Model Of Psychosocial Stress Research Articles

Reduced hepatic AdipoR2 by increased glucocorticoid mediates effect of psychosocial stress to elevate serum cholesterol

Understanding the effects of psychosocial stress on serum cholesterol may offer valuable insights into the relationship between psychological disorders and endocrine diseases. However, these effects and their underlying mechanisms have not been elucidated yet. Here we show that serum corticosterone, total cholesterol and low-density lipoprotein cholesterol (LDL-C) are elevated in a mouse model of psychosocial stress. Furthermore, alterations occur in AdipoR2-mediated AMPK and PPARα signaling pathways in liver, accompanied by a decrease in LDL-C clearance and an increase in cholesterol synthesis. These changes are further verified in wild-type and AdipoR2 overexpression HepG2 cells incubated with cortisol and AdipoR agonist, and are finally confirmed by treating wild-type and hepatic-specific AdipoR2 overexpression mice with corticosterone. We conclude that increased glucocorticoid mediates the effects of psychosocial stress to elevate serum cholesterol by inhibiting AdipoR2-mediated AMPK and PPARα signaling to decrease LDL-C clearance and increase cholesterol synthesis in liver.

Effects of Arginine-vasopressin in the Brain on Social Behavior and Communication in a Psychosocial Stress Animal Model

Psychosocial stressors (e.g., anxiety, personality traits, social isolation) are risk factors for negative health outcomes, including cardiovascular disease and neuropsychiatric disorders. However, there is a knowledge gap regarding the biological mechanisms that underlie these risk-outcome relationships. To address this gap, our team uses the Syrian hamster ( Mesocricetus auratus) as an animal model for investigating psychosocial behaviors and stress responses. Our previous findings and work reported by others indicate that the neuropeptide arginine-vasopressin (AVP) acts in the brain to regulate the expression of social behavior and communication. In the present study, stereotaxic surgeries were used to cannulate six adult hamsters (1 female, 5 males) with cannulae aimed at different forebrain regions, mostly focusing on hypothalamic areas. Cannulated animals were microinjected with 200 nl of a 9 μM AVP solution and saline in counterbalanced order with a 4-day inter-test interval. Three of the six animals displayed a type of social communication behavior called flank marking in response to AVP, whereas none of the animals flank marked in response to saline; these group differences were statistically significant (χ2 (1, N=6)= 4.0, p< 0.05). Previous research groups confirmed the anterior hypothalamic area (AHA) as a site of action for the effects of AVP on social behaviors. Our results suggest that, in addition to the AHA, the dorsomedial hypothalamic nucleus (DM) and posterior hypothalamic area (PH) may also be sites of action for AVP. We are currently testing the behavioral effects of AVP when microinjected into the midbrain. The preliminary findings reported here will help us identify areas of the brain that are part of a larger neural network that is involved in the regulation of social behavior and stress responses by AVP. Our long-term goal is to develop a psychosocial stress model to test the hypothesis that AVP may have therapeutic potential for psychosocial stress-associated conditions, including cardiovascular disease and neuropsychiatric disorders. This research is supported by NIH grant #5K01HL145339-03 (PI: M. Gil). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Postweaning Social Isolation Alters Puberty Onset by Suppressing Electrical Activity of Arcuate Kisspeptin Neurons

Introduction: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice. Methods: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period. Results: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice. Conclusion: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways.

Mitochondrial morphology in the mouse adrenal cortex: Influence of chronic psychosocial stress

