The Dorsomedial Hypothalamus and Responses to Stress

下丘脑背内侧和对压力的反应

• 批准号: 6899254
• 负责人: JOSEPH A DIMICCO
• 金额: $ 29.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899254
• 关键词: adrenocorticotropic hormone; angiotensin II; angiotensin receptor; body temperature; cardiovascular function; chemical stimulation; glutamate receptor; glutamates; hypothalamic pituitary adrenal axis; hypothalamus; immunocytochemistry; inhibitor /antagonist; laboratory rat; microinjections; muscimol; neural inhibition; neuropharmacology; neurophysiology; paraventricular nucleus; physiologic stressor; preoptic areas; prostaglandin E; radioimmunoassay; receptor expression; stress; telemetry

DESCRIPTION (provided by applicant):Stress in mammals triggers physiological changes that are thought to contribute to a wide variety of human disorders and disease states. Although the hypothalamus has long been considered the neural effector "command center" for these responses, the specific central mechanisms and pathways involved are largely unknown. Recently, the concept of "stressor-specific" neural circuits has emerged as an organizing principal for classifying various stressors into two broad categories. Thus, distinct afferent pathways may be responsible for mobilizing the same hypothalamic effector systems in response to interoceptive (also termed physiologic or systemic) stressors and exteroceptive (emotional or psychologic) stressors. Our past studies indicate that neurons responsible for generating the integrated pattern of autonomic, neuroendocrine, and behavioral changes associated with emotional stress are found in the region of the dorsomedial hypothalamus (DMH) and not in the nearby paraventricular nucleus (PVN) as was once thought. However, to date nothing is known about the pathways that may trigger or facilitate the activation of the DMH under stressful conditions. The proposed experiments will exploit key findings from the literature and our recent preliminary data that together provide a cogent rationale for the hypothesis that: (1) neurons in a specific region of the median preoptic area (mPOA) comprise an important afferent pathway capable of recruiting the neurons in the DMH responsible for increases in heart rate, body temperature, and plasma ACTH seen in air stress, an exteroceptive stress paradigm, (2) a different pathway to the PVN - one not involving the DMH - is responsible for the increases in plasma ACTH seen in hemorrhage, a classic interoceptive stressor, and (3) activation of local ionotropic glutamate receptors as well as receptors for angiotensin II (AII) is likely to play a role in one or both mechanisms. Our specific aims are to (1) characterize the effect of microinjection of AII and of glutamate receptor analogs into the DMH and the PVN on heart rate, blood pressure, plasma ACTH, core body temperature, and brown adipose tissue temperature, (2) assess the role of neurons in the DMH and the PVN and of local glutamate and AII AT-1 receptors in mediating the physiological response to chemical stimulation of the mPOA with PGE2, and (3) determine the effect of neuronal inhibition and of AII or glutamate receptor blockade in the DMH and the PVN on the physiological responses evoked by air stress and by hemorrhage. The experiments proposed will enhance our understanding of hypothalamic circuitry and function, particularly as it relates to the physiological responses to interoceptive and exteroceptive stress, and may provide compelling evidence for novel pathways and mechanisms playing key roles in mediating these responses. The results may also suggest new applications and therapeutic mechanisms for the growing family of drugs influencing AII and its receptors.

描述（由申请人提供）：哺乳动物的压力会引发生理变化，这些变化被认为会导致多种人类疾病和疾病 疾病状态。尽管下丘脑长期以来被认为是神经 这些反应的效应器“指挥中心”，具体的中心机制 所涉及的途径很大程度上是未知的。最近，概念 “压力源特异性”神经回路已成为组织原理 将各种压力源分为两大类。因此，不同的 传入通路可能负责动员相同的下丘脑 效应系统响应内感受（也称为生理或 系统性）压力源和外感受性（情感或心理）压力源。我们的 过去的研究表明，负责产生整合的神经元 与相关的自主神经、神经内分泌和行为变化模式 情绪压力存在于下丘脑背内侧 (DMH) 区域 而不是像人们曾经认为的那样位于附近的室旁核（PVN）。 然而，迄今为止，尚不清楚可能触发或 促进 DMH 在压力条件下的激活。拟议的 实验将利用文献和我们最近的主要发现 初步数据共同为假设提供了令人信服的理由 (1) 中位视前区 (mPOA) 特定区域的神经元 包括一条重要的传入通路，能够募集神经元 DMH 导致心率、体温和血浆 ACTH 增加 见于空气压力，一种外感受压力范式，（2）不同的途径 PVN（不涉及 DMH）负责增加 出血中可见的血浆 ACTH，一种经典的内感受应激源，以及 (3) 激活局部离子型谷氨酸受体以及受体 血管紧张素 II (AII) 可能在一种或两种机制中发挥作用。 我们的具体目标是 (1) 表征 AII 显微注射的效果和 谷氨酸受体类似物进入 DMH 和 PVN 对心率、血液的影响 压力、血浆 ACTH、核心体温和棕色脂肪组织 温度，(2) 评估 DMH 和 PVN 中神经元以及局部神经元的作用 谷氨酸和 AII AT-1 受体介导生理反应 用 PGE2 对 mPOA 进行化学刺激，并且 (3) 确定 DMH 中的神经元抑制和 AII 或谷氨酸受体阻断 PVN 对空气压力和出血引起的生理反应的影响。 所提出的实验将增强我们对下丘脑的理解 电路和功能，特别是与生理相关的 对内感受和外感受压力的反应，并可能提供令人信服的信息 证据表明新的途径和机制在调节这些方面发挥着关键作用 回应。研究结果还可能提出新的应用和治疗方法 越来越多的药物家族影响 AII 及其受体的机制。

项目成果

Stress-free microinjections in conscious rats.

对有意识的大鼠进行无压力显微注射。

• DOI: 10.1016/j.jneumeth.2011.05.004
• 发表时间: 2011
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Zaretsky,DmitryV;Zaretskaia,MariaV;Rusyniak,DanielE;Dimicco,JosephA
• 通讯作者: Dimicco,JosephA

Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus.

血管紧张素-II 是一种假定的神经递质，在乳酸诱导的大鼠惊恐样反应中，破坏了背内侧下丘脑的 GABA 能抑制。

• DOI: 10.1523/jneurosci.2491-06.2006
• 发表时间: 2006
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Shekhar,Anantha;Johnson,PhilipL;Sajdyk,TammyJ;Fitz,StephanieD;Keim,StanleyR;Kelley,PamelaE;Gehlert,DonaldR;DiMicco,JosephA
• 通讯作者: DiMicco,JosephA

Increase in plasma ACTH induced by urethane is not a consequence of hyperosmolality.

乌拉坦引起的血浆 ACTH 增加不是高渗透压的结果。

• DOI: 10.1016/j.neulet.2010.05.016
• 发表时间: 2010
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Zaretsky,DmitryV;Molosh,AndreiI;Zaretskaia,MariaV;Rusyniak,DanielE;DiMicco,JosephA
• 通讯作者: DiMicco,JosephA