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Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Background: Cognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of males and females across the lifespan. Results: After cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males. Conclusions: Overall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.

Sex differences exist in a variety of neurological and psychiatric diseases in terms of prevalence, manifestation, and treatment but most past research has been conducted in males. Multiple mandates have been initiated across funding agencies (National Institute of Health, Horizon Europe, Canadian Institute for Health Research) and scientific publishers (Sex and Gender Equity in Research) for biomedical and clinical research to include both males and females in research and reporting. Although more studies are including males and females in their research there are issues in how studies are incorporating males and females in their experiments, as about a third of studies that use males and females do not report sample size and only half are conducting any analysis by sex. Furthermore, what has been lacking in the literature is a detailed assessment of not only how sex is reported in papers (e.g. sample sizes disclosed, balanced design, sex used consistently throughout the experiments) but also how the variable sex is included in any analyses (e.g. covariate). Here we investigated all papers in 2009 and 2019 in three high ranking journals for each of Neuroscience and Psychiatry. We found that there was a 30% increase in the percentage of papers that included both sexes from 2009 to 2019 such that 68% of studies in Neuroscience and Psychiatry used both males and females in 2019. Despite this increase, in 2019 only 19% of all studies used an optimal design for discovery of possible sex differences and only 5% analyzed with sex as a discovery variable. Of the studies that used males and females - 25% of studies do not disclose sample sizes, 36% of studies used an unbalanced design, and 15% of studies did not use both sexes consistently throughout the paper. The percentage of single sex papers remains unchanged across the ten years at 3% for female-only studies compared to 27% for male-only studies across both disciplines. Neuroscience had fewer papers that analyzed by sex at 20% compared to 61% of Psychiatry papers. We hope that these data will make it evident that more needs to be done to improve the inclusion of males and females in future studies to improve the health of men and women.

Sex differences exist in many neurological and psychiatric diseases, but these have not always been addressed adequately in research. In order to address this, it is necessary to consider how sex is incorporated into the design (e.g. using a balanced design) and into the analyses (e.g. using sex as a covariate) in the published literature. We surveyed papers published in 2009 and 2019 across six journals in neuroscience and psychiatry. In this sample, we find a 30% increase in the percentage of papers reporting studies that included both sexes in 2019 compared with 2009. Despite this increase, in 2019 only 19% of papers in the sample reported using an optimal design for discovery of possible sex differences, and only 5% of the papers reported studies that analysed sex as a discovery variable. We conclude that progress to date has not been sufficient to address the importance of sex differences in research for discovery and therapeutic potential for neurological and psychiatric disease.

ObjectiveOlder adults with amnestic mild cognitive impairment (aMCI) develop Alzheimer’s type dementia approximately ten times faster annually than the normal population. Adrenal hormones are associated with aging and cognition. We investigated the relationship between acute stress, cortisol, and memory function in aMCI with an exploratory analysis of sex.MethodSalivary cortisol was sampled diurnally and during two test sessions, one session with the Trier Social Stress Test (TSST), to explore differences in the relationship between cortisol and memory function in age-normal cognition (NA) and aMCI. Participants with aMCI (n=6 women, 9 men; mean age=75) or similarly aged NA (n=9 women, 7 men, mean age=75) were given tests of episodic, associative, and spatial working memory with a psychosocial stressor (TSST) in the second session.ResultsThe aMCI group performed worse on the memory tests than NA as expected, and males with aMCI had elevated cortisol levels on test days. Immediate episodic memory was enhanced by social stress in NA but not in the aMCI group, indicating that stress-induced alterations in memory are different in individuals with aMCI. High cortisol was associated with impaired performance on episodic memory in aMCI males only. Cortisol in Session 1 moderated the relationship with spatial working memory, whereby higher cortisol was associated with worse performance in NA, but better spatial working memory in aMCI. In addition, effects of aMCI on perceived anxiety in response to stress exposure were moderated by stress-induced cortisol in a sex-specific manner.ConclusionsWe show effects of aMCI on Test Session cortisol levels and effects on perceived anxiety, and stress-induced impairments in memory in males with aMCI in our exploratory sample. Future studies should explore sex as a biological variable as our findings suggests that effects at the confluence of aMCI and stress can be obfuscated without sex as a consideration.

Highlights • There are behavioural and physical parallels between adolescence in rats and humans. • Adolescent social instability stress in rats impairs adult social behaviour. • The developmental trajectory of the hippocampus is altered by adolescent stressors. • Age differences in stress-induced corticosterone release are stressor-specific. • Animal models provide insights into developmental stage-specific vulnerability., Studies in animal models generate and test hypotheses regarding developmental stage-specific vulnerability that might inform research questions about human development. In both rats and humans, peer relationships are qualitatively different in adolescence than at other stages of development, and social experiences in adolescence are considered important determinants of adult social function. This review describes our adolescent rat social instability stress model and the long-lasting effects social instability has on social behaviour in adulthood as well as the possible neural underpinnings. Effects of other adolescent social stress experiences in rats on social behaviours in adulthood also are reviewed. We discuss the role of hypothalamic–pituitary–adrenal (HPA) function and glucocorticoid release in conferring differential susceptibility to social experiences in adolescents compared to adults. We propose that although differential perception of social experiences rather than immature HPA function may underlie the heightened vulnerability of adolescents to social instability, the changes in the trajectory of brain development and resultant social deficits likely are mediated by the heightened glucocorticoid release in response to repeated social stressors in adolescence compared to in adulthood.

a b s t r a c t There is a paucity of studies comparing social buffering in adolescents and adults, despite their marked differences in social behavior. We investigated whether greater effects of social buffering on plasma corticosterone concentrations and expression of Zif268 in neural regions after an acute stressor would be found in adolescent than adult rats. Samples were obtained before and after 1 h of isolation stress and after either 1 or 3 h of recovery back in the colony with either a familiar or unfamiliar cage partner. Adolescent and adult rats did not differ in plasma concentrations of corticosterone at any time point. Corticosterone concentrations were higher after 1 h isolation than at baseline (p < 0.001), and rats with a familiar partner during the recovery phase had lower corticosterone concentrations than did rats with an unfamiliar partner (p = 0.02). Zif268 immunoreactive cell counts were higher in the arcuate nucleus in both age groups after isolation (p = 0.007) and in the paraventricular nucleus of adolescents than adults during the recovery phase irrespective of partner familiarity. There was a significant decrease in immunoreactive cell counts after 1 h isolation compared to baseline in the basolateral amygdala, central nucleus of the amygdala, and in the pyramidal layer of the hippocampus (all p < 0.05). An effect of partner familiarity on Zif268 immunoreactive cell counts was found in the granule layer of the dentate gyrus irrespective of age (higher in those with a familiar partner, p = 0.03) and in the medial prefrontal cortex in adolescents (higher with an unfamiliar partner, p = 0.02). Overall, the acute stress and partner familiarity produced a similar pattern of results in adolescents and adults, with both age groups sensitive to the social context.