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了巨大而持久的影响，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塑造生理和行为调节，尽管中介机制仍然不确定。我们的研究重点将是了解产后生活中反复的压力如何影响下丘脑-垂体-肾上腺（HPA）轴（压力反应的聚合神经内分泌效应）和边缘系统（包括杏仁核）之间的反应性和相互作用，边缘系统整合了恐惧和情绪。我们提出，早期反复的压力经历，无论是重复的短暂的母亲隔离期还是适度的炎症性疼痛，都会永久地改变杏仁核、下丘脑和室旁丘脑的形态和突触可塑性，这一结构通常在慢性压力后被激活。我们将检验这些功能和形态变化是由于糖皮质激素分泌的强直性增加和内源性大麻素信号在这些结构中的功能变化的假设。这将导致杏仁核的加速补充，使幼犬过早对压力和行为恐惧学习产生过敏反应。最后，我们认为，在相同的关键发育时期，无组织的母性护理将导致幼犬扩展应激回路的变化，这种变化与慢性应激引起的变化相似，并且与重复应激相关的母性“忽视”将增加长期结果的严重性。这些实验不仅有可能确定早期重复应激暴露所改变的扩展应激回路的那些方面，而且还可能确定内源性大麻素作为调节扩展应激回路中反应性的时间和开始以及加速“成熟”的潜在关键介质。

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.