Mitochondria within the adrenal cortex play a key role in synthesizing steroid hormones. The adrenal cortex is organized in three functionally specialized zones (glomerulosa, fasciculata, and reticularis) that produce different classes of steroid hormones in response to various stimuli, including psychosocial stress. Given that the functions and morphology of mitochondria are dynamically related and respond to stress, we applied transmission electron microscopy (TEM) to examine potential differences in mitochondrial morphology under basal and chronic psychosocial stress conditions. We used the chronic subordinate colony housing (CSC) paradigm, a murine model of chronic psychosocial stress. Our findings quantitatively define how mitochondrial morphology differs among each of the three adrenal cortex zones under basal conditions, and show that chronic psychosocial stress mainly affected mitochondria in the zona glomerulosa, shifting their morphology towards the more typical glucocorticoid-producing zona fasciculata mitochondrial phenotype. Analysis of adrenocortical lipid droplets that provide cholesterol for steroidogenesis showed that chronic psychosocial stress altered lipid droplet diameter, without affecting droplet number or inter-organellar mitochondria-lipid droplet interactions. Together, our findings support the hypothesis that each adrenal cortex layer is characterized by morphologically distinct mitochondria and that this adrenal zone-specific mitochondrial morphology is sensitive to environmental stimuli, including chronic psychosocial stressors. Further research is needed to define the role of these stress-induced changes in mitochondrial morphology, particularly in the zona glomerulosa, on stress resilience and related behaviors.

Abstract P2075: The Effects Of Maternal Psychosocial Stress During Pregnancy On Offspring Heart Health

Maternal health has a substantial effect on offspring well-being and health. A significant contributing factor to maternal health is psychosocial stress. Psychosocial stress results from adverse experiences in everyday life and the inability to cope with them, resulting in anxiety and depression. Unfortunately, it is estimated that ~75% of mothers will suffer a stressful life event the year their infants are born, and upwards of 20% suffer depression. These already high levels of psychosocial stress have been exacerbated by the COVID-19 pandemic. However, it is not known if maternal psychosocial stress during pregnancy affects offspring heart health. Thus, the purpose of this study was to investigate the effects of maternal psychosocial stress during pregnancy on the heart health of offspring. We hypothesize that maternal psychosocial stress during pregnancy will have an adverse effect on offspring heart health. Methods: We used a well-established model of maternal psychosocial stress during pregnancy- restraint stress. Pregnant dams were stressed by placing them in a 50 mL conical tube (with air holes) for 2 hours / day on gestational days 10-17. Offspring heart health was assessed via echocardiography (Vevo 3100, MX550D transducer). Results: As early as one week of age (equivalent age of infancy in humans), we observed that offspring born to stressed dams exhibited decreased left ventricular fractional shortening. Further analysis using speckle tracking echocardiography was performed on offspring at 4 (equivalent age of juveniles in humans) and 12 (equivalent age of young adult in humans) weeks of age. Our data indicate that offspring from stressed dams had decreased heart performance (measured as stroke volume), remodeling observed as hypertrophy (measured as left ventricular posterior wall thickness at diastole), and diastolic dysfunction (measured as E’/A’). Conclusion: Our data indicate maternal psychosocial stress during pregnancy results in blunted left ventricular contractile and diastolic dysfunction in offspring, as well as displays adverse remodeling (i.e., hypertrophy) during infancy and through young adulthood. These data indicate that maternal psychosocial stress during pregnancy is detrimental to offspring heart health.

Intact GR dimerization is critical for restraining plasma ACTH levels during chronic psychosocial stress

