Induction Of Learned Helplessness Research Articles

The Effect of Sericin on the Cognitive Impairment, Depression, and Anxiety Caused by Learned Helplessness in Male Mice.

Learned helplessness (LH) induces cognitive and emotional abnormalities via alteration of synaptic and apoptotic markers in the hippocampus. Given the sericin's neuroprotective effects on different experimental models, this study aimed to address whether sericin is able to reduce LH-induced behavioral and molecular changes in the mouse model. Sixty male mice (3months old) were randomly divided into control, normal saline (NS), and/or different doses of sericin (Ser [100, 200, and 300mg/kg]) for 21days. Accordingly, the animals in NS and sericin-treated groups were subjected to 1day learned helplessness protocol. Behavioral deficits were evaluated and alterations in both synaptic and apoptotic factors were evaluated in the hippocampus. Induction of LH was associated with behavioral changes (depression and cognitive impairment). On the other hand, the administration of sericin effectively normalized these deficits. At molecular levels, sericin increased the levels of synaptophysin, synapsin-1, and PSD-95, and decreased apoptosis in the hippocampus. Although the exactmechanismsunderlying the neuroprotective effects of sericin are not fully understood, our results showed that this effect mediated via modulation of the synaptic and apoptotic proteins in the hippocampus of LH-subjected mice.

TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice

Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness.

Profiling and Co-expression Network Analysis of Learned Helplessness Regulated mRNAs and lncRNAs in the Mouse Hippocampus.

Although studies provide insights into the neurobiology of stress and depression, the exact molecular mechanisms underlying their pathologies remain largely unknown. Long non-coding RNA (lncRNA) has been implicated in brain functions and behavior. A potential link between lncRNA and psychiatric disorders has been proposed. However, it remains undetermined whether IncRNA regulation, in the brain, contributes to stress or depression pathologies. In this study, we used a valid animal model of depression-like symptoms; namely learned helplessness, RNA-seq, Gene Ontology and co-expression network analyses to profile the expression pattern of lncRNA and mRNA in the hippocampus of mice. We identified 6346 differentially expressed transcripts. Among them, 340 lncRNAs and 3559 protein coding mRNAs were differentially expressed in helpless mice in comparison with control and/or non-helpless mice (inescapable stress resilient mice). Gene Ontology and pathway enrichment analyses indicated that induction of helplessness altered expression of mRNAs enriched in fundamental biological functions implicated in stress/depression neurobiology such as synaptic, metabolic, cell survival and proliferation, developmental and chromatin modification functions. To explore the possible regulatory roles of the altered lncRNAs, we constructed co-expression networks composed of the lncRNAs and mRNAs. Among our differentially expressed lncRNAs, 17% showed significant correlation with genes. Functional co-expression analysis linked the identified lncRNAs to several cellular mechanisms implicated in stress/depression neurobiology. Importantly, 57% of the identified regulatory lncRNAs significantly correlated with 18 different synapse-related functions. Thus, the current study identifies for the first time distinct groups of lncRNAs regulated by induction of learned helplessness in the mouse brain. Our results suggest that lncRNA-directed regulatory mechanisms might contribute to stress-induced pathologies; in particular, to inescapable stress-induced synaptic modifications.

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition

An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803-mts was sufficient to up-regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non-depressed) and those that were susceptible (depressed). Non-depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression-like behavior.

Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons.

Animal models have been developed to investigate aspects of stress, anxiety, and depression, but our understanding of the circuitry underlying these models remains incomplete. Prior studies of the habenula, a poorly understood nucleus in the dorsal diencephalon, suggest that projections to the medial habenula (MHb) regulate fear and anxiety responses, whereas the lateral habenula (LHb) is involved in the expression of learned helplessness, a model of depression. Tissue-specific deletion of the transcription factor Pou4f1 in the dorsal MHb (dMHb) results in a developmental lesion of this subnucleus. These dMHb-ablated mice show deficits in voluntary exercise, a possible correlate of depression. Here we explore the role of the dMHb in mood-related behaviors and intrinsic reinforcement. Lesions of the dMHb do not elicit changes in contextual conditioned fear. However, dMHb-lesioned mice exhibit shorter immobility time in the tail suspension test, another model of depression. dMHb-lesioned mice also display increased vulnerability to the induction of learned helplessness. However, this effect is not due specifically to the dMHb lesion, but appears to result from Pou4f1 haploinsufficiency elsewhere in the nervous system. Pou4f1 haploinsufficiency does not produce the other phenotypes associated with dMHb lesions. Using optogenetic intracranial self-stimulation, intrinsic reinforcement by the dMHb can be mapped to a specific population of neurokinin-expressing habenula neurons. Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway.

