Learned Helplessness Paradigm Research Articles

Learned Helplessness As a Potential Transdiagnostic Therapeutic Mechanism of Classic Psychedelics

Background: Emerging literature suggests that classic psychedelics may have efficacy in treating mood and substance use disorders in humans. This has raised questions regarding the primary therapeutic mechanism of these compounds. Here, we hypothesize that the reversal of and resilience against learned helplessness may be an important driver of the therapeutic mechanisms of classic psychedelics. Furthermore, we argue that the learned helplessness paradigm can provide a robust model to investigate the behavioral and mechanistic effects of classic psychedelics in both clinical and preclinical experiments. Opinion: We highlight the learned helplessness model and its potential utility in the psychedelic sphere for several reasons. First, learned helplessness is a robust phenomenon observed across multiple mammalian species including humans, and has been well described in terms of its neurobiology, behavioral effects, and clinical implications; current efforts in psychedelic research and theories of psychedelic mechanisms have yet to achieve this level of integration. Interestingly, there is substantial overlap in the neural circuits governing resilience against learned helplessness and psychedelic actions—such as those involving the dorsal raphe nucleus. Furthermore, our hypothesis that classic psychedelics can reverse helplessness behavior fits with much of the current preclinical data, which has shown that psychedelics improve performance in behavioral despair tasks in rodents. Here we make the case for bringing attention to these congruencies in an effort to advance toward mechanistic, behavioral, and transdiagnostic insights into the therapeutic effects of classic psychedelics, with the potential for learned helplessness to help explain some positive effects across levels of analysis.

Stress promotes the infiltration of peripheral immune cells to the brain

Immune cells and the brain have a privileged interaction. Here, we report changes in the hippocampal immune microenvironment at the single cell level after stress, uncovering the tight orchestration of immune cell infiltration into the hippocampus after stress to maintain homeostasis. We show the distribution of several immune cell types in the hippocampus associated with their susceptibility or resilience to the learned helplessness paradigm in a sex- and microbiota-dependent manner using single-cell RNA sequencing and bioinformatic tools, flow cytometry, and immunofluorescence. We uncovered the presence of tissue-resident memory T cells that accumulate over time in the hippocampus of learned helpless mice, and the presence of CD74-expressing myeloid cells. These cells were found by a knockdown approach to be critical to induce resilience to learned helplessness. Altogether, these findings provide a novel overview of the neuro-immune repertoire and its impact on the landscape of the hippocampus after learned helplessness.

Serious Games Based on Cognitive Bias Modification and Learned Helplessness Paradigms for the Treatment of Depression: Design and Acceptability Study

Depression is a debilitating mental health disorder, with a large treatment gap. Recent years have seen a surge in digital interventions to bridge this treatment gap. Most of these interventions are based on computerized cognitive behavioral therapy. Despite the efficacy of computerized cognitive behavioral therapy-based interventions, their uptake is low and dropout rates are high. Cognitive bias modification (CBM) paradigms provide a complementary approach to digital interventions for depression. However, interventions based on CBM paradigms have been reported to be repetitive and boring. In this paper, we described the conceptualization, design, and acceptability of serious games based on CBM paradigms and the learned helplessness paradigm. We searched the literature for CBM paradigms that were shown to be effective in reducing depressive symptoms. For each of the CBM paradigms, we ideated how to create a game so that the gameplay was engaging while the active therapeutic component remained unchanged. We developed 5 serious games based on the CBM paradigms and the learned helplessness paradigm. The games include various core elements of gamification, such as goals, challenges, feedback, rewards, progress, and fun. Overall, the games received positive acceptability ratings from 15 users. These games may help improve the effectiveness and engagement levels of computerized interventions for depression.

Abnormal compositions of gut microbiota and metabolites are associated with susceptibility versus resilience in rats to inescapable electric stress

BackgroundIncreasing evidence suggests the role of gut microbiota in resilience versus vulnerability after stress. However, the role of gut microbiota and microbiome-derived metabolites in resilience versus susceptibility in rodents exposed to stress remains unclear. MethodsAdult male rats were exposed to inescapable electric stress under the learned helplessness (LH) paradigm. The composition of gut microbiota and metabolites in the brain and blood from control (no stress) rats, LH resilient rats, and LH susceptible rats were examined. ResultsAt the genus level, the relative abundances of Asaccharobacter, Eisenbergiella, and Klebsiella in LH susceptible rats were significantly higher than that of LH resilient rats. At the species level, the relative abundances of several microbiome were significantly altered between LH susceptible rats and LH resilient rats. Furthermore, there were several metabolites in the brain and blood altered between LH susceptible rats and LH resilient rats. A network analysis showed correlations between the abundance of several microbiome and metabolites in the brain (or blood). LimitationsDetailed roles of microbiome and metabolites are unclear. ConclusionsThese findings suggest that abnormal compositions of the gut microbiota and metabolites might contribute to susceptibility versus resilience in rats subjected to inescapable electric foot shock.

