Sex‐specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice

Abstract

Psychosocial stress promotes and links mood and cardiovascular disorders in a sex‐specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti‐inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress‐related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex‐specific mechanisms and potential approaches to stress‐dependent disease.

The sex-dependent response to psychosocial stress and ischaemic heart disease

“…The gut microbiome, the gut-brain axis and its involvement in stress-related disease, also appear sex-dependent, as are the influences of early life programming/epigenetic control, and the conditioning effects of prior stress. Our own recent work supports greater biological stress or allostatic load in female vs. male rodents subjected to chronic social stress, with evidence of greater coronary dysfunction, anxiety-like behaviour, weight loss and inflammation in females (12). However, mixed findings emerge from different animal studies, including evidence females are more susceptible to neuroendocrine and behavioural disruption (and selectively more sensitive to the cardiovascular/autonomic effects of homotypic stress) while males are more vulnerable to somatic effects of chronic stress (65).…”

“…In contrast, restraint stress selectively increases hypothalamus leptin in females (275). We recently report a fall in circulating leptin in socially stressed male but not female mice (12). Increases in leptin, potentially reflecting emerging leptinresistance, are linked to detrimental cardio-metabolic outcomes (276,277), and have been linked to disturbed ANS control and reduced heart rate variability (278).…”

“…It has been reported that chronic restraint stress reduces abdominal fat deposition in male rats while increasing fat in females (524). On the other hand, chronic social stress may induce weight loss specifically in female and not male mice (12).…”

“…These include changes in nervous and endocrine control of the cardiovascular system, whole body metabolism, immuno-inflammatory function and gut biology, together with affective/behavioural responses that reinforce cardiometabolic disease development (including inactivity, hyperphagia and biased selection of palatable sugarand fat-rich foods). Critically, the mammalian stress response and its systemic influences are highly sex-dependent, a fundamental yet still under-studied basis for sex specific disease risks and outcomes (12).…”

Evidence-based core information for health communication of tobacco control: The effect of smoking on risks of female disease

“…Especially for women, changes in their sex hormone levels (for example, the “recession” of sex hormones in menopausal women aged 45–55 years old, causing a series of physiological changes, imbalances in Nervous system activity and reduced adaptability to the outside world), as well as social stereotypes and low inclusion of women, lead to a higher prevalence of depression in this group, resulting in high smoking rates. Besides, female smoking groups are more likely to be discriminated against and stigmatized in social life ( 68 ), and they themselves are more sensitive and vulnerable to social impact (such as more passive to be exposed to smoking, more susceptible to negative emotions with smoking addiction) ( 69 ), causing further damage to their mental health. Our study found that the quality of evidence, the degree of public demand and the results of expert assessments are relatively consistent and low in this area ( Table 7 ).…”