CNS CIRCUITS MEDIATING VISCEROMOTOR RESPONSES TO STRESS

下丘脑编码基因表达的变化 神经内分泌和自主神经效应多肽，以及某些即刻- 神经元激活的早期基因标记，将被跟踪，原位， 为了应对各种压力组合，中央消融， 药理操作，或类固醇激素的干扰 环境，以便阐明神经回路和机制 通过这些截然不同的压力源来引发 整合和适当适应的下丘脑反应。一个 最初的一系列实验将通过 免疫系统介质白介素1(IL-1)发挥强大作用 刺激对应激相关下丘脑机制的影响。 以前的工作支持旁分泌效应的假说。 从延髓血管周围细胞释放的前列腺素E_2 IL-1刺激的结果，作用于前列腺素受体或 在投射到下丘脑的局部儿茶酚胺能神经元附近， 循环中IL-1水平升高对血管紧张素转换酶的刺激作用 应激相关的下丘脑效应神经元。这将通过以下方式进行测试 确定必需的分子是否在 并通过评估延髓给药是否。 前列腺素类激动剂可以模拟IL-1，合成抑制剂可以阻断IL-1 对下丘脑水平的影响。具体牵涉到 延髓内儿茶酚胺能神经元将通过评估 神经毒素在脑干或分娩水平的损伤能力 肾上腺素能受体拮抗剂在下丘脑水平阻断 下丘脑对系统性IL-1挑战的反应。的概括性 这一机制将通过确定是否干扰 上升胺能投射减轻下丘脑对更多 激烈的免疫侮辱。第二个主要目标将是使用IEG- 引导消融策略，以确定通过的路径 表面上看，更复杂的、情绪性的或神经性的压力范式出现了 调用整合的下丘脑反应和方式 下丘脑的输出可能会因为重复的结果而改变 暴露在情绪压力之下。最后一组实验将寻求 描述神经递质系统和受体机制 介导编码多肽的基因转录激活，这些多肽 控制脑下垂体-肾上腺对压力的反应，以及 它们受到类固醇激素的时相调节。 环境。这里正在仔细研究的神经和神经内分泌系统 发挥重要的生理作用，其功能障碍已被联系起来 与自身免疫性疾病、高血压和年龄等不同的病理有关- 学习和记忆方面的相关缺陷，并与 情感障碍的病因，包括神经性厌食症和重度 抑郁症。

Alterations in the expression of genes encoding hypothalamic neuroendocrine and autonomic effector peptides, and certain immediate- early gene markers of neuronal activation, will be followed, in situ, in response to various combinations of stress, central ablations, pharmacological manipulations, or perturbations in the steroid hormone environment, in order to clarify the neural circuits and mechanisms through which categorically different stressors come to elicit integrated and appropriately adaptive hypothalamic responses. An initial series of experiments will explore the mechanisms through the immune system mediator, interleukin-1 (IL-1), exerts its powerful stimulatory influence on stress-related hypothalamic mechanisms. Previous work supports the hypothesis that paracrine effects of prostaglandin E2 released from perivascular cells in the medulla as a consequence of IL-1 stimulation, and acting on a prostanoid receptor or near local catecholaminergic neurons that project to the hypothalamus, underlies the stimulatory effects of increased circulating IL-1 on stress-related hypothalamic effector neurons. This will be tested by determining whether the requisite molecules are expressed in the medulla, and by assessing whether medullary administration of. prostanoid agonists can mimic, and synthesis inhibitors block, IL-1 effects at the level of the hypothalamus. The specific involvement of medullary catecholaminergic neurons will be probed by assessing the ability of neurotoxin lesions at the level of the brainstem or delivery of adrenoceptor antagonists at the level of the hypothalamus to block hypothalamic responses to a systemic IL-1 challenge. The generality of the mechanism will be explored by determining whether disruption of ascending aminergic projections mitigates hypothalamic responses to more strenuous immune insults. A second major goal will be to employ an IEG- guided ablation strategy to identify the pathways through which ostensibly more complex, emotional or neurogenic, stress paradigms come to invoke integrated hypothalamic responses and the manner in which hypothalamic output may be modified as a consequence of repeated exposure to emotional stress. A final set of experiments will seek to characterize the neurotransmitter systems and receptor mechanisms mediating transcriptional activation of genes encoding peptides that govern pituitary-adrenal responses to stress, and the manner in which they are modulated tonically and phasically by the steroid hormone environment. The neural and neuroendocrine systems under scrutiny here play essential physiologic roles, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age- related deficits in learning and memory, and have been implicated in the etiology of affective disorders, including anorexia nervosa and major depression.