Leveraging research into sex differences and steroid hormones to improve brain health.

Sex differences, driven in part by steroid hormones, shape the structure and function of the brain throughout the lifespan and manifest across brain health and disease. The influence of steroid hormones on neuroplasticity, particularly in the adult hippocampus, differs between the sexes, which has important implications for disorders and diseases that compromise hippocampus integrity, such as depression and Alzheimer disease. This Review outlines the intricate relationship between steroid hormones and hippocampal neuroplasticity across the adult lifespan and explores how the unique physiology of male and female individuals can affect health and disease.

Inflammatory signalling during the perinatal period: Implications for short- and long-term disease risk.

During pregnancy and the postpartum, there are dynamic fluctuations in steroid and peptide hormone levels as well as inflammatory signalling. These changes are required for a healthy pregnancy and can persist well beyond the postpartum. Many of the same hormone and inflammatory signalling changes observed during the perinatal period also play a role in symptoms related to autoimmune disorders, psychiatric disorders, and perhaps neurodegenerative disease later in life.

Neural Mechanisms Mediating Sex Differences in Motivation for Reward: Cognitive Bias, Food, Gambling, and Drugs of Abuse.

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.

Sex differences in inflammation in the hippocampus and amygdala across the lifespan in rats: associations with cognitive bias.

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 in rats that varied with age.

Sex and age differences in cognitive bias and neural activation in response to cognitive bias testing.

Cognitive symptoms of depression, including negative cognitive bias, are more severe in women than in men. Current treatments to reduce negative cognitive bias are not effective and sex differences in the neural activity underlying cognitive bias may play a role. Here we examined sex and age differences in cognitive bias and functional connectivity in a novel paradigm.

An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences.

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.

Steroid hormones and hippocampal neurogenesis in the adult mammalian brain.

Hippocampal neurogenesis persists across the lifespan in many species, including rodents and humans, and is associated with cognitive performance and the pathogenesis of neurodegenerative disease and psychiatric disorders. Neurogenesis is modulated by steroid hormones that change across development and differ between the sexes in rodents and humans. Here, we discuss the effects of stress and glucocorticoid exposure from gestation to adulthood as well as the effects of androgens and estrogens in adulthood on neurogenesis in the hippocampus.

Social Instability Stress in Adolescence and Social Interaction in Female Rats.

Adolescence is a critical time of brain development for regions governing social behaviour and social learning. Social experiences influence the ongoing maturation of the neural structures and ultimately modify the social behaviour of adults in response to social cues. Social instability stress in adolescence (SS; daily 1-hour isolation + change of cage partner in postnatal days [PND] 30-45) leads to a long-lasting reduction in social interaction in SS rats compared with non-stressed (CTL) rats in males; here we investigate females.

Sex differences in cortisol and memory following acute social stress in amnestic mild cognitive impairment.

Objective: Older adults with amnestic mild cognitive impairment (aMCI) develop Alzheimer's type dementia approximately 10 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.

Adolescent social instability stress leads to immediate and lasting sex-specific changes in the neuroendocrine-immune-gut axis in rats.

Social instability stress (SS; daily 1 h isolation and change of cage partner from postnatal day (P) 30-45) in adolescence produces elevations in corticosterone during the procedure in male and female rats, but no lasting changes in hypothalamic-pituitary-adrenal (HPA) responses to psychological stressors, although deficits in social and cognitive function are evident in adulthood. Here we investigated the effects of SS in corticosterone response to an immune challenge (lipopolysaccharide, LPS, 0.1 mg/kg), on gene expression in the hippocampus, and on gut microbiota, when tested soon- (P46) or long- (P70) after SS.

Perinatal depression: Heterogeneity of disease and in animal models.

Perinatal depression (PND) can have either an antepartum or postpartum onset. Although the greatest risk factor for PND is previous depression history,de novoPND occurs with the majority of cases occurring in the postpartum. Timing of depression can impact etiology, prognosis, and response to treatment.

The effects of social instability stress and subsequent ethanol consumption in adolescence on brain and behavioral development in male rats.

Excessive drinking in adolescence continues to be a problem, and almost a quarter of young Canadians have reported consuming five or more alcoholic drinks in one occasion in recent surveys. The consequences of such drinking may be more pronounced when commenced in adolescence, given the ongoing brain development during this period of life. Here, we investigated the consequences of 3 weeks' intermittent access to ethanol in mid-adolescence to early adulthood in rats, and the extent to which a stress history moderated the negative consequences of ethanol access.

Effects of oxytocin receptor antagonism on social function and corticosterone release after adolescent social instability in male rats.

Oxytocin influences social behaviour and hypothalamic-pituitary-adrenal (HPA) function. We previously found that social instability stress (SS) from postnatal day 30 to 45 increased oxytocin receptor (OTR) densities in the lateral septum and nucleus accumbens of adolescent male rats. Here, we investigated social behaviour and HPA function in adolescent male SS rats compared with age- and sex-matched controls after intraperitoneal treatment with an OTR antagonist L-368,899 (OTR-A).