Prolactin-Releasing Peptide Contributes to Stress-Related Mood Disorders and Inhibits Sleep/Mood Regulatory Melanin-Concentrating Hormone Neurons in Rats.

Stress disorders impair sleep and quality of life; however, their pathomechanisms are unknown. Prolactin-releasing peptide (PrRP) is a stress mediator; we therefore hypothesized that PrRP may be involved in the development of stress disorders. PrRP is produced by the medullary A1/A2 noradrenaline (NA) cells, which transmit stress signals to forebrain centers, and by non-NA cells in the hypothalamic dorsomedial nucleus. We found in male rats that both PrRP and PrRP-NA cells innervate melanin-concentrating hormone (MCH) producing neurons in the dorsolateral hypothalamus (DLH). These cells serve as a key hub for regulating sleep and affective states. Ex vivo, PrRP hyperpolarized MCH neurons and further increased the hyperpolarization caused by NA. Following sleep deprivation, intracerebroventricular PrRP injection reduced the number of REM sleep-active MCH cells. PrRP expression in the dorsomedial nucleus was upregulated by sleep deprivation, while downregulated by REM sleep rebound. Both in learned helplessness paradigm and after peripheral inflammation, impaired coping with sustained stress was associated with (1) overactivation of PrRP cells, (2) PrRP protein and receptor depletion in the DLH, and (3) dysregulation of MCH expression. Exposure to stress in the PrRP-insensitive period led to increased passive coping with stress. Normal PrRP signaling, therefore, seems to protect animals against stress-related disorders. PrRP signaling in the DLH is an important component of the PrRP's action, which may be mediated by MCH neurons. Moreover, PrRP receptors were downregulated in the DLH of human suicidal victims. As stress-related mental disorders are the leading cause of suicide, our findings may have particular translational relevance.SIGNIFICANCE STATEMENT Treatment resistance to monoaminergic antidepressants is a major problem. Neuropeptides that modulate the central monoaminergic signaling are promising targets for developing alternative therapeutic strategies. We found that stress-responsive prolactin-releasing peptide (PrRP) cells innervated melanin-concentrating hormone (MCH) neurons that are crucial in the regulation of sleep and mood. PrRP inhibited MCH cell activity and enhanced the inhibitory effect evoked by noradrenaline, a classic monoamine, on MCH neurons. We observed that impaired PrRP signaling led to failure in coping with chronic/repeated stress and was associated with altered MCH expression. We found alterations of the PrRP system also in suicidal human subjects. PrRP dysfunction may underlie stress disorders, and fine-tuning MCH activity by PrRP may be an important part of the mechanism.

Outcome unpredictability affects outcome-specific motivation to learn

Outcome predictability effects in associative learning paradigms describe better learning about outcomes with a history of greater predictability in a similar but unrelated task compared with outcomes with a history of unpredictability. Inspired by the similarities between this phenomenon and the effect of uncontrollability in learned helplessness paradigms, here, we investigate whether learning about unpredictability decreases outcome-specific motivation to learn. We used a modified version of the allergy task, in which participants first observe the foods eaten by a fictitious patient, followed by allergic reactions that he subsequently suffers, some of which are perfectly predictable and others unpredictable. We then implemented an active learning method in a second task in which participants could only learn about either the previously predictable or unpredictable outcomes on each trial. At the beginning of each trial, participants had to decide whether they wanted to learn about one outcome category or the other. Participants at the beginning of the second task chose to learn about the previously predictable outcomes first and to learn about the previously unpredictable outcomes in later trials. This showed that unpredictability affects future motivation to learn in other circumstances. Interestingly, we did not find any sign of outcome predictability effect at the end of the second phase, suggesting that participants compensate for biased outcome sampling when making overt choices in ways that they may not when learning about both outcome categories simultaneously.

Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity and neuromodulatory signaling in distributed networks, modifying behavior. Here we describe changes in dopaminergic neuron activity and signaling following aversive learning in a learned helplessness paradigm in mice. A single dose of ketamine suffices to restore escape behavior after aversive learning. Dopaminergic neuron activity in the ventral tegmental area (VTA) systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of dopamine signaling. Rather than directly altering the activity of dopaminergic neurons, ketamine appears to rescue dopamine dynamics through actions in the medial prefrontal cortex (mPFC). Chemogenetic activation of Drd1 receptor positive mPFC neurons mimics ketamine's effects on behavior. Together, our data link neuromodulatory dynamics in mPFC-VTA circuits, aversive learning, and the effects of ketamine.

Computing the Uncontrollable: Insights from Computational Modelling of Learning and Choice in Depression

The learned helplessness (LH) paradigm, developed in experimental animals, has had great influence on the development of models of mood and anxiety disorders. However, the insights from this paradigm have not always translated straightforwardly into human experimental work. In particular, instrumental contingency learning experiments yielded the contradictory finding of more accurate contingency knowledge in depressed individuals (“depressive realism”: DR). A growing literature involving the application of computational modelling applied to human learning studies suggest that possible sequelae of LH in humans may be manifest in one or more potential candidate reinforcement learning-based mechanisms. This analysis suggests that the DR effect is theoretically and empirically independent of LH, despite both LH and DR being related to depression. Overall, the review highlights recent developments within the complex literature of learning and choice in depression and proposes a variety of testable predictions which may serve to delineate more precisely the presence, and neural basis, of LH-like sequelae across social and non-social learning and choice paradigms in depressed patients.

Assessing the relationship between the human learned helplessness depression model and anhedonia.

The learned helplessness (LH) model is one of the most commonly used acute stress models to explain depression and it has shown good face and predictive validity. However, despite being able to induce depressed-like behaviors and corresponding psychophysiological changes, there is little evidence showing that the LH paradigm can produce anhedonia, a core symptom seen in all forms of depression in humans. So far a couple of studies showed that rodents bred for helplessness develop anhedonic-like behaviors in response to stress; yet, to the best of our knowledge, no similar human research has tried to investigate the direct relationship between the LH model and anhedonia. In the present study, we use a modified version of the original LH task to experimentally and temporarily induce learned helplessness in college students and then examine if the human LH paradigm induces anhedonia. We aim to 1: address the ill-defined connection between the LH model and anhedonia, and 2: directly assess helplessness in humans as opposed to the majority of non-human animal subjects used in the helplessness literature. We believe that our study will fill an important gap in the learned helplessness model literature, and will advance our understanding of the relationship between depression and perceived control, as well as place limitations to what can and cannot be inferred from non-human animal data in this topic.

Stress Resilience is Associated with Hippocampal Synaptoprotection in the Female Rat Learned Helplessness Paradigm

The synaptogenic hypothesis of major depressive disorder implies that preventing the onset of depressive-like behavior also prevents the loss of hippocampal spine synapses. By applying the psychoactive drugs, diazepam and fluoxetine, we investigated whether blocking the development of helpless behavior by promoting stress resilience in the rat learned helplessness paradigm is associated with a synaptoprotective action in the hippocampus. Adult ovariectomized and intact female Sprague-Dawley rats (n = 297) were treated with either diazepam, fluoxetine, or vehicle, exposed to inescapable footshocks or sham stress, and tested in an active escape task to assess helpless behavior. Escape-evoked corticosterone secretion, as well as remodeling of hippocampal spine synapses at a timepoint representing the onset of escape testing were also analyzed. In ovariectomized females, treatment with diazepam prior to stress exposure prevented helpless behavior, blocked the loss of hippocampal spine synapses, and muted the corticosterone surge evoked by escape testing. Although fluoxetine stimulated escape performance and hippocampal synaptogenesis under non-stressed conditions, almost all responses to fluoxetine were abolished following exposure to inescapable stress. Only a much higher dose of fluoxetine was capable of partly reproducing the strong protective actions of diazepam. Importantly, these protective actions were retained in the presence of ovarian hormones. Our findings indicate that stress resilience is associated with the preservation of spine synapses in the hippocampus, raising the possibility that, besides synaptogenesis, hippocampal synaptoprotection is also implicated in antidepressant therapy.

Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms

BackgroundKetamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity. MethodsHere, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes. ResultsWe found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gαs-coupled cascades in the medial prefrontal cortex. ConclusionsOur findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats.

It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω -propyl-l-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.

