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Fritz A Henn - One of the best experts on this subject based on the ideXlab platform.
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whole brain mapping of neuronal activity in the Learned Helplessness model of depression
Frontiers in Neural Circuits, 2016Co-Authors: Fritz A Henn, Martine M Mirrione, Yongsoo Kim, Zinaida Perova, Kith PradhanAbstract:Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the Learned Helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing "helpless" behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing "resilient" behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that Helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.
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increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of Learned Helplessness behavior
Frontiers in Human Neuroscience, 2014Co-Authors: Fritz A Henn, Martine M Mirrione, Daniela Schulz, Kyle A B Lapidus, Sam Zhang, Wayne K GoodmanAbstract:Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive Learned Helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to Learned Helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.
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synaptic potentiation onto habenula neurons in the Learned Helplessness model of depression
Nature, 2011Co-Authors: Joaquin Piriz, Fritz A Henn, Martine M Mirrione, Chihye Chung, Christophe D Proulx, Daniela Schulz, Roberto MalinowAbstract:The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two Learned Helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's Helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce Learned Helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent Learned Helplessness model of depression.
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elevated spectroscopic glutamate gamma amino butyric acid in rats bred for Learned Helplessness
Neuroreport, 2007Co-Authors: Alexander Sartorius, Barbara Vollmayr, Magdalena M Mahlstedt, Fritz A Henn, Gabriele EndeAbstract:The theory of depression is dominated by the monoamine hypothesis but there is increasing evidence that beyond monoamines, glutamate (Glu) and gamma-aminobutyric acid (GABA) play an essential role in the pathogenesis of depression. In this study, the effect of alterations of GABA and Glu were investigated in the congenital Learned Helplessness paradigm. Proton magnetic resonance spectroscopy is an important monitoring tool to bridge the findings in clinical and preclinical studies. We found increased Glu/GABA ratios in the hippocampus and prefrontal cortex of placebo-treated (saline intraperitoneally) congenital Learned Helplessness rats versus wild-type rats, and a treatment-induced (desipramine 10 mg/kg intraperitoneally or electroconvulsive shock) decrease of this monoamine ratio in both brain regions. Our results corroborate previous findings of an amino-acid influence on the pathomechanisms of mood disorders.
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Reduced expression of complexins I and II in rats bred for Learned Helplessness.
Brain research, 2007Co-Authors: Mathias Zink, Barbara Vollmayr, Fritz A Henn, Peter J. Gebicke-haerter, Johannes ThomeAbstract:Disturbed synaptic transmission contributes to the pathophysiology of mood disorders. Post mortem studies reported reduced expression of the synaptic vesicle protein (SVP) complexins I and II in depression. Antidepressants were found to induce the expression of these genes. Since animals with congenital susceptibility to Learned Helplessness provide a valid animal model of depression, we investigated the expression of different SVPs in this system by semiquantitative in situ hybridization. Rats bred for congenital Learned helpless behavior (cLH, N=6) failed to interrupt foot shock currents by lever pressing (mean 12.3 failures out of 15 trials). These animals showed significantly lower expression of complexins I and II mRNA in hippocampal, limbic and cortical brain areas compared to not helpless animals (cNLH, N=6) with a mean failure rate of 0.83 out of 15 trials. Expression levels of complexins I and II significantly correlated with the failure rate in the test paradigm. In contrast, the expressions of synaptotagmin I and synaptophysin were found unchanged. This investigation provides a further validation of the LH model of depression. The experimental data fit well into current pathogenetic concepts of mood disorders and support the hypothesis, that complexins are pivotal players in the pathophysiology of depression and tentative targets of antidepressants.
Steven F. Maier - One of the best experts on this subject based on the ideXlab platform.
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Learned Helplessness at fifty insights from neuroscience
Psychological Review, 2016Co-Authors: Steven F. Maier, Martin E. P. SeligmanAbstract:Learned Helplessness, the failure to escape shock induced by uncontrollable aversive events, was discovered half a century ago. Seligman and Maier (1967) theorized that animals Learned that outcomes were independent of their responses-that nothing they did mattered-and that this learning undermined trying to escape. The mechanism of Learned Helplessness is now very well-charted biologically, and the original theory got it backward. Passivity in response to shock is not Learned. It is the default, unLearned response to prolonged aversive events and it is mediated by the serotonergic activity of the dorsal raphe nucleus, which in turn inhibits escape. This passivity can be overcome by learning control, with the activity of the medial prefrontal cortex, which subserves the detection of control leading to the automatic inhibition of the dorsal raphe nucleus. So animals learn that they can control aversive events, but the passive failure to learn to escape is an unLearned reaction to prolonged aversive stimulation. In addition, alterations of the ventromedial prefrontal cortex-dorsal raphe pathway can come to subserve the expectation of control. We speculate that default passivity and the compensating detection and expectation of control may have substantial implications for how to treat depression. (PsycINFO Database Record
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stressor controllability and Learned Helplessness the roles of the dorsal raphe nucleus serotonin and corticotropin releasing factor
Neuroscience & Biobehavioral Reviews, 2005Co-Authors: Steven F. Maier, Linda R WatkinsAbstract: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.
