and non-significant) depletion in those tested 72–96 h post-stress. These results, together with others, suggest that large stress-induced depletion of NE in the LC is involved in mediating behavioral depression brought about by severe stress. It is further suggested that the time course for behavioral recovery and for the disappearance of NE depletion in the LC that was seen in Yoked animals after stress parallels the time course previously reported by other investigators for induction of catecholamine-synthesizing enzymes — tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) — in the LC, so that induction of TH and DBH activity may be a neurochemical mechanism to bring about recovery from poststress behavioral depression.
The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 μg decreasing, and 3.0 μg increasing 5-HT dialysate concentrations. I.C.V. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 μg) and high (3 μg) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.
Corticotropin releasing factor (CRF) is an important regulator of the endocrine, behavioral, autonomic and immune responses to stress. Two high affinity CRF receptors have been identified, which are distributed in distinct anatomical regions. CRF1 receptors have been relatively well characterized and antagonists to this receptor effectively block stress-induced behaviors in rodents. The function of CRF2 receptors, which are highly expressed in limbic brain regions, is less well understood. Therefore, an antisense oligonucleotide approach was used to study the role of CRF2 receptors in the lateral septum in rats. An antisense oligonucleotide directed against the CRF2 receptor mRNA reduced expression of CRF2 receptors by 60–80%. In shock-induced freezing tests, animals administered the antisense oligonucleotide exhibited a significant reduction in freezing duration. However, pain sensitivity and locomotor activity were unaltered. A four-base mismatch of the antisense sequence had no significant effects on CRF2 receptor density and on freezing behavior. These data support the involvement of CRF2 receptors in fear conditioning. CRF1 receptor antagonists also reduce freezing in this test. Additional studies to determine the effects of simultaneous inhibition of both receptor subtypes show that rats receiving both CRF2 receptor antisense oligonucleotide and CRF1 receptor antagonist froze significantly less than animals treated with either agent alone. These results provide additional evidence for the role of CRF2 receptors in mediating the stress-induced actions of endogenous CRF.
Manipulations of the dorsal raphe nucleus (DRN) modulate the behavioral effects of exposure to inescapable shock (IS). Opiate agonists and antagonists also influence the impact of IS, but the role of the DRN in mediating these effects is unknown. The opiate antagonist naltrexone micro-injected into the region of the DRN immediately prior to IS prevented both the escape deficit and the enhancement of fear conditioning that occur 24 h later. Intra-DRN naltrexone administered at the time of later behavioral testing reduced, but did not eliminate, these effects of prior IS. Conversely, the opiate agonist morphine, in combination with a subthreshold number of 20 IS trials, induced an escape deficit and enhanced conditioned fear 24 h later. Microinjections of naltrexone into the dorsolateral periaqueductal gray area did not alter the effects of IS and electrolytic lesions of the DRN prevented the effect of the morphine-20 IS trial combination. The role of opioids in mediating the behavioral effects of IS is discussed.
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the basolateral amygdala were measured by in vivo microdialysis. Inescapable, but not escapable, shock increased extracellular 5-HT in the amygdala relative to restrained controls. Basal levels of 5-HT were elevated 24 h after inescapable shock, and previously inescapably shocked subjects exhibited an exaggerated 5-HT response to two brief footshocks. Levels of extracellular 5-HIAA did not follow any particular pattern and were not correlated with the changes in 5-HT.
A cobalt-glucose-oxidase diaminobenzidine (Co-GOD) method, employing a specific antiserum against rat corticotropin releasing factor (CRF), was applied to determine immunohistochemically a widespread and detailed localization of corticotropin releasing factor-like immunoreactivity (CRFI) in the rat brain.
Besides the CRFI cells in the paraventricular hypothalamic nucleus that project to the median eminence, CRFI cells were demonstrated in many brain regions, including the olfactory bulb, cerebral cortex, septal nuclei, hippocampus, amygdala, thalamic nuclei, medial hypothalamic nuclei, lateral hypothalamic area, perifornical area, central gray, cuneiform nucleus, inferior colliculus, raphe nuclei, mesencephalic reticular formation, laterodorsal tegmental nucleus, locus coeruleus, parabrachial nuclei, mesencephalic tract of the trigeminal nerve, pontine reticular formation, lateral superior olive, vestibular nuclei, prepositus hypoglossal nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus, lateral reticular nucleus, nucleus of the spinal tract of the trigeminal nerve, external cuneate nucleus, inferior olive, and medullary reticular formation. CRFI-reacting neural processes were also detected in these same areas. In particular, the median eminence, lateral septum, bed nucleus of the stria terminalis, mesencephalic reticular formation, parabrachial nuclei, and nucleus of the solitary tract contained large numbers of CRFI fibres.
