Stress-induced Behavioral Changes Research Articles

Non-Targeted Metabolomics Investigation of a Sub-Chronic Variable Stress Model Unveils Sex-Dependent Metabolic Differences Induced by Stress.

Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). The SCVS model of male and female mice was established in discovery and validation sets. The stress-induced behavioral phenotypic changes were similar in both sexes, however, the metabolic profiles of female plasma and brain became substantially different after stress, whereas those of males did not. Four stress-differential plasma metabolites-β-hydroxybutyric acid (BHB), L-serine, glycerol, and myo-inositol-could yield biomarker panels with excellent performance to discern the stressed individuals only for females. Disturbances in BHB, glucose, 1,5-anhydrosorbitol, lactic acid, and several fatty acids in the plasma of stressed females implied a systemic metabolic shift to β-oxidation in females. The plasma levels of BHB and corticosterone only in stressed females were observed not only in SCVS but also in an acute stress model. These results collectively suggest a sex difference in the metabolic responses by stress, possibly involving the energy metabolism shift to β-oxidation and the HPA axis dysregulation in females.

Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits

Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits. Our findings revealed potential roles of mitophagy and Mitochondrial antiviral-signaling protein (MAVS) in mediating chronic stress-induced changes in cf-mtDNA levels and social behavior. Furthermore, we showed that inhibition of Toll-like receptor 9 (TLR9) attenuates mtDNA-induced social behavior deficits. Together, these findings show that cf-mtDNA-TLR9 signaling is critical in mediating stress-induced social behavior deficits.

Date palm spathe extract reverses chronic stress-induced changes in dendritic arborization in the amygdala and impairment of hippocampal long-term potentiation.

Chronic restraint stress induces anxiety-like behaviors and emotional abnormalities via an alteration of synaptic remodeling in the amygdala and the hippocampus. Given that the date palm spathe has been shown to have neuroprotective effects on different experimental models, this study aimed to address whether the date palm spathe extract (hydroalcoholic extract of date palm spathe [HEDPP]) can reduce chronic restraint stress-induced behavioral, electrophysiological, and morphological changes in the rat model. Thirty-two male Wistar rats (weight 200-220g) were randomly divided into control, stress, HEDPP, and stress+HEDPP for 14 days. Animals were submitted to restraint stress for 2h per day for 14 consecutive days. The animals of the HEDPP and stress+HEDPP groups were supplemented with HEDPP (125mg/kg) during these 14 days, 30min before being placed in the restraint stress tube. We used passive avoidance, open-field test, and field potential recording to assess emotional memory, anxiety-like behavioral and long-term potentiation in the CA1 region of the hippocampus, respectively. Moreover, Golgi-Cox staining was used to investigate the amygdala neuron dendritic arborization. Results showed that stress induction was associated with behavioral changes (anxiety-like behavioral and emotional memory impairment), and the administration of HEDPP effectively normalized these deficits. HEDPP remarkably amplified the slope and amplitude of mean-field excitatory postsynaptic potentials (fEPSPs) in the CA1 area of the hippocampus in stressed rats. Chronic restraint stress significantly decreased the dendritic arborization in the central and basolateral nucleus of the amygdala neuron. HEDPP suppressed this stress effect in the central nucleus of the amygdala. Our findings indicated that HEDPP administration improves stress-induced learning impairment and memory and anxiety-like behaviors by preventing adverse effects on synaptic plasticity in the hippocampus and amygdala.