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6–12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1–3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.

Valproic acid improves the tolerance for the stress in learned helplessness rats

In this study, we investigated whether previously stressed rats with learned helplessness (LH) paradigm could recover from depressive-like behavior four weeks after the exposure, and also whether chronic treatment with valproic acid (VPA) could prevent behavioral despair due to the second stress on days 54 in these animals.Four weeks after induction of LH, we confirmed behavioral remission in the previously stressed rats. Two-way analysis of variance (ANOVA) performed with two factors, pretreatment (LH or Control) and drug (VPA or Saline), revealed a significant main effect of the drug on immobility time in forced swimming test. Post hoc test showed a shorter immobility time in the LH+VPA group than in the LH+Saline group. Immunohistochemical study of synapsin I showed a significant effect of drug by pretreatment interaction on immunoreactivity of synapsin I in the hippocampus: its expression levels in the regions were higher in the LH+VPA group than in the LH+Saline group.These results suggest that VPA could prevent the reappearance of stress-induced depressive-like behaviors in the rats recovering from prior stress, and that the drug-induced presynaptic changes in the expression of synapsin I in the hippocampus of LH animals might be related to improved tolerance toward the stress.

Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants

The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression-the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm-as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.

Learned helplessness in children and adolescents with juvenile rheumatic disease

Objective To examine a learned helplessness conceptualization of psychological sequela in children and adolescents with juvenile rheumatic diseases (JRD) via an experimental procedure utilizing behavior–outcome contingent and noncontingent feedback. Methods Thirty-eight children and adolescents with JRD completed measures of transient affect, self-efficacy for functional ability, and causal attributions prior to and immediately following a computerized learned helplessness induction procedure. Results Children across contingent and noncontingent feedback conditions experienced decreased positive affect with a slightly more pronounced decline in the noncontingent condition. Noncontingent feedback resulted in poorer internalization of success for problem solving, while contingent feedback resulted in greater internalization of success for problem solving. Additionally, posttreatment control self-efficacy was significantly greater for children in the contingent condition that initially endorsed higher levels of internal task attributions. Conclusions Children with JRD who experience behavior–outcome contingency in their environment may develop increased perceptions of control over functional ability. Furthermore, environmental noncontingency may result in poorer internalization of success, whereas contingent reinforcement may enhance cognitive appraisal mechanisms (i.e., causal attributions) associated with favorable disease outcome. Despite a modest decline in positive affect for children in the noncontingent condition, mood dysfunction is not entirely explicable within the context of noncontingent reinforcement.

Motivational consequences of environmental stress

Exposure to uncontrollable stimuli produces deficits in task performance linked to learned helplessness. It is not widely appreciated, however, that many of these stimuli are environmental stressors. Both acute and chronic exposure to noise, crowding, traffic congestion, and pollution are capable of causing learned helplessness in adults and children. Pre-exposure to brief, acute environmental stressors that are uncontrollable produces learned helplessness wherein participants manifest difficulties in learning a new task because of their mistaken belief that they are incapable of influencing their environment. Another index of learned helplessness, less persistence in the face of challenge also follows acute exposure to uncontrollable environmental stressors. Finally depressed affect may co-occur with learned helplessness under certain circumstances. Field studies of chronic environmental stressors reveal parallel trends. Chronic environmental stressors also heighten vulnerability to the induction of learned helplessness by acute, uncontrollable stimuli. The potential pathway linking chronic environmental stressor exposure to helplessness and then, in turn, to mental health is an important area for future research. Furthermore, the generalizability of environmental stressor-induced motivational deficits, as well as their longevity, particularly among children, remains to be investigated.

Learned Helplessness, Therapy, and Personality Traits: An Experimental Study

The authors investigated 3 aspects of the learned helplessness (LH) phenomenon: the induction of helplessness in humans by a new instrumental task, the effects of a therapy technique that relies on direct retroactive reevaluation of the helplessness experience, and the role of personality characteristics in both helplessness induction and therapy. The sample consisted of 92 Turkish Boĝaziçi University undergraduates, 42 men and 50 women. The authors exposed 2 experimental groups to an LH induction by presenting them with an unsolvable maze task; 1 group received therapy afterward, and the other group did not. There were also 2 control groups: a group that received only a solvable version of the maze and another group that received no treatment. Before the experimental procedure, all participants completed the Turkish version of the NEO-Five Factor Inventory (FFI). The authors evaluated picture-rating and anagram-solving performances to differentiate the cognitive and emotional deficits of LH. Results of the factorial analyses of variance and the Wilcoxon signed ranks test supported the success of both the helplessness induction and the therapy technique. Although no significant gender differences were found in the effects of the helplessness-induction and therapy procedures, correlation analyses revealed that individual differences, particularly in the interaction between gender and personality characteristics, can have an important impact on LH and on the capacity to benefit from therapy.

