CNS CIRCUITS MEDIATING VISCEROMOTOR RESPONSES TO STRESS

下丘脑编码基因表达的改变 神经内分泌和自主效应肽，以及某些直接- 神经元活化的早期基因标记物，将被跟踪，在原位， 响应于应力、中央消融 药理学操作或类固醇激素的扰动 环境，以澄清神经回路和机制 通过这些不同的压力源 整合和适当的适应性下丘脑反应。 一个 最初的一系列实验将通过 免疫系统介质白细胞介素-1（IL-1）发挥其强大的 对应激相关下丘脑机制的刺激作用。 以前的工作支持这一假设，旁分泌的影响， 前列腺素E2从髓质血管周围细胞释放， IL-1刺激的结果，并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， 这是循环IL-1增加的刺激作用的基础， 应激相关的下丘脑效应神经元。这将由以下人员进行测试： 确定必需的分子是否在细胞中表达， 髓质，并通过评估是否髓质管理。 前列腺素激动剂可以模拟IL-1，而合成抑制剂可以阻断IL-1 影响下丘脑的水平。 具体参与 延髓的儿茶酚胺能神经元将通过评估 神经毒素损害的能力在脑干水平或交付 肾上腺素能受体拮抗剂在下丘脑水平， 下丘脑对全身性IL-1激发的反应。 的一般性的 该机制将通过确定是否中断 上行胺能投射减轻下丘脑对更多 强烈的免疫损伤 第二个主要目标是采用国际环境治理- 引导消融策略，以确定 表面上更复杂，情感或神经性，压力模式 激发下丘脑的综合反应， 下丘脑输出可能会被修改，作为重复的结果， 暴露在情绪压力下 最后一组实验将试图 描述神经递质系统和受体机制 介导编码肽的基因的转录激活，所述肽 控制垂体肾上腺对压力的反应，以及 它们由类固醇激素进行紧张性和相位性调节 环境 神经和神经内分泌系统在这里受到仔细检查 发挥着重要的生理作用，其功能障碍与 自身免疫性疾病、高血压和衰老等多种疾病 相关的学习和记忆缺陷，并已被牵连在 情感性精神障碍的病因，包括神经性厌食症和 萧条

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.