Eucommiae cortex polysaccharides attenuate gut microbiota dysbiosis and neuroinflammation in mice exposed to chronic unpredictable mild stress: Beneficial in ameliorating depressive-like behaviors

BackgroundChronic stress alters gut microbiota composition, as well as induces inflammatory responses and behavioral deficits. Eucommiae cortex polysaccharides (EPs) have been reported to remodel gut microbiota and ameliorate obesogenic diet-induced systemic low-grade inflammation, but their role in stress-induced behavioral and physiological changes is poorly understood. MethodsMale Institute of Cancer Research (ICR) mice were exposed to chronic unpredictable stress (CUMS) for 4 weeks and then supplemented with EPs at a dose of 400 mg/kg once per day for 2 weeks. Behavioral test-specific antidepressant and anxiolytic effects of EPs were assessed in FST, TST, EPM, and OFT. Microbiota composition and inflammation were detected using 16S ribosomal RNA (rRNA) gene sequencing, quantitative RT-PCR, western blot, and immunofluorescence. ResultsWe found that EPs ameliorated gut dysbiosis caused by CUMS, as evidenced by increasing the abundance of Lactobacillaceae and suppressing the expansion of the Proteobacteria, thereby mitigating intestinal inflammation and barrier derangement. Importantly, EPs reduced the release of bacterial-derived lipopolysaccharides (LPS, endotoxin) and inhibited the microglia-mediated TLR4/NFκB/MAPK signaling pathway, thereby attenuating the pro-inflammatory response in the hippocampus. These contributed to restoring the rhythm of hippocampal neurogenesis and alleviating behavioral abnormalities in CUMS mice. Correlation analysis showed that the perturbed-gut microbiota was strongly correlated with behavioral abnormalities and neuroinflammation. LimitationsThis study did not clarify the causal relationship between EPs remodeling the gut microbiota and improved behavior in CUMS mice. ConclusionsEPs exert ameliorative effects on CUMS-induced neuroinflammation and depression-like symptoms, which may be strongly related to their beneficial effects on gut microbial composition.

Effect of Bromelain on Chronic Unpredictable Stress-induced Behavioral, Biochemical, and Monoamine Changes in Wistar Albino Rat Model of Depression.

Bromelain is a complex mixture of protease enzyme extract from the fruit or stem of the pineapple plant and it has a history of folk medicine use. It is known to have a wide range of biological actions and it is most commonly used as an anti-inflammatory agent, though scientists have also discovered its potential as an anticancer and antimicrobial agent, it has been reported to have positive effects on the respiratory, digestive, circulatory systems and potentially on the immune system. This study was designed to investigate the antidepressant potential of Bromelain in the chronic unpredictable stress (CUS) model of depression. We studied the antioxidant activity, and neuroprotective effect of Bromelain by analyzing the fear and anxiety behavior, antioxidants, and neurotransmitter levels, and also by analyzing the histopathological changes. Adult male Wistar albino rats were divided into 5 groups, Control; Bromelain; CUS; CUS + Bromelain, CUS + fluoxetine. Animals of the CUS group, CUS + Bromelain group, and CUS + Fluoxetine group were exposed to CUS for 30 days. Animals of the Bromelain group and CUS + Bromelain group were treated orally with 40mg/kg Bromelain throughout the period of CUS whereas, the positive control group was treated with fluoxetine. Results showed a significant decrease in oxidative stress marker (lipid peroxidation), and the stress hormone cortisol, in Bromelain-treated CUS-induced depression. Bromelain treatment in CUS has also resulted in a significant increase in neurotransmitter levels, which indicates the efficacy of Bromelain to counteract the monamine neurotransmitter changes in depression by increasing their synthesis and reducing their metabolism. In addition, the antioxidant activity of Bromelain prevented oxidative stress in depressed rats. Also, hematoxylin and eosin staining of hippocampus sections has revealed that Bromelain treatment has protected the degeneration of nerve cells by chronic unpredictable stress exposure. This data provides evidence for the antidepressant-like action of Bromelain by preventing neurobehavioral, biochemical, and monoamine alterations.

Recent Studies on the Development of Nicotine Abuse and Behavioral Changes Induced by Chronic Stress Depending on Gender.