Age-dependent regulation by androgens of gene expression in the anterior hypothalamus and stress-induced release of adrenal hormones in adolescent and adult male rats.

Adolescents show greater and/or more prolonged activation of the hypothalamic-pituitary-adrenal axis in response to stressors than adults, although the basis for such an age difference is not understood. We investigated developmental shifts in the regulation of HPA function by testosterone using androgen replacement in orchiectomised (OCX) pre-pubertal and post-pubertal adolescent rats and in adults, as well as using inhibitors of testosterone synthesis in non-operated rats. The expected dampening effect of testosterone in adult OCX rats did not meet statistical significance in all of the three experiments.

Adolescent social instability stress alters markers of synaptic plasticity and dendritic structure in the medial amygdala and lateral septum in male rats.

Much evidence indicates that experiences in adolescence can alter the development of social behaviour. We previously demonstrated that male rats exposed to social instability stress in adolescence (SS; 1 h isolation and return to an unfamiliar cagemate daily from postnatal day [PND] 30-45) had reduced social interaction, impaired social recognition, reduced sexual performance, and increased aggression in competition for food reward compared with non-stressed control (CTL) rats. Here, we investigated whether SS affects stellate neuron morphology using the Golgi-Cox method and several markers of synaptic plasticity using western blotting in the medial amygdala (MeA) and lateral septum (LS), sites involved in social behaviour.

Adolescent social stress and social context influence the intake of ethanol and sucrose in male rats soon and long after the stress exposures.

Social instability stress in adolescent rats (SS; postnatal day 30-45, daily 1 hr isolation +new cage partner) alters behavioural responses to psychostimulants, but differences in voluntary consumption of natural and drug rewards are unknown. SS also is associated with an atypical behavioural repertoire, for example reduced social interactions. Here, we investigated whether SS rats differ from control (CTL) rats in ethanol (EtOH) or sucrose intake in experiments involving different social contexts: alone, in the presence of an unfamiliar peer, in the presence of its cage partner, or in competition against its cage partner.

Predictors of social instability stress effects on social interaction and anxiety in adolescent male rats.

Adolescence is an important phase of development of social behaviors, which may be disrupted by the experience of stressors. We previously reported that exposure to social instability stress in adolescence (SS; postnatal day [PND] 30-45) in rats reduced social interactions with unfamiliar peers compared with non-stressed controls (CTL). In experiment 1, we replicated the effect of SS on social interaction and found that the pattern of neural activations based on Fos immunohistochemistry in brain regions during social interactions differed for SS and CTL rats.

Social instability stress in adolescent male rats reduces social interaction and social recognition performance and increases oxytocin receptor binding.

Social experiences in adolescence are essential for displaying context-appropriate social behaviors in adulthood. We previously found that adult male rats that underwent social instability stress (SS) in adolescence had reduced social interactions with unfamiliar peers compared with non-stressed controls (CTL). Here we determined whether SS altered social recognition and social reward and brain oxytocin and vasopressin receptor density in adolescence.

The sexual preference of female rats is influenced by males' adolescent social stress history and social status.

Ongoing development of brain systems for social behaviour renders these systems susceptible to the influence of stressors in adolescence. We previously found that adult male rats that underwent social instability stress (SS) in mid-adolescence had decreased sexual performance compared with control males (CTL). Here, we test the hypotheses that SS in adolescence decreases the "attractiveness" of male rats as sexual partners compared with CTL rats and that dominance status is a protective factor against the effects of SS.

Adolescent and adult male rats habituate to repeated isolation, but only adolescents sensitize to partner unfamiliarity.

We investigated whether adolescent male rats show less habituation of corticosterone release than adult male rats to acute vs repeated (16) daily one hour episodes of isolation stress, as well as the role of partner familiarity during recovery on social behavior, plasma corticosterone, and Zif268 expression in brain regions. Adolescents spent more time in social contact than did adults during the initial days of the repeated stress procedures, but both adolescents and adults that returned to an unfamiliar peer after isolation had higher social activity than rats returned to a familiar peer (p=0.002) or undisturbed control rats (p<0.

Differential effects of CB1 receptor agonism in behavioural tests of unconditioned and conditioned fear in adult male rats.

We investigated the effects of the highly selective CB1 receptor agonist ACEA and the CB1 receptor antagonist/inverse agonist AM251 on two behavioural tests of unconditioned fear, the elevated plus maze (EPM) and open field test (OFT), as well as on the recall and extinction of a conditioned auditory fear. Both ACEA and AM251 increased anxiety-like behaviour in the EPM and OFT. There was no effect of either drug on recall of the conditioned fear, and ACEA enhanced and AM251 impaired fear extinction.

Peer pressures: social instability stress in adolescence and social deficits in adulthood in a rodent model.

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 social context on endocrine function and Zif268 expression in response to an acute stressor in adolescent and adult rats.

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 1h of isolation stress and after either 1 or 3h of recovery back in the colony with either a familiar or unfamiliar cage partner.