The onset and alleviation of learned helplessness in older hospitalized people

The objective of this study was to investigate the relevance of learned helplessness (LH) and learned mastery (LM) theories in the respective development of dependence and independence in older hospitalized people. A two-staged experiment was performed. In stage I, meal-related responses of patient participants ( n = 84) were automatically completed by a researcher during two consecutive mealtime events (LH induction). LH effects were then assessed by evaluating participant performance during a controllable meal-task and a non-meal-related psychomotor task. In stage II, "helpless" participants ( n = 35) were then given an expectation of future control over the mealtime event followed by two further meals during which the researcher provided no active assistance (LM induction). LM effects were assessed as in stage I. Participants exposed to the LH inducing strategy demonstrated LH effects within both the meal and psychomotor tasks. These effects were alleviated through exposing participants to the LM inducing intervention. Exposing older hospitalized people to uncontrollable or disempowering circumstances may potentially lead them to develop a LH induced dependence. This may be alleviated by increasing patient's expectation of control leading to the development of LM.

Chronic Residential Crowding and Children's Well‐Being: An Ecological Perspective

Chronic residential crowding is associated with difficulties in behavioral adjustment at school, poor academic achievement, heightened vulnerability to the induction of learned helplessness, elevated blood pressure, and impaired parent-child interpersonal relationships among a sample of working-class, 10-to 12-year-old children living in urban India. The significant main effects of residential crowding on blood pressure and learned helplessness are moderated by gender. Residential crowding is positively associated with blood pressure only among boys and with helplessness only among girls. All analyses statistically control for household income. We then demonstrate that perceived parent-child conflict functions as an underlying, intervening process that largely accounts for several correlates of household crowding among children.

Effects of naltrexone and cross-tolerance to morphine in a learned helplessness paradigm.

Opiates have been implicated in learned helplessness (LH), a phenomenon known to be related to opiate stress-induced analgesia (SIA). In the present study, we investigated the role of opiates in the induction of LH and SIA under different conditions. Adult female Wistar rats were trained either by receiving 60 inescapable 1-mA footshocks (IS group, N = 114) or by confinement in the shock box (control or NS group, N = 92). The pain threshold of some of the animals was immediately evaluated in a tail-flick test while the rest were used 24 h later in a shuttle box experiment to examine their escape performance. The opiate antagonist naltrexone (0 or 8 mg/kg, ip) and the previous induction of cross-tolerance to morphine by the chronic administration of morphine (0 or 10 mg/kg, sc, for 13 days) were used to identify opiate involvement. Analysis of variance revealed that only animals in the IS group demonstrated antinociception and an escape deficit, both of which were resistant to the procedures applied before the training session. However, the escape deficit could be reversed if the treatments were given before the test session. We conclude that, under our conditions, induction of the LH deficit in escape performance is not opiate-mediated although its expression is opiate-modulated.

Learned helplessness increases 5-hydroxytryptamine 1B receptor mRNA levels in the rat dorsal raphe nucleus

Learned helplessness is a behavioral condition induced by exposure to inescapable stress that models aspects of stress-related disorders including depression and posttraumatic stress disorder, and has been associated with diminished serotonin release in the rat frontal cortex. Our hypothesis was that presynaptic 5-hydroxytryptamine1B (5-HT1B) receptors, which inhibit the synthesis and release of serotonin in nerve terminals, may be increased in learned helplessness. Postsynaptic 5-HT1B mRNA hybridization levels in the hippocampus or frontal cortex were unchanged following induction of learned helplessness; however, presynaptic 5-HT1B mRNA hybridization signal in the dorsal raphe nucleus of helpless rats was 25% higher than control values. There was no change in dorsal raphe serotonin transporter mRNA level. The detection of increased 5-HT1B mRNA levels in the dorsal raphe nucleus suggests an increased capacity to synthesize presynaptic 5-HT1B receptors and could account for diminished serotonin neurotransmission in learned helplessness.

