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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. In a first experiment, we found that female rats exposed to adolescent SS also showed the decrement in social interaction irrespective of age at which tested, and replicated the effects previously found in males. In experiment 2, which involved females only, SS and CTL rats did not differ in anxiety-like behaviour in the elevated plus maze (EPM) and the reduction in social interaction was not significant. Nevertheless, when tested in adolescence at P47 (and not at P71), SS female rats had higher corticosterone release during the social interaction test than did CTL rats, and they exhibited a different pattern of neural activation as measured by immunoreactivity to the protein products of zif268 and c-fos (SS CTL in medial prefrontal cortex and SS CTL in hippocampus), and reduced oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus than did CTL rats. These results extend our previous findings of effects of SS in adolescent female rats on behavioural responses to psychostimulants to social behaviour, and point to directions for investigations of the neural mechanisms involved.

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. On PND 46, 24 h after the last stress exposure, SS rats had increased dendritic arborisation, a greater number of dendrite terminals, and a higher average dendrite branch order in the anterodorsal MeA compared with CTL rats. SS rats had reduced dendritic arborization and a reduced total length of dendrite matter in the anteroventral MeA and a reduced number of dendrite terminals in the posterodorsal MeA compared with CTL rats. Moreover, SS rats had a reduced number of dendritic spines in the dorsal LS compared with CTL rats. SS rats had less synaptophysin in the MeA and more CaMKII in the LS than did CTL rats, and did not differ in spinophilin, PSD95, or glucocorticoid receptor protein expression in the MeA and LS. We discuss how changes in neural structure and in markers of synaptic plasticity the MeA and LS of adolescent SS rats compared with CTL rats may underlie their differences in social behaviour.

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. The temporal pattern of corticosterone release after LPS differed between SS and control rats irrespective of the time since SS exposure in females, whereas in males, SS did not alter corticosterone release after LPS. Expression of genes in the hippocampus relevant to immune and HPA function differed between saline-treated SS and control rats depending on sex and time tested, but with lasting consequences of SS in both sexes. LPS-treatment altered hippocampal gene expression, with bigger effects of LPS evident in control than in SS female rats, and the opposite in male rats. Further, effects sometimes depended on the age at time of LPS treatment. SS and control rats differed in both fecal and colon microbiome composition in all but P46 males, and stress history, sex, and age influenced the effects of an immune challenge on the gut microbiome. In sum, adolescent stress history has consequences for immune function into adulthood that may involve effects on the gut microbiome.

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.

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). Regardless of OTR antagonism, adolescent SS rats spent more time in social approach (investigation through wire mesh) but less time in social interaction (physical interaction) with unfamiliar same-sex and same-age peers than did controls. However, OTR-A-treatment caused SS rats to be more socially avoidant than OTR-A-treated controls and saline-treated rats of the same condition. Additionally, the predicted rise in plasma corticosterone in response to OTR-A treatment was blunted in SS rats. Fos immunoreactivity (IR) was used as a marker of neural activation in social brain regions and oxytocin-IR was examined in the paraventricular nucleus of the hypothalamus (PVN) in response to interacting with unfamiliar peers in SS and control rats after OTR-A treatment. OTR-A treatment had little effect on Fos-IR and oxytocin-IR in the analyzed brain regions, but SS rats had lower Fos-IR and oxytocin-IR in the PVN and greater Fos-IR in subregions of the prefrontal cortex, and hippocampus, and lateral septum than did controls. Finally, binding density of OTR was measured in the PVN and hippocampus, and greater OTR binding density was found in the PVN of SS rats. Together, these data demonstrate a greater influence of OTR antagonism on social behaviour and a reduced influence of OTR antagonism on HPA responses after adolescent SS in male rats. The results also suggest that differences in neural functioning in the prefrontal cortex, hippocampus and lateral septum of adolescent SS rats may be involved in their altered social behaviour relative to that of controls.

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. In experiment 2, we found that individual differences in novelty-seeking behavior on PND 30 and SS exposure were unique predictors of anxiety in the elevated plus maze on PND 46, and interacted to predict social interaction on PND 47; among high novelty-seeking rats, SS and CTL rats do not differ, whereas among low-novelty seeking rats, SS rats engaged in less social interaction than did CTL rats. Thus, high novelty-seeking may be a resilience factor against the effects of social stressors in adolescence.