Anti-inflammatory IL-10 administration rescues depression-associated learning and memory deficits in mice

BackgroundMajor depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning and memory processes, suggesting that an anti-inflammatory approach might be beneficial for both depression and cognition.MethodsWe subjected mice to the learned helplessness paradigm and evaluated novel object recognition and spatial memory. Mice were treated with IL-10 intranasally or/and microglia cells were depleted using PLX5622. Statistical differences were tested using ANOVA or t tests.ResultsWe first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impairs novel object recognition (NOR) and spatial working memory. LH mice also exhibit reduced hippocampal dendritic spine density and increased microglial activation compared to non-shocked (NS) mice or mice that were subjected to the learned helpless paradigm but did not exhibit learned helplessness (non-learned helpless or NLH). These effects are mediated by microglia, as treatment with PLX5622, which depletes microglia, restores learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impairs learning and memory and reduces hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice produce molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels are reduced in LH mice, and IL-10 administration is sufficient to restore NOR, spatial working memory, and hippocampal dendritic spine density in LH mice, and in NLH mice treated with PLX5622 consistent with a pro-cognitive role for IL-10.ConclusionsAltogether these data demonstrate the critical role of IL-10 in promoting learning and memory after learned helplessness.

Antidepressant effects of 3-(3,4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide involve TSPO-mediated mitophagy signalling pathway.

Piper laetispicum C. DC is one of the Chinese herbal medicines used for alleviating depressive disorders. G11-5 [3-(3, 4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide] is synthesized based on the chemical structure of an activeintegrant of Piper laetispicum C. DC. The present study assessed the antidepressant effect of G11-5 and investigated the underlying mechanism with learned helplessness (LH) and social defeat stress (SDS) mice model of depression. In the LH model, mice were exposed to 60 inescapable electric shocks once a day for three consecutive days followed by 2-week drug administration and helpless behaviour assessment. In the SDS model, mice were subjected to repeated social defeat by an aggressive CD-1 mouse once a day for consecutive 10days. Following oral administration for 2weeks, the mice were subjected to a series of behavioural tests including social interaction test. G11-5 significantly decreased the number of escape failures induced by LH paradigm, meanwhile increased the social interaction ratio and shortened the immobility time in forced swimming test for the SDS-exposed mice, suggesting remarkable antidepressant effect. Moreover, G11-5 ameliorated the changes in mitophagy-related proteins induced by two stress exposures and restored retrograde axonal transport and neurotransmitter release. Our findings suggested that G11-5 exhibited an obvious antidepressant through TSPO-mediated mitophagy pathway.

Preconditioning by Moderate Hypoxia Increases the Amount of Corticosteroid Receptors in the Rat Brain in a Model of Depression

Abstract—The involvement of corticosteroid brain receptors in the antidepressant-like effects of moderate hypobaric hypoxia was studied in a rat model of depression (the learned helplessness paradigm) using immunohistochemistry. The formation of a depressive-like state is accompanied by a significant deficiency in glucocorticoid receptors in the brain which is most pronounced in the dentate gyrus of the hippocampus, as well as by a considerable shift in the relative balance between gluco- and mineralocorticoid receptors towards the latter. The use of hypoxic preconditioning prior to stress exposure in the learned helplessness paradigm prevented the development of depression and eliminated receptor deficiency by post-stress day 10 in the hypothalamus and during the first day of the observation in the neocortex. In the hippocampus of preconditioned animals, stress adaptation was accompanied by an acute and consistent increase in glucocorticoid receptor immunoreactivity, with a relative balance of the two receptor types in the CA1 field, and considerable glucocorticoid receptor prevalence in the dentate gyrus. It may be assumed that deficiency and imbalance of hippocampal corticosteroid receptors is one of the most important molecular mechanisms of glucocorticoid regulation dysfunction in stress-induced psychopathologies, whereas the post-stress activation of receptor expression contributes to the manifestation of the antidepressant-like effects of moderate hypoxia. The data obtained expand the current views on the endocrine mechanisms of the formation and prevention of depressive disorders and increase the translation potential of moderate hypoxia as a drug-free strategy for their treatment.

Allopregnanolone induces antidepressant-like effects through BDNF-TrkB signaling independent from AMPA receptor activation in a rat learned helplessness model of depression

Allopregnanolone (ALLO, 3α5α-tetrahydroprogesterone) was found to be effective for depressed patients. Animal models of depression indicate that ALLO is associated with the pathophysiology of depression. Traditional antidepressant drugs produce antidepressant effects via the monoamine system, with consequent up-regulation of brain-derived neurotrophic factor (BDNF). This study was designed to examine whether the antidepressant effects of ALLO involve BDNF-TrkB signaling or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation on the learned helplessness paradigm. The antidepressant-like effect of ALLO infusion into the cerebral ventricle was blocked by coinfusion of TrkB inhibitor ANA-12, but not by co-administration of AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX). Thus, the antidepressant-like effect of ALLO involves BDNF signaling independent from AMPA receptor activation.

