Neuroscience
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Review
The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior.
Adolescence is a period of significant neurobiological change that occurs as individuals transition from childhood to adulthood. Because the nervous system is in a relatively labile state during this stage of development, it may be especially sensitive to experience-induced plasticity. ⋯ Whenever possible, our focus is on studies that use comparison groups of adolescent- and adult-exposed subjects as this is a more direct test of the hypothesis that adolescence represents a period of enhanced vulnerability to the effects of drug-induced plasticity. Lastly, we suggest areas of future investigation that are needed and methodological concerns that should be addressed.
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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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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.
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Adolescence is a time of continued brain maturation, particularly in limbic and cortical regions, which undoubtedly plays a role in the physiological and emotional changes coincident with adolescence. An emerging line of research has indicated that stressors experienced during this crucial developmental stage may affect the trajectory of this neural maturation and contribute to the increase in psychological morbidities, such as anxiety and depression, often observed during adolescence. ⋯ More specifically, we examine how stress at prepubertal and early adolescent stages of development affects the morphological plasticity of limbic and cortical brain regions, as well as the enduring effects of adolescent stress exposure on these brain regions in adulthood. We suggest that, due to a number of converging factors during this period of maturation, the adolescent brain may be particularly sensitive to stress-induced neurobehavioral dysfunctions with important consequences on an individual's immediate and long-term health and well-being.
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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.