Male C57BL/6N mice exposed to the chronic subordinate colony housing (CSC; 19 days) paradigm, a preclinically validated model of chronic psychosocial stress, are characterized by unaffected basal morning plasma corticosterone (CORT) concentrations despite adrenal and pituitary hyperplasia and increased adrenocorticotropic hormone (ACTH) plasma concentrations, compared with single-housed control (SHC) mice. However, as CSC mice are still able to show an increased CORT secretion towards novel heterotypic stressors, these effects might reflect an adaptation rather than a functional breakdown of general hypothalamus-pituitary-adrenal (HPA) axis functionality. In the present study we used male mice of a genetically modified mouse line, to investigate whether genetically-driven ACTH overexpression compromises adaptational processes occurring at the level of the adrenals during CSC exposure. Experimental mice carried a point mutation in the DNA binding domain of the glucocorticoid (GC) receptor (GR), attenuating dimerization of GR (GRdim), resulting in a congenially compromised negative feedback inhibition at the level of the pituitary.In line with previous studies, CSC mice in both the wild type (WT; GR+/+) and GRdim group developed adrenal enlargement. Moreover, compared with respective SHC and WT mice, CSC GRdim mice show increased basal morning plasma ACTH and CORT concentrations. Quantitative polymerase chain reaction (qPCR) analysis revealed neither a genotype effect, nor a CSC effect on pituitary mRNA expression of the ACTH precursor proopiomelanocortin (POMC). Finally, CSC increased anxiety-related behavior, active coping and splenocyte in vitro (re)activity in both WT and GRdim mice, while a CSC-induced increase in adrenal lipid vesicles and splenic GC resistance was detectable only in WT mice. Of note, lipopolysaccharide (LPS)-stimulated splenocytes of GRdim mice were resistant to the inhibitory effects of CORT.Together our findings support the hypothesis that pituitary ACTH protein concentration is negatively controlled by GR dimerization under conditions of chronic psychosocial stress, while POMC gene transcription is not dependent on intact GR dimerization under both basal and chronic stress conditions. Finally, our data suggest that adrenal adaptations during chronic psychosocial stress (i.e., ACTH desensitization), aiming at the prevention of prolonged hypercorticism, are protective only to a certain threshold of plasma ACTH levels.

Otilonium Bromide Prevents Cholinergic Changes in the Distal Colon Induced by Chronic Water Avoidance Stress, a Rat Model of Irritable Bowel Syndrome.

Irritable Bowel syndrome (IBS) is a highly widespread gastrointestinal disorder whose symptomatology mainly affect the large intestine. Among the risk factors, psychosocial stress is the most acknowledged. The repeated water avoidance stress (rWAS) is considered an animal model of psychosocial stress that is capable of mimicking IBS. Otilonium bromide (OB), which is orally administered, concentrates in the large bowel and controls most of the IBS symptoms in humans. Several reports have shown that OB has multiple mechanisms of action and cellular targets. We investigated whether the application of rWAS to rats induced morphological and functional alterations of the cholinergic neurotransmission in the distal colon and whether OB prevented them. The results demonstrated that rWAS affects cholinergic neurotransmission by causing an increase in acid mucin secretion, in the amplitude of electrically evoked contractile responses, abolished by atropine, and in the number of myenteric neurons expressing choline acetyltransferase. OB counteracted these changes and also showed an intrinsic antimuscarinic effect on the post-synaptic muscular receptors. We assume that the rWAS consequences on the cholinergic system are linked to corticotrophin-releasing factor-1 (CRF1) receptor activation by the CRF hypothalamic hormone. OB, by interfering with the CFR/CRFr activation, interrupted the cascade events responsible for the changes affecting the rWAS rat colon.

Impacts of Subchronic and Mild Social Defeat Stress on Plasma Putrefactive Metabolites and Cardiovascular Structure in Male Mice.

Psychosocial stress precipitates mental illnesses, such as depression, and increases the risk of other health problems, including cardiovascular diseases. In this study, we observed the effects of psychosocial stress on the histopathological features of systemic organs and tissues in a mouse psychosocial stress model, namely the subchronic and mild social defeat stress (sCSDS) model. There were several pathological findings in the tissues of both sCSDS and control mice. Mild fibrosis of the heart was observed in sCSDS mice but not in control mice. Extramedullary hematopoiesis in the spleen and hemorrhage in the lungs were observed in both the control and sCSDS mice. Focal necrosis of the liver was seen only in control mice. Furthermore, putrefactive substances in the blood plasma were analyzed because these metabolites originating from intestinal fermentation might be linked to heart fibrosis. Among them, plasma p-cresyl glucuronide and p-cresyl sulfate concentrations significantly increased owing to subchronic social defeat stress, which might influence cardiac fibrosis in sCSDS mice. In conclusion, several pathological features such as increased cardiac fibrosis and elevated plasma putrefactive substances were found in sCSDS mice. Thus, sCSDS mice are a potential model for elucidating the pathophysiology of psychosocial stress and heart failure.

