Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate.

Chronic vicarious social defeat stress attenuates new-born neuronal cell survival in mouse hippocampus

Social adversity in adolescence is prevalent and can negatively impact mental health trajectories. Modeling social stress in adolescent male and female rodents is needed to understand its effects on ongoing brain development and behavioral outcomes. The chronic social defeat stress paradigm (CSDS) has been widely used to model social stress in adult C57BL/6 male mice by leveraging on the aggressive behavior displayed by an adult male rodent to an intruder invading its territory. An advantage of this paradigm is that it allows to categorize defeated mice into resilient and susceptible groups based on their individual differences in social behavior 24 h after the last defeat session. Implementing this model in adolescent C57BL/6 mice has been challenging because adult or adolescent mice do not typically attack early adolescent male or female mice and because adolescence is a short period of life, encompassing discreet temporal windows of vulnerability. This limitation was overcome by adapting an accelerated version of the CSDS to be used for adolescent male and female mice. This 4-day stress paradigm with 2 physical attack sessions per day uses a C57BL/6 male adult to prime the CD-1 mouse for aggressiveness such that it readily attacks the male or female adolescent mouse. This model was termed accelerated social defeat stress (AcSD) for adolescent mice. Adolescent exposure to AcSD induces social avoidance 24 h later in both males and females, but only in a subset of defeated mice. This vulnerability occurs despite the number of attacks being consistent across sessions between resilient and susceptible groups. The AcSD model is short enough to allow exposure during discrete periods within adolescence, allows the segregation of mice according to the presence or absence of social avoidance behavior, and is the first model available to study social defeat stress in adolescent C57BL/6 female mice.

Background: Cannabis is one of the most frequently used substances by adolescents. Early exposure to psychoactive compounds has been shown to alter normal brain development and has consequences for psychiatric illness and behaviour in adulthood. In this study, we explored the effects of adolescent synthetic cannabinoid exposure on susceptibility to stress in adulthood, in addition to changes in impulsive behaviour. Methods: Chronic treatment with synthetic cannabinoid WIN55,212-2 (WIN) at various doses in adolescent mice was followed by the chronic social defeat stress paradigm in adulthood to assay changes in susceptibility to stress. We then employed the operant Go/No-Go task to investigate changes in impulsivity. Results: No changes in susceptibility to stress were identified (χ2(3)=0.585, p=0.900). Strikingly, we demonstrated a dose dependent decrease in impulsivity of adolescent WIN-treated subjects as measured using the Go/No-Go task (F(3, 20)=5.743, p=0.0053). Limitations: The main limitation of our findings is the small sample size, particularly for assaying changes in susceptibility to stress using the chronic social defeat stress paradigm. Furthermore, the single housing of animals and suboptimal performance of controls may have affected our findings in the Go/No-Go task. Conclusion: Overall, this study presents a novel behavioural finding consequent to adolescent exposure to cannabinoids. Further research into the long-term effects of cannabinoid use in adolescence is needed, especially in light of its prevalent use and legalization in Canada.

Cytokine and endocrine parameters in mouse chronic social defeat: Implications for translational ‘cross-domain’ modeling of stress-related brain disorders

Chronic stress is a crucial public issue that occurs when a person is repetitively stimulated by various stressors. Previous researches have reported that chronic stress induces spermatogenesis dysfunction in the reproductive system, but its molecular mechanisms remain unclear. The nectin protein family, including nectin-1 to nectin-4, is Ca(2+)-independent immunoglobulin-like cell adhesion molecules, that are widely expressed in the hippocampus, testicular tissue, epithelial cells and other sites. Nectin-3 contributes to the sperm development at the late stage, and the abnormal expression of nectin-3 impairs spermatogenesis. Some recent studies have demonstrated that stress induces a decrease in nectin-3 expression in the hippocampus via corticotropin-releasing hormone (CRH) to corticotropin-releasing hormone receptor 1 (CRHR1) pathway. Here, we tested whether chronic stress also caused a reduction in nectin-3 expression in the testis. We established a chronic social defeat stress paradigm, which provides naturalistic and complex chronic stress inmale C57BL/6 mice. After 25 days of chronic social defeat stress, the mice showed weight loss, thymic atrophy and some other typical symptoms of chronic stress (e.g.anxiety-like behavior and social avoidance behavior). We found gonad atrophy, testicular histological structure changes and semen quality reductions in the stressed mice. The stressed male mice significantly spent more time to impregnate the female mice than the control male mice. Moreover, nectin-3 protein levels in stressed mice were significantly decreased in the testes compared with those in control mice. In addition, we found that the CRHR1 expression level was increased in the testes of stressed mice. Therefore, we demonstrated a decreased level of nectin-3 expression and an increase in CRHR1 expression in the testis after exposure to chronic stress, which may provide a potential therapeutic target for the spermatogenesis dysfunction induced by chronic stress.