The widespread localization of CRFI demonstrated in the present study strongly suggests that CRF, like many other neurohormones and peptides, may act as a neurotransmitter and/or neuromodulator in numerous extra-hypothalamic circuits, as well as participate in neuroendocrine regulation.
The central nucleus of the amygdala, bed nucleus of the stria terminalis, and central gray are important components of the neural circuitry responsible for autonomic and behavioral responses to threatening or stressful stimuli. Neurons of the amygdala and bed nucleus of the stria terminalis that project to the midbrain central gray were tested for the presence of peptide immunoreactivity. To accomplish this aim, a combined immunohistochemical and retrograde tracing technique was used. Maximal retrograde labeling was observed in the amygdala and bed nucleus of the stria terminalis after injections of retrograde tracer into the caudal ventrolateral midbrain central gray. The majority of the retrogradely labeled neurons in the amygdala were located in the medial central nucleus, although many neurons were also observed in the lateral subdivision of the central nucleus. Most of the retrogradely labeled neurons in the BST were located in the ventral and posterior lateral subdivisions, although cells were also observed in most other subdivisions. Retrogradely labeled neurotensin, corticotropin releasing factor (CRF), and somatostatin neurons were mainly observed in the lateral central nucleus and the dorsal lateral BST. Retrogradely labeled substance P-immunoreactive cells were found in the medial central nucleus and the posterior and ventral lateral BST. Enkephalin-immunoreactive retrogradely labeled cells were not observed in the amygdala or bed nucleus of the stria terminalis. A few cells in the hypothalamus (paraventricular and lateral hypothalamic nuclei) that project to the central gray also contained CRF and neurotensin immunoreactivity. The results suggest the amygdala and the bed nucleus of the stria terminalis are a major forebrain source of CRF, neurotensin, somatostatin, and substance P terminals in the midbrain central gray.
Ascending projections from the dorsal raphe nucleus (DR) were examined in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). The majority of labeled fibers from the DR ascended through the forebrain within the medial forebrain bundle. DR fibers were found to terminate heavily in several subcortical as well as cortical sites.
The following subcortical nuclei receive dense projections from the DR: ventral regions of the midbrain central gray including the ‘supraoculomotor central gray’ region, the ventral tegmental area, the substantia nigra-pars compacta, midline and intralaminar nuclei of the thalamus including the posterior paraventricular, the parafascicular, reuniens, rhomboid, intermediodorsal/mediodorsal, and central medial thalamic nuclei, the central, lateral and basolateral nuclei of the amygdala, posteromedial regions of the striatum, the bed nucleus of the stria terminalis, the lateral septal nucleus, the lateral preoptic area, the substantia innominata, the magnocellular preoptic nucleus, the endopiriform nucleus, and the ventral pallidum. The following subcortical nuclei receive moderately dense projections from the DR: the median raphe nucleus, the midbrain reticular formation, the cuneiform/pedunculopontine tegmental area, the retrorubral nucleus, the supramammillary nucleus, the lateral hypothalamus, the paracentral and central lateral intralaminar nuclei of the thalamus, the globus pallidus, the medial preoptic area, the vertical and horizontal limbs of the diagonal band nuclei, the claustrum, the nucleus accumbens, and the olfactory tubercle.
The piriform, insular and frontal cortices receive dense projections from the DR; the occipital, entorhinal, perirhinal, frontal orbital, anterior cingulate, and infralimbic cortices, as well as the hippocampal formation, receive moderately dense projections from the DR.
Some notable differences were observed in projections from the caudal DR and the rostral DR. For example, the hippocampal formation receives moderately dense projections from the caudal DR and essentially none from the rostral DR. On the other hand, virtually all neocortical regions receive significantly denser projections from the rostral than from the caudal DR.
The present results demonstrate that dorsal raphe fibers project significantly throughout widespread regions of the midbrain and forebrain.