Psychosocial Stress Induces Orofacial Mechanical Allodynia Due to the Enhancement of Transient Receptor Potential Ankyrin 1 Expression in Trigeminal Ganglion Neurons via the Increment of the Trace Amine-Associated Receptor 7f Expression

(1) Background: Chronic psychosocial stress can lead to oral dysesthesia with tongue pain. We examined whether psychosocial stress causes orofacial pain, and analyzed the comprehensive gene expression patterns of circulating cells and transient receptor potential ankyrin 1 (TRPA1) expression in trigeminal ganglion (TG) neurons in a mouse model of psychosocial stress. (2) Methods: Mice were divided into two groups: one group was kept in confrontational housing, and the other group was kept in single housing. Blood, adrenal gland, and tongue were collected. The head withdrawal threshold (HWT) of mechanical stimulation to the whisker pad skin was measured. TRPA1-positive TG neurons were immunohistochemically examined. DNA microarray analysis and quantitative reverse transcription polymerase chain reaction analysis were performed. (3) Results: The HWT was significantly lower in mice under the psychosocial stress condition compared to non-stressed mice. In stress-loaded mice, the number of TRPA1-positive TG neurons was significantly increased. Moreover, we showed that trace amine-associated receptor 7f expression was upregulated in circulating cells in blood and downregulated in the tongue. (4) Conclusions: Our results indicated that chronic psychosocial stress induced the orofacial mechanical allodynia through enhancement of TRPA1 expression in TG neurons with changes in the levels of trace amine-associated receptor 7f.

The PMN-MDSC – A key player in glucocorticoid resistance following combined physical and psychosocial trauma

Stress-associated somatic and psychiatric disorders are often linked to non-resolving low-grade inflammation, which is promoted at least in part by glucocorticoid (GC) resistance of distinct immune cell subpopulations. While the monocyte/macrophage compartment was in the focus of many clinical and preclinical studies, the role of myeloid-derived suppressor cells (MDSCs) in stress-associated pathologies and GC resistance is less understood. As GC resistance is a clear risk factor for posttraumatic complications in patients on intensive care, the exact interplay of physical and psychosocial traumatization in the development of GC resistance needs to be further clarified.In the current study we employ the chronic subordinate colony housing (CSC) paradigm, a well-characterized mouse model of chronic psychosocial stress, to study the role of myeloid cells, in particular of MDSCs, in innate immune activation and GC resistance following combined psychosocial and physical (e.g., bite wounds) trauma. Our findings support the hypothesis that stress-induced neutrophils, polymorphonuclear (PMN)-MDSCs and monocytes/monocyte-like (MO)-MDSCs get primed and activated locally in the bone marrow as determined by toll-like receptor (TLR)2 upregulation and increased basal and lipopolysaccharide (LPS)-induced in vitro cell viability. These primed and activated myeloid cells emigrate into the peripheral circulation and subsequently, if CSC is accompanied by significant bite wounding, accumulate in the spleen. Here, PMN-MDSCs and monocytes/MO-MDSCs upregulate TLR4 expression, which exclusively in PMN-MDSCs promotes NF-κB hyperactivation upon LPS-stimulation, thereby exceeding the anti-inflammatory capacities of GCs and resulting in GC resistance.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) System of the Central Amygdala Mediates the Detrimental Effects of Chronic Social Defeat Stress in Rats.

