Neuroscience
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Review
From the stressed adolescent to the anxious and depressed adult: investigations in rodent models.
Anxiety and depression are the most prevalent of the psychiatric disorders. The average age of onset of these disorders is in adolescence, and stressful experiences are recognized as an important pathway to such dysfunction. ⋯ The focus of the review is investigations in which adolescent rodents were exposed to chronic stressors, describing our research using social instability stress and that of other researchers using various social and non-social stressors. The evidence to date suggests stress in adolescence alters the trajectory of brain development, and particularly that of the hippocampus, increasing anxiety and depressive behaviour in adulthood.
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The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. ⋯ The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild-type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated Nrg1(Tn) females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function.
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Early exposure to stressful life events plays a significant role in adolescent depression. Clinical studies have identified a number of factors that increase the risk of depression, including sex of the subject, duration of the stressor, and genetic polymorphisms that elevate serotonin levels. In this study we used the maternal separation (MS) model to investigate to what extent these factors interacted during development to manifest in depressive-like behavior in male and female rats. ⋯ Fluoxetine exposure at P9-16 increased helplessness in controls. Fluoxetine decreased helplessness in MS males independent of age, but increases helplessness in MS females. This study highlights the importance of age of MS (MS between P2-9 increases helplessness in males more than females), the duration of the stressor (previous results show females are effected by longer MS [P2-20], but not shorter [this study]), and that elevated serotonin increases escape latencies to a greater extent in females.
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Chronic stress is known to modulate cannabinoid CB1 receptor binding densities in corticolimbic structures, in a region-dependent manner; however, the ontogeny of these changes and the degree to which they recover following exposure to stress have yet to be determined. To this extent, we examined both the immediate and sustained effects (following a 40-day recovery period) of a repeated restraint stress paradigm (30-min restraint/day for 10 days) on CB1 receptor binding in the prefrontal cortex (PFC), hippocampus and amygdala in both adolescent (stress onset at post-natal day [PND] 35) and adult (stress onset at PND 75) male Sprague-Dawley rats. Consistent with previous reports, we found that repeated stress in adult rats resulted in an increase in CB1 receptor binding in the PFC, a reduction in CB1 receptor binding in the hippocampus and no effect in the amygdala. ⋯ Adolescents similarly exhibited this rebound increase in hippocampal CB1 receptor binding, despite a lack in immediate downregulation following repeated restraint. Of particular interest, adolescents exposed to stress were found to have a sustained downregulation of prefrontocortical CB1 receptors in adulthood, which may relate to some of the reported sustained behavioral effects of stress in adolescence. Collectively, these data indicate that the effects of chronic stress on cannabinoid CB1 receptor binding are modulated by the age of stress exposure and period of recovery following the cessation of stress.
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In adult rodents, endocannabinoids (eCBs) regulate fast glucocorticoid (GC) feedback in the hypothalamus-pituitary adrenal (HPA) axis, acting as retrograde messengers that bind to cannabinoid receptors (CB1R) and inhibit glutamate release from presynaptic CRH neurons in the paraventricular nucleus of the hypothalamus (PVN). During the first two weeks of life, rat pups exhibit significant CRH and ACTH responses to stress although the adrenal GC output remains reduced. At the same time, pups also display increased sensitivity to GC feedback, but it is unclear whether eCBs play a role in mediating fast GC feedback in neonatal life. ⋯ Methylprednisolone suppressed ACTH stress responses although AM251 still delayed restoration of ACTH levels to the baseline. This suggests that the eCB effect on ACTH secretion in neonates is most evident when there is a dynamic fluctuation of corticosterone levels. Interestingly, AM251 increased basal and stimulated corticosterone secretion in all treatments including MET, suggestive of a direct action of CB1R blockade on adrenal steroidogenesis.