McCormick CM, Mathews IZ. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav 86: 220-233

Behavioural Neuroscience, Center for Neuroscience and Department of Psychology, Brock University, St Catharines ON, Canada.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 03/2007; 86(2):220-33. DOI: 10.1016/j.pbb.2006.07.012
Source: PubMed


The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.

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    • "Males and females exhibit different stress sensitivity and coping mechanisms; In contrast to males, who habituate to chronic stress situations, females show a longer, more robust stress-induced rise in CORT levels (Falconer and Galea, 2003; Galea et al., 1997) and express higher peak CORT levels in response to stress (McCormick and Mathews, 2007). Moreover it has to be kept in mind that the qualities depends on the stressor employed and the species (Bowman et al., 2001; Dalla et al., 2008; Wolf et al., 2001). "
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    ABSTRACT: The peripartum period represents a time when all mammalian species undergo substantial physiological and behavioural changes, which prepare the female for the demands of motherhood. In addition to behavioural and physiological alterations, numerous brain regions, such as the medial prefrontal cortex, olfactory bulb, medial amygdala and hippocampus are subject to substantial peripartum-associated neuronal, dendritic and synaptic plasticity. These changes, which are temporally- and spatially-distinct are strongly influenced by gonadal and adrenal hormones, such as estrogen and cortisol/corticosterone, which undergo dramatic fluctuations across this period. In this review, we describe our current knowledge regarding these plasticity changes and describe how stress affects such normal adaptations. Finally, we discuss the mechanisms potentially underlying these neuronal, dendritic and synaptic changes and their functional relevance for the mother and her offspring.
    Full-text · Article · Jan 2016 · Frontiers in Neuroendocrinology
    • "Adolescence is a developmental period of increased stress vulnerability because of the ongoing neuroplasticity (Compas et al, 1993; McCormick and Mathews, 2007) and the immaturity of adaptive processes that are necessary for coping (Gunnar et al, 2009; McCormick and Mathews, 2010; McCormick et al, 2010). For individuals exposed to early life stress, the inability to appropriately adapt to stressors could contribute to the development of psychiatric disorders in adulthood (Halligan et al, 2007; Lupien et al, 2009). "
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    ABSTRACT: Early life stress is associated with the development of psychiatric disorders. Because the locus coeruleus-norepinephrine (LC-NE) system is a major stress-response system that is implicated in psychopathology, developmental differences in the response of this system to stress may contribute to increased vulnerability. Here LC single unit and network activity were compared between adult and adolescent rats during resident-intruder stress. In some rats LC and medial prefrontal cortex (mPFC) coherence was quantified. The initial stress tonically activated LC neurons and induced theta oscillations, while simultaneously decreasing LC auditory-evoked responses in both age groups. Stress increased LC-mPFC coherence within the theta range. With repeated exposures, adolescent LC neuronal and network activity remained elevated even in the absence of the stressor and were unresponsive to stressor presentation. In contrast, LC neurons of adult rats exposed to repeated social stress were relatively inhibited in the absence of the stressor and mounted robust responses upon stressor presentation. LC sensory-evoked responses were selectively blunted in adolescent rats exposed to repeated social stress. Finally, repeated stress decreased LC-mPFC coherence in the high frequency range (beta and gamma) while maintaining strong coherence in the theta range, selectively in adolescents. Together, these results suggest that adaptive mechanisms that promote stress recovery and maintain basal activity of the brain norepinephrine system in the absence of stress are not fully developed or are vulnerable stress-induced impairments in adolescence. The resulting sustained activation of the LC-NE system after repeated social stress may adversely impact on cognition and future social behavior of adolescents.Neuropsychopharmacology accepted article preview online, 11 September 2015. doi:10.1038/npp.2015.289.
    No preview · Article · Sep 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Interestingly, when glucocorticoid negative feedback was already lost in Sim1Cre GRe3D mice, the difference between sexes at circadian peak is also lost; suggesting perhaps that the function of estradiol may also depend on PVN GR availability. There may also be an influence of CBG which binds to circulating glucocorticoids and regulates its bioavailability (Mattos et al., 2013), and is expressed more in females than males (Mataradze et al., 1992; McCormick & Mathews, 2007; Tinnikov, 1999). Interactions between sex hormones, CBG and GR may therefore contribute to the differences observed in our studies. "
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    ABSTRACT: Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as post-natal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at post-natal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.
    Full-text · Article · Jun 2015 · Stress (Amsterdam, Netherlands)
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