Many psychiatric diseases stem from an inability to cope with stressful events, as chronic stressors can precipitate or exacerbate psychopathologies. The neurobiological mechanisms underlying the response to chronic stress and the resulting anxiety states remain poorly understood. Stress neuropeptides in the extended amygdala circuitry mediate the behavioral response to stress, and hyperactivity of these systems has been hypothesized to be responsible for the emergence of persistent negative outcomes and for the pathogenesis of anxiety-related and trauma-related disorders. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1R are highly expressed within the central amygdala (CeA) and play a key role in stress regulation. Here, we used chronic social defeat stress (CSDS), a clinically relevant model of psychosocial stress that produces robust maladaptive behaviors in rodents. We found that 10 days of CSDS cause a significant increase in PACAP levels selectively in the CeA of rats, as well as an increase in PAC1R mRNA. Using a viral vector strategy, we found that PAC1R knock-down in the CeA attenuates the CSDS-induced body weight loss and prevents the CSDS-induced increase in anxiety-like behavior. Notably, CSDS animals display reduced basal corticosterone (CORT) levels and PAC1R knock-down in CeA further reduce them. Finally, the CeA PAC1R knock-down blocks the increase in corticotropin-releasing factor (CRF) immunoreactivity induced by CSDS in CeA. Our findings support the notion that the persistent activation of the PACAP-PAC1R system in the CeA mediates the behavioral outcomes of chronic psychosocial stress independently of the hypothalamic-pituitary-adrenal axis, perhaps via the recruitment of the CRF system.

Low-to-moderate level of perceived stress strengthens working memory: Testing the hormesis hypothesis through neural activation

The negative impact of stress on neurocognitive functioning is extensively documented by empirical research. However, emerging reports suggest that stress may also confer positive neurocognitive effects. This hypothesis has been advanced by the hormesis model of psychosocial stress, in which low-moderate levels of stress are expected to result in neurocognitive benefits, such as improved working memory (WM), a central executive function. We tested the hormesis hypothesis, purporting an inverted U-shaped relation between stress and neurocognitive performance, in a large sample of young adults from the Human Connectome Project (n = 1000, Mage = 28.74, SD = 3.67, 54.3% female). In particular, we investigated whether neural response during a WM challenge is a potential intermediary through which low-moderate levels of stress confer beneficial effects on WM performance. Further, we tested whether the association between low-moderate prolonged stress and WM-related neural function was stronger in contexts with more psychosocial resources. Findings showed that low-moderate levels of perceived stress were associated with elevated WM-related neural activation, resulting in more optimal WM behavioral performance (α *β = −0.02, p = .046). The strength of this association tapered off at high-stress levels. Finally, we found that the benefit of low-moderate stress was stronger among individuals with access to higher levels of psychosocial resources (β = −0.06, p = .021). By drawing attention to the dose-dependent, nonlinear relation between stress and WM, this study highlights emerging evidence of a process by which mild stress induces neurocognitive benefits, and the psychosocial context under which benefits are most likely to manifest.

Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis

Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid and oxidative homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.

Effect of the dietary intake of fish oil on psycho-social behavioral disorder caused by social-defeat stress

Exposure to psychosocial stress is a risk factor for human diseases such as depression. Social defeat stress (SDS) is a well-known rodent model of human psychosocial stress, and animals exposed to SDS show social avoidance behavior. Fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), is expected to decrease the risk of depressive disorders. In this study, we determined whether fish oil affects the social behavior of SDS-exposed mice and measured serotonin levels and expression of genes related to tryptophan (TRP) metabolism in the hippocampus. The experimental animals were fed a diet containing fish oil during SDS exposure. For the fish oil treatment, experimental mice were fed a diet containing fish oil at low (L-FO), middle (M-FO), and high (H-FO) concentrations. The control group was supplemented with an equivalent amount of canola oil (no fish oil: N-FO). After the SDS protocol, we performed a social interaction test and assessed the sociality of experimental mice. In the N-FO group, SDS-exposed mice showed negative social interactions compared with non-stressed mice. The L-FO and H-FO groups showed negative social interactions after SDS exposure; however, the M-FO group did not exhibit negative social behavior. The serotonin levels of SDS-exposed mice were lower than those of non-stressed mice in the N-FO group. In contrast with these results in the N-FO group, there was no difference in serotonin levels between SDS-exposed and non-stressed mice in the FO groups. In addition, the expression of genes related to TRP metabolism in SDS-exposed mice increased in the N-FO group, but not in the FO group. These results suggest that fish oil improves the psychosocial behavioral disorders caused by SDS. This improvement could be explained by the increase in serotonin synthesis in the hippocampus.

