PATHWAYS INTEGRATING STRESS AND CARDIOVASCULAR RESPONSES

描述(申请人摘要)：心血管感官信息是 由孤束核(NTS)接收和处理，然后 转送至延髓腹外侧区的中继器 以高度分化的投射方式对自主神经效应器的反应 脑干和脊髓，以及神经分泌神经元群在 下丘脑室旁核(PVH)。而基本的刺激效应 这个网络中的关系得到了合理的理解，仍然存在 在提供一体化的中间途径的知识方面存在重大差距 回应。在神经元激活的即刻早期基因(IEG)标记的指导下， 编码关键效应器或递质相关基因表达的变化 分子将被跟踪，在原位，以应对心血管挑战， 中枢消融和药物治疗，并辅之以 光镜和电子显微镜下的神经解剖束示踪实验 水平，以澄清中介通路的功能组织 神经内分泌和自主神经对循环系统扰动的反应 周围的环境。初步研究将利用IEG划分NT的能力 推测接受初级动脉压力感受器传入的人群 确定如何将其分配给计划到 交感神经运动前神经元、迷走神经运动神经元和 支配PVH内不同的神经分泌神经元群。接下来， 蓝斑和局灶性压力敏感投射的组织 将测定PVH的GABA能中间神经元，以及它们对 对血压和/或容量有不同影响的挑战将是 特色化的。第三，将使用神经毒素损伤方法来评估 来自尾侧延髓和尾侧核的胺能通路的作用 蓝斑介导失血诱导的激活和生物合成反应 在大细胞和小细胞神经分泌神经元中；局部微量注射 实验将评估肾上腺素受体拮抗剂的干扰能力。 由出血引起的反应。最后，隔膜的一个离散方面 区域参与了压力感受器介导的抑制 大细胞神经分泌神经元。激发毒素损失的方法将是 用于评估该细胞群在调节效应中的贡献 对PVH效应者群体的升压和降压挑战。神经学 接受检查的神经内分泌系统调节基本生理 过程，其失调，孤立或相互作用， 与多种形式的高血压的发生有关。这方面的内容 电路是一种很有前途的新型抗高血压药物的靶点 制药公司。预计结果将有助于更清晰地 了解其职能组织。

DESCRIPTION (applicant's abstract): Cardiovascular sensory information is received and processed by the nucleus of the solitary tract (NTS) and then forwarded to relays in the ventrolateral medulla (VLM) that launch adaptive responses by way of highly differentiated projections to autonomic effectors in the brainstem and spinal cord, and to neurosecretory neuron populations in the paraventricular hypothalamic nucleus (PVH). While basic stimulus-effect relationships in this network are reasonably well understood, there remain major gaps in knowledge of the intervening pathways that provide for integrated responses. Guided by immediate-early gene (IEG) markers of neuronal activation, changes in the expression of genes encoding key effector or transmitter-related molecules will be followed, in situ, in response to cardiovascular challenges, central ablations, and pharmacologic manipulations, and complemented with neuroanatomical tract tracing experiments at the light and electron microscopic levels, to clarify the functional organization of pathways that mediate neuroendocrine and autonomic responses to perturbations in the circulatory milieu. An initial study will exploit the ability of IEGs to demarcate NTS populations presumed to receive primary arterial baroreceptor afferent input to determine how this may be distributed to populations that project to sympathetic premotor neurons, vagal cardiomotor neurons, and cells that innervate distinct neurosecretory neuron populations in the PVH. Next, the organization of barosensitive projections to the locus coeruleus and of local GABAergic interneurons to the PVH will be determined, and their responses to challenges that differentially affect blood pressure and/or volume will be characterized. Third, neurotoxin lesioning methods will be used to evaluate the roles of aminergic pathways arising from the caudal medulla and from the locus coeruleus mediating hemorrhage-induced activational and biosynthetic responses in magno- and parvo-cellular neurosecretory neurons; local microinjection experiments will assess the ability of adrenoceptor antagonists to interfere with hemorrhage-induced responses. Finally, a discrete aspect of the septal region has been implicated in the baroreceptor-mediated inhibition of magnocellular neurosecretory neurons. Excitotoxin lesioning methods will be used to evaluate the contribution of this cell group in mediating the effects of hyper- and hypotensive challenges on PVH effector populations. The neural and neuroendocrine systems under scrutiny mediate essential physiologic processes, dysregulations of which have, in isolation or interactively, been implicated in the genesis of multiple forms of hypertension. Aspects of this circuitry are targeted by a promising new class of antihypertensive pharmaceuticals. The results are expected to contribute to clearer understanding of its functional organization.