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

应激是多种疾病的核心，因为它对大脑神经传递和可塑性产生巨大而持久的影响，从而增加了疾病的易感性。尽管调节机制尚不清楚，但人们现在已经认识到，在发育期暴露于应激事件可以形成生理和行为调节。我们的研究重点将是了解出生后反复应激如何塑造下丘脑-垂体-肾上腺(HPA)轴的反应以及下丘脑-垂体-肾上腺(HPA)轴和边缘系统(包括杏仁核)之间的反应和相互作用。HPA轴是应激反应的汇聚神经内分泌效应器，边缘系统(包括杏仁核)整合了恐惧和情绪。我们认为，以反复短暂的母体隔离期或轻度炎症性疼痛的形式出现的早期重复应激经历将永久性地改变杏仁核、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应激后被激活。我们将检验这一假设，即这些功能和形态的变化是由于糖皮质激素分泌的紧张性增加和这些结构中的内源性大麻信号的功能变化所致。这将导致杏仁核加速招募，使幼崽对压力和行为恐惧学习过早过敏。最后，我们认为，在相同的关键发育期，无序的母体护理将导致幼崽扩展应激回路的变化，这与慢性应激引起的变化相似，而与反复应激相关的母体“忽视”将加剧长期结果的严重性。这些实验不仅有可能确定扩展应激回路中那些被早期重复应激暴露改变的方面，而且还有可能确定内源性大麻素是调节扩展应激回路中响应性和加速“成熟”的时间和开始的潜在关键介质。

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.