When rats are exposed to highly stressful events over which they have no control, they subsequently show many of the symptoms seen in depression in humans. In the attempt to discover neurochemical factors underlying depression, the neurochemical basis of stress-induced behavioural depression in rats has been studied extensively. Initial research (1968-1976) indicated that behavioural depression in this model was produced by alteration of noradrenaline (NA) concentrations in the brain. More recent research has indicated that the critical change may be a large depletion of NA in the locus ceruleus (LC). Behavioural depression may result when such NA depletion is sufficient to reduce NA release in the LC region, leading to a 'functional blockade' of inhibitory alpha 2-receptors in that brain region. Studies have now shown that behavioural depression after uncontrollable shock can be mimicked by pharmacological blockade of alpha 2-receptors in the LC region. Conversely, behavioural depression can be eliminated by either infusion of clonidine into the LC to replace at the alpha 2-receptors the NA depleted after uncontrollable shock, or infusion of pargyline into the LC to prevent the depletion of NA that otherwise follows uncontrollable shock. If alpha 2-receptors are functionally blocked in depression, then release of NA in regions innervated by the LC should be increased and stimulation of postsynaptic adrenoceptors outside the LC should be higher than normal. Thus, higher-than-normal stimulation of postsynaptic NA receptors should also produce behavioural depression; this has been demonstrated.
Although perceptions of control occupied a central role in the development of learned helplessness theory, recent helplessness research has not considered controllability judgments when relating attributions to depression. Supporting the importance of this construct, the research discussed in this article found evidence that judgments of control interact with other attributions in predicting depression. Specifically, in a prospective study of stress and well-being in adolescence, internal, stable, and global attributions for negative events attributed to uncontrollable causes were found to be positively related to increases in depression (as predicted by the reformulated helplessness theory), but internal and global attributions for negative events attributed to controllable causes were found to be inversely related to increases in depression. The discussion considers the implications of the findings for understanding the nature of the relation between attributions for naturally occurring life events and depression.
A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons.
The present study was aimed at testing the hypothesis (based mainly on biochemical evidence) of the implication of brain serotonergic neurons in the induction of learned helplessness (escape deficit) and its reversal by antidepressants in rats. After desipramine (25 mg/kg IP)-pretreatment rats were either sham-operated or infused with 5,7-dihydroxytryptamine (5,7-DHT, 3 micrograms of free base in 0.4 microliter saline containing 0.02% ascorbic acid) into the midbrain raphe area. Three weeks later, experimental animals were exposed to 60 randomized inescapable shocks (0.8 mA; 15 sec duration), control rats being not shocked, and 48 hr later, they were subjected to daily shuttle-box sessions (30 trials/day; ITI = 30 sec) on 3 consecutive days in order to assess escape deficits. After inescapable shock pretreatment separate groups of rats were given twice daily injections of clomipramine (total daily dose: 32 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg), nialamide (32 mg/kg) or saline. After behavioral testing, animals were sacrificed, and tryptophan hydroxylase activity was assayed in the cerebral cortex, the hippocampus and the striatum. We found that damage to serotonergic neurons associated with a 70% loss of tryptophan hydroxylase activity altered neither escape deficits produced by prior exposure to inescapable shock, nor the ability of either antidepressant studied to reverse escape failures in the shuttle-box paradigm. These findings cast some doubts on the hypothesized crucial role of serotonergic neurons in helpless behavior and its reversal by antidepressants.
A peptide with high potency and intrinsic activity for stimulating the secretion of corticotropin-like and beta -endorphin-like immunoactivities by cultured anterior pituitary cells has been purified from ovine hypothalamic extracts. The primary structure of this 41-residue corticotropin- and beta -endorphin-releasing factor has been determined to be: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Leu-Asp-Ile-Ala-NH2 The synthetic peptide is active in vitro and in vivo.
Administration of a benzodiazepine, chlordiazepoxide (CDP), prior to exposure to inescapable shock prevented both the long-term analgesia and the shuttle-escape deficit typically observed following inescapable shock. If given only prior to testing, CDP had little effect. The protective effects of CDP were determined not to be a result of state dependency or a general facilitatory effect of the drug on escape performance. It is suggested that the induction of anxiety or fear by inescapable shock is critical in mobilizing endogenous changes such as transmitter depletion which are thought to be responsible for the deficits observed.