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freewheel running prevents Learned Helplessness behavioral depression role of dorsal raphe serotonergic neurons
The Journal of Neuroscience, 2003Co-Authors: Benjamin N Greenwood, Steven F. Maier, Teresa E Foley, Heidi E W Day, Jay Campisi, Sayamwong H Hammack, Serge Campeau, Monika FleshnerAbstract:Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are implicated in mediating Learned Helplessness (LH) behaviors, such as poor escape responding and expression of exaggerated conditioned fear, induced by acute exposure to uncontrollable stress. DRN 5-HT neurons are hyperactive during uncontrollable stress, resulting in desensitization of 5-HT type 1A (5-HT1A) inhibitory autoreceptors in the DRN. 5-HT1A autoreceptor downregulation is thought to induce transient sensitization of DRN 5-HT neurons, resulting in excessive 5-HT activity in brain areas that control the expression of Learned Helplessness behaviors. Habitual physical activity has antidepressant/anxiolytic properties and results in dramatic alterations in physiological stress responses, but the neurochemical mediators of these effects are unknown. The current study determined the effects of 6 weeks of voluntary freewheel running on LH behaviors, uncontrollable stress-induced activity of DRN 5-HT neurons, and basal expression of DRN 5-HT1A autoreceptor mRNA. Freewheel running prevented the shuttle box escape deficit and the exaggerated conditioned fear that is induced by uncontrollable tail shock in sedentary rats. Furthermore, double c-Fos/5-HT immunohistochemistry revealed that physical activity attenuated tail shock-induced activity of 5-HT neurons in the rostral–mid DRN. Six weeks of freewheel running also resulted in a basal increase in 5-HT1A inhibitory autoreceptor mRNA in the rostral–mid DRN. Results suggest that freewheel running prevents behavioral depression/LH and attenuates DRN 5-HT neural activity during uncontrollable stress. An increase in 5-HT1A inhibitory autoreceptor expression may contribute to the attenuation of DRN 5-HT activity and the prevention of LH in physically active rats.
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exposure to the stressor environment prevents the temporal dissipation of behavioral depression Learned Helplessness
Biological Psychiatry, 2001Co-Authors: Steven F. MaierAbstract:Abstract Background: Exposure to uncontrollable stressors such as inescapable shock (IS) produces a set of behavioral changes such as poor escape learning that have been called behavioral depression and Learned Helplessness. This paradigm has been proposed to be a model of depression and of anxiety-related disorders such as posttraumatic stress disorder (PTSD). However, the behavioral changes persist for only a few days after the stressor, rendering the phenomenon questionable as a model. However, the original traumatic experience is re-experienced in PTSD and rumination occurs in depression. In a series of experiments we therefore sought to determine whether behavioral depression/Learned Helplessness could be made to endure by periodically "reminding" the subject of the original IS experience. Methods: Rats exposed to IS were tested for escape learning at various times thereafter. In different experiments the subjects were exposed to the environment in which IS had occurred at differing points in the interval between IS and escape testing. Results: Exposure to the environment in which IS had occurred prolonged the duration of behavioral depression/Learned Helplessness, and repeated exposures prolonged it indefinitely. This effect required exposure to the cues that had been present during IS (i.e., reminding) and was not duplicated by exposure to other stressors or stress environments. Conclusions: Behavioral depression/Learned Helplessness can be maintained over time by processes that may be similar to those occurring in depression and PTSD, thereby strengthening the possibility that this paradigm is indeed a reasonable model of these disorders.