Effect of neonatal handling on learned helplessness model of depression

The present study was undertaken to investigate the effects of neonatal handling on learned helplessness (LH) model of depression in the rat. We also investigated the effect of neonatal handling on behavior in an open field test of emotionality. The handling procedure reduced helplessness behavior, with a decrease in the number of escape failures, an increase in the number of avoidance responses, and a decrease in the escape latency in the shuttle-box after induction of LH. In addition, handling during infancy decreased the number of boli in an open field test, which suggests that the level of emotivity in adulthood was reduced. It is suggested that handling in infancy improves behavioral adaptation to the environment, including enhanced adaptive response to stress.

Does learned helplessness induction by haloperidol involve serotonin mediation?

Learned helplessness (LH) is a behavioral depression following inescapable stress. Helpless behavior was induced in naive rats by the dopamine D 2 receptor haloperidol (HDL) in a dose-dependent manner, with the greatest effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol (IP) increased release of serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo microdialysis. Perfusion of HDL through the probe in MPC caused increased cortical 5-HT release, as did perfusion of both dopamine and the dopamine agonist apomorphine. Our previous work found that increased 5-HT release in MPC correlates with the development of LH. The present work suggests that increased DA release in MPC, known to occur with both inescapble stress and with HDL, may play a necessary but not sufficient role in the development of LH. Also, this suggests that increased DA activity in MPC leads to increased 5-HT release in MPC and to subsequent behavioral depression.

Effect of mixed (RB 38A) and selective (RB 38B) inhibitors of enkephalin degrading enzymes on a model of depression in the rat

This is a study of the effects of the endogenous opioid peptides, enkephalins, on learned helplessness, an experimental model of depression in rats. For this purpose, the responses induced by RB 38A, a mixed inhibitor of enkephalin catabolism, and RB 38B, a selective inhibitor of neutral endopeptidase EC 3.4.24.11, were compared with the antidepressive effect induced by imipramine, RB 38A and RB 38B induced an imipramine-like effect in reducing helpless behavior, as illustrated by the decrease in the number of escape failures. According to the different pharmacological potential of both inhibitors to reduce enkephalin metabolism, complete inhibition of enkephalins (RB 38A) produced a higher response than that obtained with a partial inhibitor (RB 38B). On the other hand, naloxone (NLX) was found to facilitate the induction of learned helplessness, and to antagonize the effect of both enkephalin-degrading enzyme inhibitors. These results suggest that modifications in the activity of the endogenous opioid system could take place in this model of depression. The antidepressant-like effects induced by RB 38B, and especially by RB 38A, in the learned helplessness paradigm suggest that new mixed enkephalinase inhibitors, able to cross the blood-brain barrier, could provide a new strategy in the treatment of affective disorders.

Repression-sensitization differences in recovery from learned helplessness.

The performance of repressors and sensitizers on a solvable anagram task was assessed after either a short delay (0 to 30 min) or a long delay (2 to 6 hr) following a standard learned helplessness induction. Results indicated that all subjects exposed to the learned helplessness induction exhibited performance deficits, compared with control subjects exposed to no induction. Furthermore, subjects who were tested after the short delay did not perform as well as subjects tested after a long delay. No difference in overall anagram performance was found between repressors and sensitizers. Consistent with theoretical predictions, however, the anagram performance of repressor subjects was significantly better in the long-delay than in the short-delay condition; this significant recovery effect between short- and long-delay conditions was not obtained for sensitizer subjects. Possible theoretical mechanisms for these effects and implications for future research are noted.

The involvement of endogenous opiate systems in learned helplessness and stress-induced analgesia.

The participation of endogenous opiate systems in the induction and expression of learned helplessness (LH) and stress-induced analgesia (SIA) was investigated in rats exposed to escapable and inescapable footshock. Following an initial footshock, analgesia was observed only in those animals that could not control their stress exposure and this SIA was prevented by the administration of naloxone. Analgesia was no longer evident in this inescapable group after 48 h. However, exposure to a shuttlebox escape task at this time reinstated the SIA but did not produce SIA in animals previously exposed to escapable footshock. Shuttlebox escape deficits indicative of LH were also exhibited by animals that received an inescapable footshock stress 48 h prior to testing. The analgesia and LH observed in the inescapable group were not affected by the administration of naloxone (3 mg/kg, IP) 10 min before shuttlebox exposure but were prevented when the same dose of naloxone was given before the initial stress. Thus, endogenous opiates clearly participate in the initial induction of LH and SIA and, although the degree of endogenous opiate involvement in the subsequent expression of these behaviors is unclear, it seems evident that their expression can occur in the presence of opiate antagonism and may therefore require the participation of additional transmitter systems.