Ketamine sex- and dose-dependently mitigates behavioral sequelae induced by a predator-based psychosocial stress model of post-traumatic stress disorder

Current pharmacotherapy for post-traumatic stress disorder (PTSD), a debilitating psychiatric condition that develops in a subset of traumatized individuals, is inadequate. Over the past two decades, numerous studies have shown that ketamine, a non-competitive NMDA receptor antagonist, exerts rapid antidepressant effects in both humans and rodents, but the anxiolytic profile of ketamine, as well as its ability to treat PTSD-related symptoms, is still unclear. Thus, we examined the ability of a single administration of ketamine to prevent the onset of PTSD-like sequelae in a chronic psychosocial stress model of PTSD. Adult male and female Sprague-Dawley rats were exposed to a cat on two occasions, in combination with chronic social instability. Immediately following the cat exposure on Day 1, rats were given intraperitoneal injections of 10 mg/kg or 15 mg/kg ketamine or vehicle; control rats were injected with vehicle. Three weeks after the second cat exposure, we assessed symptoms of hyperarousal and anxiety-like behavior in the rats. In males, chronic stress led to greater anxiety on the elevated plus maze and in the open field; in females, chronic stress resulted in an exaggerated startle response and greater anxiety in the open field. These effects were most effectively prevented by the administration of 10 mg/kg ketamine. These findings demonstrate that ketamine can prophylactically prevent the onset of PTSD-like behaviors in males and females. Their sex-dependent nature is consistent with previous preclinical research and highlights the need for future research to examine their neurobiological basis.

A psychosocial stress model using witnessing social defeat scenes

A psychosocial stress model using witnessing social defeat scenes

Establishment of the Mouse Model of Social Avoidance Induced by Female-Directed Female Aggression

Background Most preclinical research on the effects of stress has been done on male subjects, even though women are more prone than men to experience stress-related problems. Chronic social defeat stress (CSDS) is a rodent model of psychosocial stress. However, this model has been challenged in female mouse studies since neither male nor female resident mice attack intruder females. A female-to-female CSDS model is needed to investigate the physiological and behavioral aspects. Methods The intruders were either male or female C57BL/6J mice, whereas the residents were male or ovariectomized (OVX) female CD-1 mice. The CD-1 aggressor mice had direct physical contact with the C57BL/6J mice for 10 min before initiating sensory contact with them for 24 h. Jump escape and freezing were evaluated during the social defeat of days 1 and 12. Experimental C57BL/6J mice underwent a social interaction test after suffering social defeat for 12 days. Results We found that the number of attack bites and attack latency had a significant negative correlation during the selection of aggressors. In the single-housed OVX mice, 34% of mice met the criterion of the selection of aggressors. However, single-housed OVX mice did not show sustained aggressive behavior (eg, attack bites) through the 12-day CSDS. As a result, we did not find susceptible mice during the social interaction test. In contrast, during the selection of aggressors, 42% of OVX mice housed with partners satisfied the criterion and displayed consistently aggressive behavior. CSDS produced susceptible (50%) and resilient (50%) phenotypes during the social interaction test. Notably, male and OVX female CD-1 mice housed with partners had similar amounts of attack bites and attack rates over the 12-day CSDS. Finally, we found that chronically socially defeated male and female mice displayed different coping behaviors (eg, active vs passive) with social defeat. Conclusions Our study demonstrates that OVX CD-1 mice housed with mates exhibited territorial aggression toward female intruders, producing susceptibility and resilience to social avoidance. Additionally, socially defeated male and female mice displayed different behavioral susceptibility to social defeat.

MGluR5-Mediated eCB Signaling in the Nucleus Accumbens Controls Vulnerability to Depressive-Like Behaviors and Pain After Chronic Social Defeat Stress.

Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice.

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship.