Early chronic stress effects on hypothalamic and amygdala function: the role of endocannabinoids, corticosterone and maternal care as regulators

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Stress is at the core of a multitude of diseases because of its large and prolonged impact on brain neurotransmission and plasticity, which increases vulnerability to illness. Exposure to stressful events during the developmental period is now recognized to shape physiological and behavioral regulation, although the mediating mechanisms are still uncertain. Our research focus will be to understand how repeated stress during postnatal life shapes the responsiveness and interactions between the hypothalamus-pituitary-adrenal (HPA) axis, the convergent neuroendocrine effector of stress responses, and the limbic system (including the amygdala), which integrates fear and emotions. We propose that early repeated stressful experience in the form of either repeated short maternal isolation periods or modest inflammatory pain will permanently alter morphology and synaptic plasticity in the amygdala, hypothalamus and paraventricular thalamus, a structure that is typically activated following chronic stress. We will test the hypothesis that these functional and morphological changes are due to the tonic increase of glucocorticoid secretion and functional changes in the endocannabinoid signal within these structures. This will lead to an accelerated recruitment of the amygdala, conferring premature hypersensitivity to stress and behavioral fear learning in young pups. Finally, we suggest that disorganized maternal care during this same critical developmental period will induce changes to the extended stress circuitry in pups that are similar to those induced by chronic stress and that maternal "neglect" associated with repeated stress will enhance the severity of the long term outcome. These experiments have the potential to identify not only those facets of the extended stress circuitry that are altered by early repeated stress exposure but also to pinpoint endocannabinoids as potential critical mediators regulating the timing and onset of responsivity and accelerated "maturation" in the extended stress circuitry.