Learned Helplessness Procedure Research Articles

Post-Stress Fructose and Glucose Ingestion Exhibit Dissociable Behavioral and Physiological Effects.

An acute traumatic event can lead to lifelong changes in stress susceptibility and result in psychiatric disease such as Post-Traumatic Stress Disorder (PTSD). We have previously shown that access to a concentrated glucose solution for 24 h beginning immediately after trauma decreased stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. The current study sought to investigate the peripheral physiological effects of post-stress glucose consumption. We exposed 128 male Sprague-Dawley rats to inescapable and unpredictable 1-milliamp electric tail shocks or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution, 40% fructose solution, or water. Blood and liver tissue were extracted and processed for assay. We assessed corticosterone, corticosteroid-binding globulin (CBG), glucose, and liver glycogen concentrations at various time points following stress. We found that rats given access to glucose following exposure to traumatic shock showed a transient rise in blood glucose and an increase in liver glycogen repletion compared to those that received water or fructose following exposure to electric shock. We also found that animals given glucose following shock exhibited reduced free corticosterone and increased CBG compared to their water-drinking counterparts. However, this difference was not apparent when glucose was compared to fructose. These data suggest that post-stress glucose prophylaxis is likely not working via modulation of the HPA axis, but rather may provide its benefit by mitigating the metabolic challenges of trauma exposure.

Glutamatergic synaptic plasticity in the periaqueductal gray governs fear-induced depression-like behavior in rats

IntroductionMajor depressive disorder affecting more than 110 million people worldwide every year is a heterogeneous illness influenced by a variety of factors, including repeated stressful factors. Despite widely research during the past several decades, the pathophysiology and neurobiological mechanisms of depressive disorders remain unclear. Ventrolateral periaqueductal gray (vlPAG), a midbrain nucleus, has been considered as an important part of the circuitry that involves in stress-induced depression-like behaviors. Dysregulation of glutamatergic neurotransmission in depressed patients suggests that glutamate-mediated excitatory system is critical involved in the depressive disorders.ObjectivesIt is still unclear that whether vlPAG involves in fear condition-elicited depression-like behavior.AimsWe investigated the synaptic transmission in the vlPAG to examine whether vlPAG participates in fear-induced depression-like behavior in rats.MethodsDepression-like behaviors, in the rats, were induced by learned helplessness procedure. The synaptic transmission was conducted by whole-cell patch-clamp recording in the rat brain slices containing periaqueductal gray.ResultsRats receiving learned helplessness procedure displayed high failure rate in the escapable foot-shock test compared to control group. Both amplitude and frequency of miniature excitatory postsynaptic currents were significant reduced compared to control group, suggesting reduced presynaptic glutamate release and postsynaptic responses were involved in the learned helplessness procedure-induced depression behavior in rats.ConclusionsReduced glutamatergic transmission in the vlPAG contributes to learned helplessness procedure-induced depression-like behavior in rats through pre – and post-synaptic mechanisms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens andperiaqueductal grey.

An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined.

Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events.

Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress.

When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical-genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.

Ginsenoside Rb3 exerts antidepressant-like effects in several animal models

Total ginsenosides have been shown to have therapeutic actions as antidepressants. We report a major active ingredient of total ginsenosides, the ginsenoside Rb3 (Rb3), which may have antidepressant-like effects. Using the forced swim test, tail suspension test, and learned helplessness procedure, we found that Rb3 had significant anti-immobility effects in mice in the forced swim and tail suspension tests and reduced the number of escape failures in the learned helplessness procedure. In a reserpine-induced syndrome model, Rb3 attenuated hypothermia, palpebral ptosis, and akinesia. In the chronic mild stress model, chronic Rb3 administration reversed the decrease in locomotor activity, novelty-suppressed feeding, and sucrose preference. Furthermore, neurochemical tests were performed to support our hypothesis that biochemical variations (i.e. brain-derived neurotrophic factor and the monoamine neurotransmitters 5-hydroxytryptamine, dopamine, and norepinephrine) are involved in Rb3's antidepressant-like effects. Finally, we found, using whole-cell patch-clamp recordings, that the action potential transmission in neurons within the somatosensory cortex was excited by Rb3 perfusion and blocked with Panax notoginseng total saponins extracted from leaves. This study provides evidence for the mechanism of action of the antidepressant-like effects of Rb3.

