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Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility.

ABSTRACT: Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases.Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, orexin expression and activation were determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the orexin promoter. Designer receptors exclusively activated by designer drugs were used to inhibit orexin activation throughout repeated restraint to determine if the stress-related impairments in female rats could be reduced.Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared with male rats. Increased orexin expression and activation were observed in female rats compared with male rats. The higher expression of orexin messenger RNA in female rats was due to actions of glucocorticoid receptors on the orexin promoter, as determined by chromatin immunoprecipitation. Inhibition of orexins using designer receptors exclusively activated by designer drugs in female rats throughout repeated restraint abolished their heightened hypothalamic-pituitary-adrenal responsivity and reduced stress-induced cognitive impairments.Orexins mediate the impairments in adaptations to repeated stress and in subsequent cognitive flexibility exhibited by female rats and provide evidence for a broader role for orexins in mediating functions relevant to stress-related psychiatric diseases.

SUBMITTER: Grafe LA

PROVIDER: S-EPMC5359079 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility.

Grafe Laura A LA Cornfeld Amanda A Luz Sandra S Valentino Rita R Bhatnagar Seema S

Biological psychiatry 20161018 8

<h4>Background</h4>Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases.<h4>Methods</h4>Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive f ...[more]

PMID: 27955897

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Project description:Cognitive control and (cognitive) flexibility play an important role in an individual's ability to adapt to continuously changing environments. In addition to facilitating goal-directed behaviors, cognitive control and flexibility have been implicated in emotion regulation, and disturbances of these abilities are present in mood and anxiety disorders. In the context of stressful experiences, the reported studies examined processes related to cognitive control and flexibility, emotional regulation and depressive symptoms. To this end, a brief (18-item) self-report measure - the Cognitive Control and Flexibility Questionnaire (CCFQ) - was developed. This questionnaire measures an individual's perceived ability to exert control over intrusive, unwanted (negative) thoughts and emotions, and their ability to flexibly cope with a stressful situation. In Study 1, the CCFQ was assessed among both university students (N = 300) and a community sample (N = 302). Preliminary analyses suggested a stable and reliable two-factor structure, that of cognitive control over emotion, and appraisal and coping flexibility. Scores on the CCFQ were strongly associated with greater depressive symptoms, even after controlling for other measures that had been taken to reflect cognitive control and (in)flexibility (e.g., the Ruminative Response Scale; Perseverative Thinking Questionnaire). In Study 2 (N = 368), lower scores on the CCFQ were related to more negative stressor appraisals (i.e., greater perceived threat and uncontrollability) of a personally meaningful stressful event. Perceptions of threat and uncontrollability, in turn, partially accounted for the association between CCFQ subscale scores and depressive symptoms. The relation between lower CCFQ scores and heightened depressive symptoms was also partially accounted for by less frequent engagement in problem-focused coping and more use of emotion-focused methods. In Study 3 (N = 47 females), lower scores on the cognitive control over emotion component of the CCFQ predicted elevated negative affect and an exacerbated cortisol response following an acute psychosocial stressor (Trier Social Stress Test). The present research points to the CCFQ as a useful self-report tool to identify ways through which cognitive control and flexibility might be manifested in stressful situations, and how reductions in flexibility might be accompanied by elevated symptoms of depression.

Project description:OBJECTIVE:We determined whether there are sex differences in the prevalence and profile of HIV-associated neurocognitive impairment, and whether sex moderates the effect of HIV-serostatus on neurocognitive impairment among HIV-positive and HIV-negative individuals. Secondarily, we assessed whether differences were explained by greater biopsychosocial risk factors in HIV-positive women. DESIGN:An observational cohort study. METHODS:Analyses included 1361 HIV-positive (204 women) and 702 HIV-negative (214 women) (ages?=?18-79 years) participants from the UCSD HIV Neurobehavioral Research Program. Demographically corrected standardized T-scores from 15 neuropsychological tests were used to calculate domain-specific and global deficit scores (GDS). GDS at least 0.5 defined neurocognitive impairment. Biopsychosocial risk factors included low education, low reading level (education quality), lifetime substance use disorders, depressed mood (clinically significant depressive symptoms and/or current major depressive disorder) and a cumulative syndemic count (sum of biopsychosocial risk factors, range?=?0-4). Race-stratified analyses were conducted. Analyses were adjusted for relevant demographic and clinical factors. RESULTS:HIV-associated neurocognitive impairment was more prevalent in women versus men; however, the difference was eliminated after adjustment for reading level. In sex-stratified logistic regressions, the association between HIV-seropositivity and higher likelihood of neurocognitive impairment was stronger in women versus men; however, the association was attenuated in women, but not men, after adjusting for reading level. These results in the overall sample were specific to blacks. Sex differences in the profile of HIV-associated neurocognitive impairment varied by race. CONCLUSION:Women, particularly black women, were most at-risk for HIV-associated neurocognitive impairment. Higher rates of HIV-associated neurocognitive impairment in women versus men may reflect differences in educational quality.

Project description:BackgroundOur previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones?MethodsFor the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined.ResultsWe now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females.ConclusionsWe propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.

Project description:ImportanceSex differences in dementia risk are unclear, but some studies have found greater risk for women.ObjectiveTo determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.Design, setting, and participantsThis cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.ExposureSex.Main outcomes and measuresThe primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.ResultsAmong 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).Conclusions and relevanceThe results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

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Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility.

Publications

Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility.

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