The distribution of corticotropin-releasing factor (CRF)-immunoreactive cells and fibers has been examined in the brains of normal adult rats, and in the brains of animals that had been pretreated with intraventricular injections of colchicine, or had been adrenalectomized 3-60 days before perfusion. The results suggest that CRF immunoreactivity is localized in at least three functionally distinct systems. First, most of the CRF-stained fibers in the neurohemal zone of the median eminence, which presumably modulate the release of ACTH and beta-endorphin from the pituitary, appear to arise in the paraventricular nucleus of the hypothalamus (PVH). About 2,000 CRF-stained cells are distributed throughout all eight parts of the PVH, although a majority (80%) of the cells are concentrated in the parvocellular division, and a smaller number (about 15%) are found in parts of the magnocellular division in which oxytocinergic cells predominate. This appears to be the only CRF-stained pathway in the brain that is affected (increased staining intensity) by adrenalectomy. Second, a series of cell groups in the basal telencephalon, hypothalamus, and brain stem that are known to play a role in the mediation of autonomic responses contain CRF-stained neurons. These areas, which are interconnected by stained fibers in the medial forebrain bundle and the periventricular system, include the central nucleus of the amygdala, substantia innominata, bed nucleus of the stria terminalis, medial and lateral preoptic areas, lateral hypothalamic area, central gray, laterodorsal tegmental nucleus, locus ceruleus, parabrachial nucleus, dorsal vagal complex, and regions containing the A1 and A5 catecholamine cell groups. And third, scattered CRF-stained cells are found throughout most areas of the cerebral cortex. Most such cells are confined to layers II and III in the neocortex, and their bipolar shape suggests that they are interneurons. These cells are most common in limbic regions including prefrontal areas, the cingulate gyrus, and areas bordering the rhinal fissure. Scattered immunoreactive cells are also found in dorsal parts of the dentate gyrus and Ammon's horn. These results suggest that the PVH plays a critical role in the modulation of ACTH and beta-endorphin release from the pituitary, and that CRF-containing pathways in the brain are involved in the mediation of autonomic responses.
Corticotropin-releasing factor (CRF) is the primary factor involved in controlling the release of ACTH from the anterior pituitary and also acts as a neurotransmitter in a variety of brain systems. The actions of CRF are mediated by G-protein coupled membrane bound receptors and a high affinity CRF receptor, CRF1, has been previously cloned and functionally characterized. We have recently isolated a cDNA encoding a second member of the CRF receptor family, designated CRF2, which displays approximately 70% homology at the nucleotide level to the CRF1 receptor and exhibits a distinctive pharmacological profile. The present study utilized in situ hybridization histochemistry to localize the distribution of CRF2 receptor mRNA in rat brain and pituitary gland and compared this with the distribution of CRF1, receptor expression. While CRF1 receptor expression was very high in neocortical, cerebellar, and sensory relay structures, CRF2 receptor expression was generally confined to subcortical structures. The highest levels of CRF2 receptor mRNA in brain were evident within the lateral septal nucleus, the ventromedial hypothalamic nucleus and the choroid plexus. Moderate levels of CRF2 receptor expression were evident in the olfactory bulb, amygdaloid nuclei, the paraventricular and suraoptic nuclei of the hypothalamus, the inferior colliculus and 5-HT-associated raphe nuclei of the midbrain. CRF2-expressing cells were also evident in the bed nucleus of the stria terminalis, the hippocampal formation and anterior and lateral hypothalmic areas. In addition, CRF2 receptor mRNA was also found in cerebral arterioles throughout the brain. Within the pituitary gland, CRF2 receptor mRNA was detectable only at very low levels in scattered cells while CRF1 receptor mRNA was readily detectable in anterior and intermediate lobes. This heterogeneous distribution of CRF1 and CRF2 receptor mRNA suggests distinctive functional roles for each receptor in CRF-related systems. The CRF1 receptor may be regarded as the primary neuroendocrine pituitary CRF receptor and important in cortical, cerebellar and sensory roles of CRF. The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF.
Systemic administration of benzodiazepines before exposure to inescapable shock (IS) blocks the enhanced fear conditioning and escape learning deficits that follow exposure to IS, whereas administration before the subsequent behavioral testing eliminates the enhanced fear but not the interference with escape. The failure of benzodiazepines to reduce the IS-produced escape learning deficit when given before testing is inconsistent with a recent proposal that interference with escape is mediated by an IS-induced sensitization of dorsal raphe nucleus (DRN) activity. The present experiments demonstrate that chlordiazepoxide will block both the enhancement of fear and interference with escape responding when given before either IS or testing if microinjected in the region of the DRN. This suggests that systemic benzodiazepines fail to block escape deficits when given before testing because action at a site distant from the DRN counters the effect of the drug at the DRN.