Nowadays, stressful situations are an unavoidable element of everyday life. Stressors activate a number of complex mental and physiological reactions in the organism, thus affecting the state of health of an individual. Stress is the main risk factor in the development of mental disorders, such as depression and other disorders developing as a result of addiction. Studies indicate that women are twice as likely as men to develop anxiety, depression and therefore addiction, e.g., to nicotine. Even though the data presented is indicative of significant differences between the sexes in the prevalence of these disorders, the majority of preclinical animal models for investigating stress-induced disorders use predominantly male subjects. However, the recent data indicates that this type of studies has also been launched in female rodents. Therefore, conducting research on both sexes allows for a more accurate understanding and assessment of the impact of stress on stress-induced behavioral, peripheral and molecular changes in the body and brain. In this manuscript we have gathered the data from 41 years (from 1981-2022) on the influence of stress on the development of depression and nicotine addiction in both sexes.

Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. Physiological and behavioral evaluations were conducted throughout the stress paradigm to determine if exercise blunts the effects of UCMS. Chronic stress induced voluntary wheel running (VWR) and weight loss in male and female mice. Compared to males, increased VWR was reported in females who also regained their weight lost by the end of the UCMS protocol. Exercise promoted resilience to stress-induced hyponeophagia in the novelty-suppressed feeding test and increased sucrose consumption. Exercise induced a sex-specific reduction in immobility and avoidance behavior in the tail suspension and open field tests and increased exploratory behavior in the light-dark test. These results indicate that exercise can promote resilience to the behavioral effects of chronic stress in males and females, and can affect behavior independent of chronic stress.

Состояние функций нервной системы крыс Вистар при применении пептида тафтцин-ПГП (селанк) в условиях иммобилизационного стресса

The aim of the study was to investigate the state of functions of the nervous system of Wistar rats upon application of the peptide taftsin-PGP under conditions of chronic stress. Materials and methods. The experiments were performed on 45 male Wistar rats weighing 200-230 g. Selank peptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro) was injected intraperitoneally at doses of 80, 250 and 750 μg/kg 15 min before stressor exposure. Animals were divided into 5 groups (n = 9): 1 - control (non-stressed animals injected with saline); 2 - stress (stressed animals injected with saline); 3-5 - stress+taftsin-PGP at doses of 80, 250 and 750 µg/kg. Animals were stressed for 28 days; from days 15 to 28, they were injected with selank/saline. The neurotropic effects of selank were evaluated in the elevated plus-maze, open field (OF) and forced swimming tests. To assess the severity of stress response, the concentration of corticosterone in rat serum was evaluated using enzyme immunoassay. Results. It was found that 28-day immobilisation stress caused disturbances of nervous system functions in the form of increased anxiety, horizontal, vertical, locomotor activity, emotionality and expression of depressive behaviour, as well as increased concentration of corticosterone in blood serum of experimental animals. Taftsin-PGP administration against the background of preliminary stressing (from the 15th to the 28th day of the experiment) contributed to a decrease in the severity of stress-induced behavioural changes in rats: at a dose of 750 µg/kg the peptide had anxiolytic effect, 250 µg/kg - antidepressant effect. At the same time, these changes occurred against the background of a significant decrease in serum corticosterone level. Conclusion. Thus, selank corrects stress-induced changes in the state of nervous system functions under 28-day restraint stress.

The Effect of Earthing Mat on Stress-Induced Anxiety-like Behavior and Neuroendocrine Changes in the Rat.

Grounding is a therapeutic technique that involves doing activities that "ground" or electrically reconnect us to the earth. The physiological effects of grounding have been reported from a variety of perspectives such as sleep or pain. However, its anti-stress efficacy is relatively unknown. The present study investigated the stress-related behavioral effects of earthing mat and its neurohormonal mechanisms in the Sprague-Dawley male rat. Rats were randomly divided into four groups: the naïve normal (Normal), the 21 days immobilization stressed (Control), the 21 days stressed + earthing mat for 7 days (A7) or 21 days (A21) group. The depressive-and anxiety like behaviors were measured by forced swimming test (FST), tail suspension test (TST) and elevated plus maze (EPM). Using immunohistochemistry, the expression of corticotrophin-releasing factor (CRF) and c-Fos immunoreactivity were analyzed in the brain. In the EPM, time spent in the open arm of the earthing mat groups was significantly increased compared to the Control group (p < 0.001), even though there were without effects among groups in the FST and TST. The expression of CRF immunoreactive neurons in the earthing mat group was markedly decreased compared to the Control group. Overall, the earthing mat reduced stress-induced behavioral changes and expression of c-Fos and CRF immunoreactivity in the brain. These results suggest that the earthing mat may have the potential to improve stress-related responses via the regulation of the corticotrophinergic system.