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. We confirmed that SS rats spent less time interacting with unfamiliar peers than did CTL rats (p=0.006). Furthermore, CTL rats showed a preference for novel over familiar conspecifics in a social recognition test whereas SS rats did not, which may reflect reduced recognition, impaired memory, or reduced preference for novelty in SS rats. The reward value of social interactions was not affected by SS based on conditioned place preference tests and based on the greater time SS rats spent investigating stimulus rats than did CTL rats when the stimulus rat was behind wire mesh (p=0.03). Finally, oxytocin receptor binding density was higher in the dorsal lateral septum and nucleus accumbens shell in SS rats compared with CTL rats (p=0.02, p=0.01, respectively). No effect of SS was found for vasopressin 1a receptor binding density in any of the brain regions analyzed. We discuss the extent to which the differences in social behavior exhibited after social instability in adolescence involve changes in social salience and social competency, and the possibility that changes in oxytocin signaling in the brain underlie the differences in social behavior.

Organ systems are sensitive to malleability by environmental stressors during times of rapid development and biological transitions. For the developing nervous system, there are three windows of heightened sensitivity to environmental stressors, the prenatal, neonatal, and adolescent periods, although the brain maintains some sensitivity throughout the lifespan. Glucocorticoid hormones are the signaling molecules that underlie the effects of environmental stressors, able to affect all aspects of neuronal development from cell birth to cell death. This chapter provides an overview of how environmental stressors result in long-lasting changes during the different windows of brain development. The extent to which stress-induced developmental changes are adaptive or maladaptive depends on the neural region, the severity and duration of the stressor exposure, the sex and genotype of the individual, and the quality of the individual’s environment in life stages beyond the stress exposures.

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. Nevertheless, in each, adolescents had higher post-stress concentrations of corticosterone compared to adults despite similar concentrations of testosterone. The effect of testosterone was in the opposite direction in post-pubertal adolescents compared to that in adults, with testosterone replacement leading to increased rather than lower corticosterone concentration. Testosterone replacement decreased arginine vasopressin and corticotrophin-releasing hormone immune-reactive cell counts in the paraventricular nucleus at all ages. In a fourth experiment, we provide evidence that the basis of the age difference in corticosterone release is because of a greater conversion of testosterone to oestradiol in adolescents and a greater conversion of testosterone to dihydrotestosterone in adults: aromatase inhibition had little effect in adults and attenuated the age difference by decreasing stress-induced corticosterone release in adolescents. By contrast, 5α-reductase inhibition or an androgen receptor antagonist had little effect in adolescents and attenuated the age difference by increasing stress-induced corticosterone release in adults. In the adrenal gland, adolescents had reduced 5α-reductase and androgen receptor gene expression. There also were age differences in the regulation of hypothalamic mRNA expression of androgen receptors, oestrogen receptors and aromatase by testosterone. In sum, the results suggest that developmental shifts in the synthesis of testosterone and the regulation of gene expression are factors with respect to age differences in corticosterone release in response to stressors.

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 (p0.001). Both ages showed evidence of habituation, with reduced corticosterone response to repeated than acute isolation (p=0.01). Adolescents, however, showed sensitized corticosterone release to repeated compared with an acute pairing with an unfamiliar peer during recovery (p=0.03), a difference not found in adults. Consistent with habituation of corticosterone release, the repeated isolation groups had lower Zif268 immunoreactive cell counts in the paraventricular nucleus (p0.001) and in the arcuate nucleus (p=0.002) than did the acute groups, and adolescents had higher Zif268 immunoreactive cell counts in the paraventricular nucleus than did adults during the recovery period (p0.001), irrespective of stress history and partner familiarity. Partner familiarity had only modest effects on Zif268 immunoreactivity, and experimental effects on plasma testosterone concentrations were only in adults. The results highlight social and endocrine factors that may underlie the greater vulnerability of the adolescent period of development.

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. Further, though both the low (0.1 mg/kg) and high (0.5 mg/kg) dose of ACEA facilitated fear extinction, the low dose attenuated, and the high dose potentiated, fear induced corticosterone release suggesting independent effects of the drug on fear and stress responses. Although the extent to which cannabinoids are anxiogenic or anxiolytic has been proposed to be dose-dependent, these results indicate that the same dose has differential effects across tasks, likely based in differences in sensitivities of CB1 receptors to the agonist in the neural regions subserving unconditioned and conditioned fear.

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.