Most behavioral and neurochemical changes produced by inescapable shock dissipate in 1-3 days. However, daily running activity is depressed for 14-42 days following one to three sessions of inescapable shock. In the present experiments, we sought to determine whether factors known to be important in the development of the short-term effects of exposure to inescapable shock would also be important in the production of the long-term effect of inescapable shock on daily activity. Three factors were examined: a) the escapability of the shock; short-term behavioral changes generally do not occur if the shock is escapable; b) naltrexone pretreatment; the opioid antagonist naltrexone typically prevents many of the short-term behavioral sequelae of inescapable shock; c) treatment with the anxiogenic beta-carboline FG-7142; administration of this compound alone frequently mimics inescapable shock in its ability to transiently disrupt behavior. The inescapable shock-induced reduction in daily activity did not depend upon escapability of the stressor. In addition, naltrexone did not prevent and FG-7142 did not induce the reduction in daily activity associated with stressor exposure.
Effects of benzodiazepine receptor-active compounds on inescapable shock-produced changes in social interaction were studied in the rat. Inescapably shocked animals exhibited less social interaction in a novel situation than did escapably shocked or unshocked rats 24 h after shock. Administration of the selective benzodiazepine receptor antagonist flumazenil at the time of shock prevented the decrease in social interaction. Social interaction was unaffected by the same treatment at the time of measurement. Reduction in social interaction induced by inescapable stress endured for 48-72 h following stressor exposure but was absent 168 h after stress. It was subject to antagonist blockade at all measured time points. Stress-induced decreases in social interaction were also blocked by the benzodiazepine chlordiazepoxide given at the time of shock treatment. The receptor antagonist did not reverse this blockade. An inverse agonist, the beta-carboline FG 7142, administered in place of inescapable shock, produced an identical pattern of social interaction in a dose-dependent manner. The inverse agonist effect was also reversed by the antagonist. The results from antagonist, agonist, and inverse agonist treatments all suggest that an endogenous benzodiazepine receptor inverse agonist is released at the time of inescapable shock and is involved in producing the changes in social interaction subsequently measured.
Estimates of 5-hydroxytryptamine (5-HT) turnover in response to 30 min of inescapable, randomly presented, loud sound (sound stress) were obtained for regions of rat brain containing 5-HT perikarya by means of 5-hydroxytryptophan (5-HTP) accumulation after administration of an inhibitor of aromatic amino acid decarboxylase (100 mg/kg i.p., m-hydroxybenzylhydrazine, NSD 1015). Sound stress increased 5-HTP accumulation in the median raphe nucleus (MRN) twofold over that from sham-stressed controls, but did not change 5-HTP accumulation significantly in dorsal raphe nucleus (DRN) or hindbrain. These findings indicate that the 5-HT perikarya of the MRN but not those of the DRN or hindbrain are activated by sound stress, thus, provide further evidence for a functional distinction between the 5-HT neurons of these two midbrain nuclei.
The spectrum of efficacy of the serotonin selective reuptake inhibitor (SSRI) antidepressant drugs continues to expand. In fact, no psychiatric syndrome seems to worsen with these agents, and few studies fail to demonstrate clinical improvement in some patients, regardless of any nosologic nicety, such as precise DSM diagnosis. This suggests that the biological rubric of psychopathology is dimensional rather than categorical. New research using in vivo microdialysis shows differences in neurochemistry among SSRIs, wherein fluoxetine blocks reuptake of dopamine and norepinephrine, as well as serotonin, in medial prefrontal cortex, and fluvoxamine has a relatively more selective neurochemical profile. In the animal model of learned helplessness, which is a biobehavioral model for stress-induced anxiety causing depression, the SSRIs including fluvoxamine prevent helplessness. From these and other data, a neurotransmitter balance theory of biopsychopathology is formulated. In this hypothetical construct, dopamine, norepinephrine, and GABA modulate thought, anxiety, and mood, respectively. Serotonin is a stabilizing agent, which assists in returning the mind to its homeostatic setpoint.