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT2A receptor-dependent head twitch behaviors or consistent changes in 5-HT2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.

Withania somnifera Extracts Promote Resilience against Age-Related and Stress-Induced Behavioral Phenotypes in Drosophila melanogaster; a Possible Role of Other Compounds besides Withanolides.

Withania somnifera (WS) extracts have been used in traditional medicine for millennia to promote healthy aging and wellbeing. WS is now also widely used in Western countries as a nutritional supplement to extend healthspan and increase resilience against age-related changes, including sleep deficits and depression. Although human trials have supported beneficial effects of WS, the study designs have varied widely. Plant material is intrinsically complex, and extracts vary widely with the origin of the plant material and the extraction method. Commercial supplements can contain various other ingredients, and the characteristics of the study population can also be varied. To perform maximally controlled experiments, we used plant extracts analyzed for their composition and stability. We then tested these extracts in an inbred Drosophila line to minimize effects of the genetic background in a controlled environment. We found that a water extract of WS (WSAq) was most potent in improving physical fitness, while an ethanol extract (WSE) improved sleep in aged flies. Both extracts provided resilience against stress-induced behavioral changes. WSE contained higher levels of withanolides, which have been proposed to be active ingredients, than WSAq. Therefore, withanolides may mediate the sleep improvement, whereas so-far-unknown ingredients enriched in WSAq likely mediate the effects on fitness and stress-related behavior.

Sustained TNF signaling is required for the synaptic and anxiety-like behavioral response to acute stress

Acute stress triggers plasticity of forebrain synapses as well as behavioral changes. Here we reveal that Tumor Necrosis Factor α (TNF) is a required downstream mediator of the stress response in mice, necessary for stress-induced synaptic potentiation in the ventral hippocampus and for an increase in anxiety-like behaviour. Acute stress is sufficient to activate microglia, triggering the long-term release of TNF. Critically, on-going TNF signaling specifically in the ventral hippocampus is necessary to sustain both the stress-induced synaptic and behavioral changes, as these could be reversed hours after induction by antagonizing TNF signaling. This demonstrates that TNF maintains the synaptic and behavioral stress response in vivo, making TNF a potential novel therapeutic target for stress disorders.

ACh signaling modulates activity of the GABAergic signaling network in the basolateral amygdala and behavior in stress-relevant paradigms.

The balance between excitatory and inhibitory (E/I) signaling is important for maintaining homeostatic function in the brain. Indeed, dysregulation of inhibitory GABA interneurons in the amygdala has been implicated in human mood disorders. We hypothesized that acetylcholine (ACh) signaling in the basolateral amygdala (BLA) might alter E/I balance resulting in changes in stress-sensitive behaviors. We therefore measured ACh release as well as activity of calmodulin-dependent protein kinase II (CAMKII)-, parvalbumin (PV)-, somatostatin (SOM)- and vasoactive intestinal protein (VIP)-expressing neurons in the BLA of awake, behaving male mice. ACh levels and activity of both excitatory and inhibitory BLA neurons increased when animals were actively coping, and decreased during passive coping, in the light-dark box, tail suspension and social defeat. Changes in neuronal activity preceded behavioral state transitions, suggesting that BLA activity may drive the shift in coping strategy. In contrast to exposure to escapable stressors, prolonging ACh signaling with a cholinesterase antagonist changed the balance of activity among BLA cell types, significantly increasing activity of VIP neurons and decreasing activity of SOM cells, with little effect on CaMKII or PV neurons. Knockdown of α7 or β2-containing nAChR subtypes in PV and SOM, but not CaMKII or VIP, BLA neurons altered behavioral responses to stressors, suggesting that ACh signaling through nAChRs on GABA neuron subtypes contributes to stress-induced changes in behavior. These studies show that ACh modulates the GABAergic signaling network in the BLA, shifting the balance between SOM, PV, VIP and CaMKII neurons, which are normally activated coordinately during active coping in response to stress. Thus, prolonging ACh signaling, as occurs in response to chronic stress, may contribute to maladaptive behaviors by shifting the balance of inhibitory signaling in the BLA.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Chronic stress-induced synaptic changes to corticotropin-releasing factor-signaling in the bed nucleus of the stria terminalis.

