NEUROPEPTIDE CO-EXPRESSION IN THE HYPOTHALAMUS

哺乳动物的下丘脑代表了最后的 适应性神经内分泌和自主神经对应激反应的整合 是有效的。编码下丘脑神经肽标记物的信使RNA 神经内分泌和自主效应神经元，以及某些即刻早期 作为神经元激活的诱导指标的基因产物， 细胞外刺激，将遵循，在原位，在响应各种 压力的组合，荷尔蒙环境的扰动，以及离散的 中心和外周消融，以便定义和表征 调节自适应和集成内脏功能的功能电路 应对具体挑战。最初的一系列研究将测试 室周结构的一般性和特异性 与终板相关的介导协调和分化 慢性高渗刺激对下丘脑神经分泌功能的影响 细胞类型。平行实验将确定免疫系统是否 激发（全身性细胞因子注射）可传递至下丘脑 通过涉及腹部迷走神经的内感受通路的效应神经元 和髓质儿茶酚胺能神经元。第二组实验将 采用类似的策略来识别促进启动的途径 和维持下丘脑神经内分泌和自主反应， 间歇性足电击，神经源性应激模型。这将涉及 在完整的大鼠中的即时早期基因定位，以及在具有 控制类固醇滴度，以区分压力和 类固醇敏感成分。 这将与现场 评估下丘脑效应神经元中的相关mRNA，以及 评估这些应激效应的候选传入介质， 离散纤维横切和兴奋毒素损伤技术。最终 一组研究将力求加深对场地的理解， 肾上腺抑制性反馈控制的机制 下丘脑-垂体-肾上腺中央支皮质类固醇 轴被施加。河豚毒素介导的突触阻滞将用于 类固醇操纵的动物，以估计类固醇 对下丘脑靶点的影响可能是跨突触介导的。 特异性皮质类固醇受体的脑内给药 拮抗剂将伴随全身激素水平的扰动 为了确定反馈是否是分布式函数，需要 多个位点的同时受体占据。局灶性下丘脑外 皮质类固醇的施用将与暴露于 确定反馈效应是否可被调节的特定应激源 特别是在特定模态的感觉中继所涉及的通路上。 这里仔细检查的电路有助于实现 个体和物种的生存，并直接关系到许多 因压力而加重的病理，包括心血管疾病 疾病，免疫系统功能障碍和情感障碍，如 神经性厌食症和严重抑郁症。

The mammalian hypothalamus represents the site at which the final integration of adaptive neuroendocrine and autonomic responses to stress is effected. Messenger RNAs encoding neuropeptide markers for hypothalamic neuroendocrine and autonomic effector neurons, and certain immediate-early gene products that serve as inducible indices of neurons activated by extracellular stimuli, will be followed, in situ, in response to various combinations of stress, perturbations in the hormonal milieu, and discrete central and peripheral ablations in order to define and characterize functional circuits mediating adaptive and integrated visceromotor responses to specific challenges. An initial set of studies will test the generality and specificity with which circumventricular structures associated with the lamina terminalis mediate coordinate and differential effects of chronic hyperosmotic challenge on hypothalamic neurosecretory cell types. Parallel experiments will determine whether an immune system challenge (systemic cytokine injection) may be conveyed to hypothalamic effector neurons via interoceptive pathways involving the abdominal vagus and medullary catecholaminergic neurons. A second set of experiments will employ a similar strategy to identify pathways subserving the initiation and maintenance of hypothalamic neuroendocrine and autonomic responses to intermittent footshock, a model for neurogenic stress. This will involve immediate-'early gene mapping in intact rats, and in animals with controlled steroid titers, to allow distinction between stress and steroid-sensitive components. This will be complemented with in situ assessments of relevant mRNAs in hypothalamic effector neurons, and evaluation of candidate afferent mediators of these stress effects using discrete fiber transection and excitotoxin lesioning techniques. A final group of studies will seek to refine understanding of the site(s) and mechanism(s) through which the inhibitory feedback control by adrenal corticosteroids of the central limb of the hypothalamo-pituitary-adrenal axis is exerted. Tetrodotoxtn-mediated synaptic blockade will be used in steroid-manipulated animals to estimate the extent to which steroid effects on hypothalamic targets may be mediated transsynaptically. Intracerebral administration of specific corticosteroid receptor antagonists will be coupled with perturbation in systemic hormone levels to determine whether feedback is a distributed function, requiring concurrent receptor occupancy at multiple sites. Focal extrahypothalamic administration of corticosteroids will be coupled with exposure to a specific stressor to determine whether feedback effects may be mediated specifically on pathways involved as sensory relays for a given modality. The circuitry under scrutiny here subserves functions essential to the survival of individuals and species, and relates directly to the many pathologies that are exacerbated by stress, including cardiovascular disease, immune system dysfunction, and affective disorders such as anorexia nervosa and major depression.