CRF-Norepinephrine Interactions in Stress and Depression

描述（由申请人提供）：有大量证据表明，含有去甲肾上腺素（NE）和促肾上腺皮质激素释放因子（CRF）的脑神经元在压力时被激活，这两种神经递质的激活与压力相关的行为反应有关，并且两者都可能与焦虑和抑郁有关。含有NE和CRF的神经元之间的相互作用是广泛的。去甲肾上腺素能神经元可以刺激含有crf的神经元，启动对应激反应至关重要的下丘脑-垂体-肾上腺（HPA）轴的激活，而大脑中的其他crf神经元也可能受到影响。脑内给药CRF可激活NE神经元，特别是蓝斑（LC）细胞体的神经元。因此，有人提出抑郁症可能是由于这些相互作用的敏感化，创造了一个“前馈”机制，其中每个系统激活另一个系统。涉及的脑回路可能包括杏仁核中央核、终纹床核和外侧隔，以及下丘脑室旁核和LC。这项研究旨在将我们之前的研究集中在CRF和NE的相互作用上，以阐明对慢性压力的适应细节，这可能为焦虑障碍和抑郁的机制提供见解。本提案的具体目的是通过检查慢性应激动物对急性应激和CRF的行为、去肾上腺素能和HPA反应的适应性，来确定这种前馈假设是否合理。

DESCRIPTION (provided by applicant): There is extensive evidence that brain neurons containing norepinephrine (NE) and corticotropin-releasing factor (CRF) are activated during stress, that activations of these two neurotransmitters are related to stress-related behavioral responses, and that both may be involved in anxiety and depression. Interactions between neurons containing NE and CRF are extensive. Noradrenergic neurons are among those that can stimulate CRF-containing neurons initiating the activation of the hypothalamo-pituitary-adrenal (HPA) axis, critical in the stress response, while other CRF-neurons in the brain may also be affected. Intracerebral administration of CRF activates NE neurons, especially those with cell bodies in the locus coeruleus (LC). Thus it has been proposed that depression may result from a sensitization of these interactions, creating a "feed forward" mechanism in which each system activates the other. The brain circuits involved may include the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the lateral septum, in addition to the hypothalamic paraventricular nucleus and the LC. The research proposed aims to focus our previous work on CRF and NE interactions to elucidate details of the adaptations to chronic stress that may provide insight into the mechanisms involved in anxiety disorders and depression. The specific aim of this proposal is to determine whether or not such a feed-forward hypothesis is reasonable, by examining the adaptation in the behavioral, noradrenergic and HPA responses to acute stress and CRF in chronically stressed animals. This will be done by assessing the behavioral responses and NE release and plasma corticosterone in response to acute stress, and comparing these to the responses to intracerebral injection of CRF. The specific aims will be to determine the neurochemical (NE) and behavioral responses of chronically stressed rats to acute footshock and to CRF injected locally into the LC. Two different chronic stressor paradigms will be used: footshock and exposure to the odor of a predator (fox urine). The NE responses will be determined initially by measuring NE metabolites, but this will be followed by studies using in vivo chronoamperometry and microdialysis in rats. We will determine and compare the subtype(s) of CRF receptor involved in the responses to footshock and to CRF administration. The results should establish a model and indicate the nature of the cerebral structures involved, so that we can subsequently test the feed-forward hypothesis