The sexually dimorphic bed nucleus of the stria terminalis (BNST) is comprised of several distinct regions, some of which act as a hub for stress-induced changes in neural circuitry and behavior. In rodents, the anterodorsal BNST is especially affected by chronic exposure to stress, which results in alterations to the corticotropin-releasing factor (CRF)-signaling pathway, including CRF receptors and upstream regulators. Stress increases cellular excitability in BNST CRF+ neurons by potentiating miniature excitatory postsynaptic current (mEPSC) amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K+ current that stabilizes membrane potential). Rodent anterodorsal and anterolateral BNST neurons are also critical regulators of behavior, including avoidance of aversive contexts and fear learning (especially that of sustained threats). These rodent behaviors are historically associated with anxiety. Furthermore, BNST is implicated in stress-related mood disorders, including anxiety and Post-Traumatic Stress Disorders in humans, and may be linked to sex differences found in mood disorders.

Inducible Nitric Oxide Synthase Inhibition in the Medial Prefrontal Cortex Attenuates the Anxiogenic-Like Effect of Acute Restraint Stress via CB1 Receptors.

Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB1 cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB1 antagonist; 100 pmol), and/or 1400W (iNOS selective inhibitor; 10−4, 10−3, or 10−2 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400W prevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects.

Stress-induced behavioral changes in Iraqi dentistry academics during the COVID-19 outbreak

Introduction: Studies of dental practitioners performed around the world demonstrate that COVID-19 pandemic negatively impacts their daily activities lives, social functions, and health-care providing duties. The aim of the study is to evaluate the pandemic-induced psychological stress and associated factors on dental academics in Iraq.Methods: We conduct an observational study using a self-administered survey to obtain data from dental academics in many colleges of dentistry within Baghdad city. A closed-ended questionnaire was utilized, to assess post-traumatic responses to particular events. The Impact of Event Scale was used to assess the level of stress in the first of two outcomes. The second depicts the effects of COVID-19 on behavioral changes.Results: A total of 108 participants from seven colleges in Bagdad responded. About 38% reported a state of severe stress, 46.3% showed moderate stress, and 13.9% complained of mild states of stress. Stress levels were found to be substantially linked to fear of infection, worries about professional responsibilities, and limited mobility.Conclusion: The pandemic stress induces psychological and behavioral changes on the Iraqi dental educators, which can never be eliminated.

Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance.

Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.

Epigenetic mechanisms impacted by chronic stress across the rodent lifespan

Exposures to stress at all stages of development can lead to long-term behavioural effects, in part through changes in the epigenome. This review describes rodent research suggesting that stress in prenatal, postnatal, adolescent and adult stages leads to long-term changes in epigenetic regulation in the brain which have causal impacts on rodent behaviour. We focus on stress-induced epigenetic changes that have been linked to behavioural deficits including poor learning and memory, and increased anxiety-like and depressive-like behaviours. Interestingly, aspects of these stress-induced behavioural changes can be transmitted to offspring across several generations, a phenomenon that has been proposed to result via epigenetic mechanisms in the germline. Here, we also discuss evidence for the differential impact of stress on the epigenome in males and females, conscious of the fact that the majority of published studies have only investigated males. This has led to a limited picture of the epigenetic impact of stress, highlighting the need for future studies to investigate females as well as males.

Chronic stress-induced behavioral changes through the neuron-microglia interaction

Chronic stress-induced behavioral changes through the neuron-microglia interaction