Enkephalins, endogenous ligands for delta opioid receptors (DORs), are highly enriched in the nucleus accumbens (NAc). They are implicated in depression but their role in the NAc, a critical brain region for motivated behavior, is not fully investigated. To provide insight into enkephalin function we used a chronic social defeat stress paradigm, where animals are either categorized as susceptible or resilient to stress based on their performance in a social interaction test. Compared to controls, susceptible animals showed reduced enkephalin levels in the NAc. Such decrease in enkephalin levels is not due to a change in mRNA of its precursor protein, proenkephalin, in susceptible mice but is consistent with increased mRNA levels of enkephalinases in the NAc of susceptible animals. Systemic administration of enkephalinase inhibitors or NAc infusion of the DOR agonist, SNC80, caused a resilient outcome to CSDS. Both treatments increased phosphorylation of ERK, which was downregulated by social defeat stress. To further validate these results, we also used Q175 knock-in mice, an animal model of Huntington's disease in which enkephalin levels are reduced in striatum and comorbidity with mood disorders is common. Consistent with data in wild-type mice, Q175 animals showed reduced enkephalin levels in the NAc and enhanced susceptibility to a social defeat stress. Overall, our data implicate that depression-like behavior induced by social defeat stress arises from disrupted DOR signaling resulting from lowered levels of enkephalins, which is partly mediated through elevated expression of enkephalinases.

The ephrin B2 (EphB2) receptor is a tyrosine kinase receptor that is associated with synaptic development and maturation. It has recently been implicated in cognitive deficits and anxiety. However, still unknown is the involvement of EphB2 in the vulnerability to stress. In the present study, we observed decreases in EphB2 levels and their downstream molecules in the medial prefrontal cortex (mPFC) but not in the orbitofrontal cortex (OFC) in mice that were susceptible to chronic social defeat stress. The activation of EphB2 receptors with EphrinB1-Fc in the mPFC produced stress-resistant and antidepressant-like behavioral effects in susceptible mice that lasted for at least 10 days. EphB2 receptor knockdown by short-hairpin RNA in the mPFC increased the susceptibility to stress and induced depressive-like behaviors in a subthreshold chronic social defeat stress paradigm. These behavioral effects were associated with changes in the phosphorylation of cofilin and membrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and the expression of some synaptic proteins in the mPFC. We also found that EphB2 regulated stress-induced spine remodeling in the mPFC. Altogether, these results indicate that EphB2 is a critical regulator of stress vulnerability and might be a potential target for the treatment of depression.

Chronic activation of the stress response can lead to a number of metabolic disturbances such as obesity, metabolic syndrome, Type II diabetes and car- diovascular disease. The exact mechanisms underlying these metabolic changes are currently uncharacterized. Traditionally, many of these effects have been at- tributed to the increased levels of circulating glucocorticoids (cortisol in humans and corticosterone in rodents) as a function of hypothalamic pituitary adrenal (HPA) axis hyperactivity. However, recent evidence suggests that the gut de- rived hormone ghrelin may be a key contributor to the physiological changes generated in response to chronic stress. Ghrelin is a gut-brain peptide that promotes appetite and the accumulation of adipose tissue by encouraging the utilization of carbohydrates as a fuel source, while sparing fat tissue. Inter- estingly, plasma ghrelin concentrations increase in response to stressful stimuli, and remain elevated following cessation of the stressor. The present thesis was aimed at investigating the role of ghrelin in mediating stress-induced metabolic changes. In addition, this thesis explores the efficacy of potential therapeutic treatments of stress-induced metabolic disorders. Overall, the data presented in this thesis suggests that ghrelin elicits an increase in caloric intake in response to stress while promoting the utilization of carbohydrates as a fuel source. Central ghrelin signalling is required to elicit the metabolic consequences of a chronic social defeat stress. Increased ghrelin secretion in response to stress caused a significant increase in visceral adipose tissue and produced a hormonal profile indicative of obesity and metabolic syndrome. Animals lacking a functional ghrelin signalling system do not show these metabolic changes. Pharmacologi- cal blockade of ghrelin with a putative GOAT inhibitor was sufficient to reduce stress-induced ghrelin secretion and subsequent caloric intake, thereby improv- ing the metabolic outcome of a chronic social defeat stress paradigm.