Prelimbic medial prefrontal cortex disruption during adolescence increases susceptibility to helpless behavior in adult rats

Major depressive disorder (MDD) is a disabling mental disorder worldwide. Several animal models have been used to study the neurobiology of this disorder, including the learned helplessness (LH) paradigm, in which susceptible animals show helpless behavior indicated by fails to escape a controllable footshock. This behavior has been associated with a downregulation of ventral tegmental area (VTA) dopamine (DA) system activity. The prelimbic portion of the prefrontal cortex (plPFC) plays an important role in the modulation of helpless behavior, but so far there is no evidence indicating that its developmental disruption alters susceptibility to helpless behavior. We investigated the impact of plPFC lesion performed at adolescence (postnatal day 31–33) or adulthood (postnatal day 70–72) on anxiety responses (elevated plus-maze), susceptibility to helpless behavior, and the VTA DA system activity in adult Sprague-Dawley rats. Whereas adult plPFC lesions induced neither anxiety responses nor increased susceptibility to helpless behavior (plPFC lesion: 33.3% of helplessness; controls: 30.8% of helplessness rats), adolescent plPFC lesions induced anxiety responses and increased the proportion of rats showing helpless at adulthood (plPFC lesion: 92.3% helplessness; controls: 42.1% helplessness rats). Moreover, only helpless rats in the groups showed a decreased VTA DA system population activity that was confined to the medial portion of the VTA. These findings suggest that the impairment of plPFC activity during adolescence occurs during a critical window for the development of helpless behavior in adult rats, indicating that predisposition or early life adverse events that impair plPFC activity may enhance susceptibility to depression in adulthood.

Noradrenergic System Variability in Resilience Against Stress

While stress can precipitate the onset of psychiatric disorders in some individuals, others escape these conditions, an ability defined as resilience. In the chronic social defeat stress model (CSDS), the locus coeruleus-noradrenergic (LC-NE) system appears essential for resilience via its downstream inhibition of dopaminergic neurons. However, its contribution in resilience against different stress modalities is unclear. Our objective is to define how resilience is dependent upon the noradrenergic system in the learned helplessness (LH) paradigm, based on the avoidance of a previously inescapable footshock.

Antidepressant-like action of hypoxic postconditioning is accompanied by the up-regulation of hippocampal HIF-1α and erythropoietin

Objective. The aim of the study was to reveal the role of HIF-1 in the effects of hypoxic postconditioning in the rat experimental model of depression learned helplessness.
 Materials and methods. The studies were performed in the learned helplessness paradigm which represents a reliable experimental model of depression in rats. The development of the pathology was evaluated in the behavioral open field test and by the baseline level of plasma corticosterone. Correction of behavioral deficit was performed by three episodes of hypoxic postconditioning (360 mmHg, 2 h). Changes in the immunopositivity of HIF-1 and erythropoietin in the hippocampus of rats were evaluated. An inhibitor of HIF-1 subunit translation topotecan (1 mg/kg, i.p., Santa Cruz, USA) was used on the 4th day after the footshock stress. On the 9th day, animals were tested in the open field test to assess the level of depressive-like behavior.
 Results. It was shown that postconditioning by three episodes of mild hypobaric hypoxia resulted in the correction of behavioral deficit produced by the learned helplessness aversive stress, and the levels of corticosterone did not differ from the baseline in these animals. These behavioral and hormonal effects were accompanied by the increased level of immunopositive HIF-1 and its transcriptional downstream target erythropoietin in the dorsal and ventral hippocampus. Using of HIF-1 inhibitor topotecan dramatically worsen the severity of the depressive-like symptoms.
 Conclusion. The findings suggest that HIF-1 appears to have the antidepressant-like activities and that hypoxic postconditioning-induced stimulation of HIF-1 and erythropoietin level might contribute to the endogenous mechanisms which compensate for the pathogenic effects of stressors, particularly for the development of stress-induced depression.

Monoaminergic balances predict non-depression-like phenotype in Learned Helplessness Paradigm

Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. Here, we measured the levels of monoamines, including noradrenaline (NA), serotonin (5-HT), and dopamine (DA), and their metabolites in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), hippocampus, nucleus accumbens (NAc), amygdala, and striatum in LH, non-LH, and non-manipulated (naïve) rats. Compared with LH rats, non-LH rats showed lower 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and NA turnovers in the amygdala and higher 5-HT levels in the NAc. Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.