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

Imaging Technique Explored As Depression Treatment

Imaging Technique Explored As Depression Treatment

Antidepressant-like effects of CP-154,526, a selective CRF 1 receptor antagonist

The effects of CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7 H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine), a selective corticotropin releasing factor (CRF 1) receptor antagonist, were examined in the learned helplessness procedure, a putative model of depression with documented sensitivity to diverse classes of antidepressant drugs. Rats were exposed to a series of inescapable foot shocks on three consecutive days and tested in a shock-escape procedure on the fourth day. Animals exposed to `helplessness' training performed poorly in the shock-escape test compared with control animals not receiving inescapable shocks. CP-154,526 (10–32 mg/kg, intraperitoneally) dose-dependently reversed the escape deficit when administered 60 min prior to the test session, but had no effect on the performance of control rats not receiving prior exposure to inescapable stress. In comparison, the tricyclic antidepressant imipramine (17.8 mg/kg) reversed the escape deficit after repeated, but not acute, administration. These data support evidence implicating stress systems in the pathophysiology of depression, and suggest potential efficacy of small-molecule CRF receptor antagonists in the treatment of affective disorders. © 1997 Elsevier Science B.V. All rights reserved.

Increased 5-HT 2 receptor-mediated behavior 11 days after shock in learned helplessness rats

In the learned helplessness procedure, rats can be differentiated into two distinct groups. Learned helplessness (LH) rats do not learn to escape a controllable shock while non-learned helplessness (NLH) rats learn this response. This deficit in performance in LH rats lasted for 11 days. In LH rats, pretreatment with acute desipramine (15 mg/kg i.p.) or chronic diazepam (0.95 mg/kg/day p.o. for 7 days) did not produce recovery from this deficit of performance, but pretreatment with chronic desipramine (17.7 mg/kg/day p.o. for 7 days) or chronic mianserin (6.1 mg/kg/day p.o. for 7 days) led to recovery. Before presentation of uncontrollable shock, there was no difference between LH and NLH rats, but 11 days after the shock, head shakes induced by (±)-1-(2,5-demethoxy-4-iodophenyl)-2-aminopropane (DOI) in LH rats was significantly more frequent than those in NLH and naive rats without change of [ 3H]ketanserin binding. The basal corticosterone level was higher in LH rats than in NLH rats. These findings suggest that the learned helplessness model is a reliable animal model of depression accompanied by 5-HT 2 receptor hypersensitivity.

Effects of an extract of Ginkgo Biloba (EGB 761) on “learned helplessness” and other models of stress in rodents

The effects of repeated oral administration of an extract of Ginkgo Biloba (EGB 761) on various behavioral models of stress in rodents were investigated. The models in rats included “learned helplessness,” shock-suppressed licking (Vogel conflict test) and forced swimming-induced immobility (“behavioral despair”). The models in mice included shock-suppressed exploration (four plates test), spontaneous exploration (staircase test) and food consumption in a novel situation (emotional hypophagia). Further tests in rats examined the effects of EGB 761 on memory (passive avoidance test) and responsiveness to shock to determine whether the preventive effects observed with EGB 761 in the learned helplessness procedure were due either to drug-induced impairment of memory or to reduced shock sensitivity. In all experiments EGB 761 was administered over 5 days at daily doses of 50 and 100 mg/kg PO. In some experiments (Vogel test, four plates test, staircase test, emotional hypophagia) the effects of acute administration were also investigated. The results showed that repeated administration of EGB 761 (50 and 100 mg/kg/day) before exposure to unavoidable shock (preventive treatment) clearly reduced the subsequent avoidance deficits in the learned helplessness procedure but was less effective when first administered after “helplessness” induction (curative treatment). EGB 761 did not affect performance in the passive avoidance task or alter the animals' response to electric shock, suggesting that the effects observed in the learned helplessness procedure were not due to impaired memory or reduced shock sensitivity. Anxiolytic-like activity was also seen in the emotional hypophagia test in mice where repeated administration of EGB 761 increased the amount of food consumed. EGB 761 after acute or repeated administration had no marked effects in the other models tested. The results suggest that EGB 761 reduces the consequences of stress in some experimental situations but that this effect cannot be assimilated to either classical antidepressant or anxiolytic activity.

CONTROL AND BELIEF IN THE JUST WORLD: WHAT'S GOOD ALSO CAN BE BAD

The just world hypothesis provides an explanation for the finding that observers derogate victims. By admitting the appropriateness of a victim's fate., observers may develop a sense of control over the possibility of similar fates. Two experiments investigated the relationship between, the magnitude of motivation for control over the environment and tendency to derogate victims. In Experiment One, situational controllability and uncontrollability were manipulated within a learned helplessness procedure and derogation of a victimized stranger assessed. In Experiment Two, subjects completed the Need for Control and Belief in the Just World scales, measures of the motivation for environmental control and the tendency to derogate victims. The results indicate that motivation and need for control underlie victim derogation.