Resilience to chronic stress is associated with specific neurobiological, neuroendocrine and immune responses

Klotho is a life extension factor that has the ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here, we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, in which mice are categorized as either susceptible or unsusceptible based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice compared to control or unsusceptible mice. Genetic knockdown of klotho in the NAc induced behavioral alterations relevant to depression in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the behavioral responses to stress in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases in total and synaptic GluN2B expression that were identical to those in susceptible mice. Elevation of klotho in the NAc reversed the reductions in GluN2B expressions and altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates behavioral responses to stress by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, providing new insights into the molecular basis of major depression.

Antidepressant action of HDAC inhibition in the prefrontal cortex

ABSTRACTBACKGROUNDPsychological stress causes gut dysbiosis, which is associated with adverse effects on physical and mental health in humans and mice. Understanding the specific taxa of gut bacteria changed by stress, and whether stress differentially alters their relative abundance in males and females, has important implications for stress-related disorders.METHODSWe modeled individual differences in resilience or susceptibility using the chronic social defeats stress (CSDS) paradigm. Here, C57BL/6 mice are exposed to a novel retired breeder CD-1 aggressor for 10 minutes per day for 10 days. In this paradigm, resilient and susceptible subpopulations can be identified using the social interaction paradigm following CSDS. Fecal samples were collected following Day 1 and Day 10 of CSDS. 16S ribosomal RNA sequencing was used to identify the relative abundance of 200 bacteria species. We analyzed group differences in phyla, genera, and species in CD-1 aggressors along with resilient, susceptible, and non-stressed control male and female C57/BL/6 intruders.RESULTSStress reduced microbiome diversity and caused gut dysbiosis in all groups, including aggressors. CSDS altered the relative abundance of every phylum detected. We report genera whose relative abundance was changed by CSDS or sex. Increases in the relative abundance of an unculturedRuminococcusspecies on day 1 predicted aspects of social behavior, with a stronger correlation in stressed females compared to males.CONCLUSIONSCSDS causes gut dysbiosis in male and female mice, with generally similar effects in mice that behave differently following stress.ONE SENTENCE SUMMARYWe report the effects of chronic social defeat stress on gut dysbiosis in aggressors, non-defeated controls, and male and female mice that are either resilient or susceptible to the adverse effects of stress.IN THIS ISSUE SUMMARYWe characterize changes to the gut microbiome of male and female mice that are either resilient or susceptible to the adverse effects of social stress. Stress shifted the relative abundance of broad and specific taxa, which sometimes differed between males and females. We found that the abundance of an unculturedRuminococcusspecies on day 1 predicted social behavior following stress. This effect was primarily observed in females.

5-HT1A Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience

Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.

Stress-related mood disorders are more prevalent in females than males, yet preclinical chronic stress paradigms were developed in male rodents and are less effective in female rodents. Here we characterize a novel chronic non-discriminatory social defeat stress (CNSDS) paradigm that results in comparable stress effects in both sexes. Male and female C57BL/6J mice were simultaneously introduced into the home cage of resident CD-1 aggressors for 10 daily 5-min sessions. CD-1 aggressors attacked males and females indiscriminately, resulting in stress resilient and susceptible subpopulations in both sexes. CD-1 aggressors attacked C57BL/6J male intruders faster and more frequently than female intruders. However, CNSDS similarly induced negative valence behaviors in SUS mice of both sexes relative to RES and CNTRL mice. Furthermore, SUS male and female mice displayed similar increases in plasma corticosterone levels following CNSDS exposure relative to pre-stress exposure levels. The estrous cycle did not impact CD-1 attack behavior or negative valence behaviors. Thus, CNSDS induces chronic stress behavioral and neuroendocrine effects in both male and female C57BL/6J mice and allows direct comparisons between sexes. Adoption of this modified social defeat paradigm will help advance the initiative to include female rodents in preclinical chronic stress research.