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Learned Helplessness: A Theory for the Age of Personal Control
1993Co-Authors: Christopher Peterson, Steven F. Maier, Martin E. P. SeligmanAbstract:1. Introduction 1.1 The Phenomena of Helplessness and Personal Control 1.2 The Theory of Learned Helplessness 1.3 Three Uses of "Learned Helplessness" 1.4 Learned Helplessness: Inward, Downward, and Outward 1.5 Why Learned Helplessness Has Been Controversial 1.6 Why Learned Helplessness Has Been Popular 2. Learned Helplessness in Animals 2.1 Learned Helplessness Theory 2.2 The Controversy 2.3 Contiguity Versus Contingency 2.4 Representation and Expectation 2.5 What We Know 2.6 What We Don't Know 3. The Biology of Learned Helplessness 3.1 Norepinephrine 3.2 Gamma-Aminobutyric Acid 3.3 Endogenous Opiates 3.4 Transmitters, Neuromodulators, and Hormones 3.5 Corticotrophin Releasing Hormone (CRH) 3.6 Issues Omitted 3.7 What We Know 3.8 What We Don't Know 4. Learned Helplessness in People 4.1 Criteria of Learned Helplessness 4.2 Operationalizing Learned Helplessness in the Laboratory 4.3 A Meta-Analysis of Human Helplessness Studies 4.4 Other Aspects of Human Helplessness 4.5 The Generality of Learned Helplessness Among People 4.6 Cognition and Self-Report 4.7 Other Explanations 4.8 What We Know 5. The Attributional Reformulation 5.1 Historical Background: Attribution Theory and Theorizing 5.2 Causal Explanations and Locus of Control 5.3 The Reformulated Learned Helplessness Model 5.4 Assessing Explanatory Style 5.5 Empirical Studies of Explanatory Style 5.6 What We Know 5.7 What We Don't Know 6. Learned Helplessness and Depression 6.1 What Is Depression? 6.2 The Reformulation of the Learned Helplessness Model of Depression 6.3 Modernity and Depression 6.4 Controversies 6.5 What We Know 6.6 What We Don't Know 7. Learned Helplessness and Social Problems 7.1 Survey of Applications 7.2 What We Know 7.3 What We Don't Know 8. Learned Helplessness and Physical Health 8.1 Some Groundrules 8.2 Risk Factors for Illness 8.3 Mechanisms 8.4 Health and Illness in Animals Versus People 8.5 What We Know 8.6 What We Don't Know 9. Epilogue 9.1 A Brief History of Choices 9.2 The Importance of Control 9.3 Learned Helplessness as a Model of Scientific Dispute and Progress 9.5 Optimism Institutes
Martine M Mirrione - One of the best experts on this subject based on the ideXlab platform.
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whole brain mapping of neuronal activity in the Learned Helplessness model of depression
Frontiers in Neural Circuits, 2016Co-Authors: Fritz A Henn, Martine M Mirrione, Yongsoo Kim, Zinaida Perova, Kith PradhanAbstract:Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the Learned Helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing "helpless" behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing "resilient" behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that Helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.
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increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of Learned Helplessness behavior
Frontiers in Human Neuroscience, 2014Co-Authors: Fritz A Henn, Martine M Mirrione, Daniela Schulz, Kyle A B Lapidus, Sam Zhang, Wayne K GoodmanAbstract:Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive Learned Helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to Learned Helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.
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synaptic potentiation onto habenula neurons in the Learned Helplessness model of depression
Nature, 2011Co-Authors: Joaquin Piriz, Fritz A Henn, Martine M Mirrione, Chihye Chung, Christophe D Proulx, Daniela Schulz, Roberto MalinowAbstract:The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two Learned Helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's Helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce Learned Helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent Learned Helplessness model of depression.
Peter Gass - One of the best experts on this subject based on the ideXlab platform.
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Learned Helplessness unique features and translational value of a cognitive depression model
Cell and Tissue Research, 2013Co-Authors: Barbara Vollmayr, Peter GassAbstract:The concept of Learned Helplessness defines an escape or avoidance deficit after uncontrollable stress and is regarded as a depression-like coping deficit in aversive but avoidable situations. Based on a psychological construct, it ideally complements other stress-induced or genetic animal models for major depression. Because of excellent face, construct, and predictive validity, it has contributed to the elaboration of several pathophysiological concepts and has brought forward new treatment targets. Whereas Learned Helplessness can be modeled not only in a broad variety of mammals, but also in fish and Drosophila, we will focus here on the use of this model in rats and mice, which are today the most common species for preclinical in vivo research in psychiatry.
