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

压力是许多疾病的核心，因为它对大脑神经传递和可塑性产生巨大而持久的影响，从而增加了对疾病的脆弱性。在发育期间暴露于压力事件现在被认为是形成生理和行为调节，虽然调解机制仍然不确定。我们的研究重点将是了解在出生后的生活中反复的压力如何塑造下丘脑-垂体-肾上腺（HPA）轴，压力反应的会聚神经内分泌效应器和边缘系统（包括杏仁核）之间的反应和相互作用，整合恐惧和情绪。我们提出，早期重复的压力经验，无论是重复的短期产妇隔离期或温和的炎症性疼痛的形式将永久改变形态和突触可塑性的杏仁核，下丘脑和室旁丘脑，一个结构，通常是激活慢性应激。我们将测试的假设，这些功能和形态的变化是由于紧张性增加糖皮质激素分泌和功能的变化，在这些结构内的内源性大麻素信号。这将导致杏仁核的加速募集，使幼犬对压力和行为恐惧学习过早过敏。最后，我们认为，混乱的孕产妇护理在同一个关键的发展时期将引起变化的扩展压力电路在小狗是类似的慢性压力和母亲的“忽视”与反复的压力将提高长期的严重后果。这些实验不仅有可能确定那些方面的扩展的压力电路，改变了早期重复的压力暴露，但也查明内源性大麻素作为潜在的关键介质调节的时间和发病的响应性和加速“成熟”的扩展的压力电路。

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.