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Learned Helplessness validity and reliability of depressive like states in mice
Brain Research Protocols, 2005Co-Authors: Sabine Chourbaji, Christiane Zacher, Carles Sanchissegura, Christof Dormann, Barbara Vollmayr, Peter GassAbstract:The Learned Helplessness paradigm is a depression model in which animals are exposed to unpredictable and uncontrollable stress, e.g. electroshocks, and subsequently develop coping deficits for aversive but escapable situations (J.B. Overmier, M.E. Seligman, Effects of inescapable shock upon subsequent escape and avoidance responding, J. Comp. Physiol. Psychol. 63 (1967) 28-33 ). It represents a model with good similarity to the symptoms of depression, construct, and predictive validity in rats. Despite an increased need to investigate emotional, in particular depression-like behaviors in transgenic mice, so far only a few studies have been published using the Learned Helplessness paradigm. One reason may be the fact that-in contrast to rats (B. Vollmayr, F.A. Henn, Learned Helplessness in the rat: improvements in validity and reliability, Brain Res. Brain Res. Protoc. 8 (2001) 1-7)--there is no generally accepted Learned Helplessness protocol available for mice. This prompted us to develop a reliable Helplessness procedure in C57BL/6N mice, to exclude possible artifacts, and to establish a protocol, which yields a consistent fraction of helpless mice following the shock exposure. Furthermore, we validated this protocol pharmacologically using the tricyclic antidepressant imipramine. Here, we present a mouse model with good face and predictive validity that can be used for transgenic, behavioral, and pharmacological studies.
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social and structural housing conditions influence the development of a depressive like phenotype in the Learned Helplessness paradigm in male mice
Behavioural Brain Research, 2005Co-Authors: Sabine Chourbaji, Christiane Zacher, Carles Sanchissegura, Rainer Spanagel, Peter GassAbstract:Abstract Structural and social factors are known to play a crucial role in the pathogenesis of depression. Since animal models of depression are a major tool to gain insights into the mechanisms involved in the pathophysiology of this disease it is important not only to exploit but also to be aware of factors that may affect these models. As housing represents a fundamental external factor, which is controversially debated to affect the animals’ emotionality, this study aimed to investigate the impact of different social and structural housing conditions on the development of a depressive-like syndrome in the Learned Helplessness paradigm. Group housing in an impoverished environment led to an increased vulnerability in the Learned Helplessness paradigm. Groups that were housed enriched, however, were less helpless. Furthermore impoverished conditions did not increase the vulnerability in single housed animals. Regarding emotionality in the animals, basal anxiety was reduced and the exploration was enhanced by group housing and enriched environment. These results suggest that housing conditions significantly influence the outcome of Learned Helplessness studies.
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rats with congenital Learned Helplessness respond less to sucrose but show no deficits in activity or learning
Behavioural Brain Research, 2004Co-Authors: Barbara Vollmayr, Peter Gass, Rainer Spanagel, Daniel Bachteler, Valentina Vengeliene, Fritz A HennAbstract:Inbred rat strains for congenital Learned Helplessness (cLH) and for congenital resistance to Learned Helplessness (cNLH) were investigated as a model to study genetic predisposition to major depression. Congenitally helpless rats respond less to sucrose under a progressive ratio schedule. This is not confounded by locomotor hypoactivity: in contrast, cLH rats show a slight hyperactivity during the first 5 min of an open field test. cLH rats acquire operant responding to sucrose as readily as cNLH rats and exhibit normal memory acquisition and retrieval in the Morris water maze, thus ruling out general learning deficits as the cause of the decreased response to sucrose. Reduced total responses and reduced breaking points for sucrose in the cLH strain argue for anhedonia, which is an analogue to loss of pleasure essential for the diagnosis of major depressive episodes, and thus confirm the validity of congenitally Learned helpless rats as a model of major depression.
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reduced cell proliferation in the dentate gyrusis not correlated with the development of Learned Helplessness
Biological Psychiatry, 2003Co-Authors: Barbara Vollmayr, Peter Gass, Claudia Simonis, Silja Weber, Fritz A HennAbstract:Abstract Background A plethora of indirect findings suggests that mood disorders may be caused by or result in structural changes in the brain, namely decreased hippocampal cell proliferation. Methods To test for these hypotheses, we used a rat model of depression, Learned Helplessness. Moderate unpredictable and inescapable foot shocks induced Learned Helplessness only in a portion of the rats. Rats that showed helpless behavior were compared to those behaving normally after inescapable shock. Proliferating cells in the dentate gyrus were labeled with BrdU (bromodeoxyuridine). Results Helpless behavior appeared before the decrease of dentate gyrus cell proliferation was maximal. Cell proliferation was decreased to the same extent in animals that developed Helplessness as those that were not helpless. Furthermore, immobilization stress, which reduced the rate of cell proliferation, did not induce Learned Helplessness. Conclusion These results are in line with reports that the rate of dentate gyrus cell proliferation is acutely down-regulated by stress, but the development of helpless behavior does not correlate with this process. Further studies will have to clarify if during Learned helpless behavior neurogenesis is impaired by altered differentiation or survival of cells.
Monika Fleshner - One of the best experts on this subject based on the ideXlab platform.
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early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on Learned Helplessness behaviours and alter gene expression within neural circuits important for stress resistance
European Journal of Neuroscience, 2017Co-Authors: Agnieszka Mika, Benjamin N Greenwood, Heidi E W Day, Alexander Martinez, Nicole L Rumian, Maciej Chichlowski, Brian Berg, Monika FleshnerAbstract:Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health-promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce Learned Helplessness behaviours such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioural and biological responses to stress later in life. Juvenile, male F344 rats were fed diets containing either GOS and PDX alone, LAC alone, or GOS, PDX and LAC. All diets altered gut bacteria, while diets containing GOS and PDX increased Lactobacillus spp. After 4 weeks, rats were exposed to inescapable stress, and either immediately killed for blood and tissues, or assessed for Learned Helplessness 24 h later. Diets did not attenuate stress effects on spleen weight, corticosterone and blood glucose; however, all diets differentially attenuated stress-induced Learned Helplessness. Notably, in situ hybridization revealed that all diets reduced stress-evoked cfos mRNA in the dorsal raphe nucleus (DRN), a structure important for Learned Helplessness behaviours. In addition, GOS, PDX and LAC diet attenuated stress-evoked decreases in mRNA for the 5-HT1A autoreceptor in the DRN and increased basal BDNF mRNA within the prefrontal cortex. These data suggest early life diets containing prebiotics and/or LAC promote behavioural stress resistance and uniquely modulate gene expression in corresponding circuits.
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exercise Learned Helplessness and the stress resistant brain
Neuromolecular Medicine, 2008Co-Authors: Benjamin N Greenwood, Monika FleshnerAbstract:Exercise can prevent the development of stress-related mood disorders, such as depression and anxiety. The underlying neurobiological mechanisms of this effect, however, remain unknown. Recently, researchers have used animal models to begin to elucidate the potential mechanisms underlying the protective effects of physical activity. Using the behavioral consequences of uncontrollable stress or “Learned Helplessness” as an animal analog of depression- and anxiety-like behaviors in rats, we are investigating factors that could be important for the antidepressant and anxiolytic properties of exercise (i.e., wheel running). The current review focuses on the following: (1) the effect of exercise on the behavioral consequences of uncontrollable stress and the implications of these effects on the specificity of the “Learned Helplessness” animal model; (2) the neurocircuitry of Learned Helplessness and the role of serotonin; and (3) exercise-associated neural adaptations and neural plasticity that may contribute to the stress-resistant brain. Identifying the mechanisms by which exercise prevents Learned Helplessness could shed light on the complex neurobiology of depression and anxiety and potentially lead to novel strategies for the prevention of stress-related mood disorders.
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freewheel running prevents Learned Helplessness behavioral depression role of dorsal raphe serotonergic neurons
The Journal of Neuroscience, 2003Co-Authors: Benjamin N Greenwood, Steven F. Maier, Teresa E Foley, Heidi E W Day, Jay Campisi, Sayamwong H Hammack, Serge Campeau, Monika FleshnerAbstract:Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are implicated in mediating Learned Helplessness (LH) behaviors, such as poor escape responding and expression of exaggerated conditioned fear, induced by acute exposure to uncontrollable stress. DRN 5-HT neurons are hyperactive during uncontrollable stress, resulting in desensitization of 5-HT type 1A (5-HT1A) inhibitory autoreceptors in the DRN. 5-HT1A autoreceptor downregulation is thought to induce transient sensitization of DRN 5-HT neurons, resulting in excessive 5-HT activity in brain areas that control the expression of Learned Helplessness behaviors. Habitual physical activity has antidepressant/anxiolytic properties and results in dramatic alterations in physiological stress responses, but the neurochemical mediators of these effects are unknown. The current study determined the effects of 6 weeks of voluntary freewheel running on LH behaviors, uncontrollable stress-induced activity of DRN 5-HT neurons, and basal expression of DRN 5-HT1A autoreceptor mRNA. Freewheel running prevented the shuttle box escape deficit and the exaggerated conditioned fear that is induced by uncontrollable tail shock in sedentary rats. Furthermore, double c-Fos/5-HT immunohistochemistry revealed that physical activity attenuated tail shock-induced activity of 5-HT neurons in the rostral–mid DRN. Six weeks of freewheel running also resulted in a basal increase in 5-HT1A inhibitory autoreceptor mRNA in the rostral–mid DRN. Results suggest that freewheel running prevents behavioral depression/LH and attenuates DRN 5-HT neural activity during uncontrollable stress. An increase in 5-HT1A inhibitory autoreceptor expression may contribute to the attenuation of DRN 5-HT activity and the prevention of LH in physically active rats.