Cellular and Synaptic Physiology of the Dorsomedial Hypothalamus

下丘脑背内侧的细胞和突触生理学

• 批准号: RGPIN-2016-06257
• 负责人: Crosby, Karen
• 金额: $ 2.04万
• 依托单位: Mount Allison University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=616192
• 关键词: Cellular; Synaptic; Physiology; Dorsomedial; Hypothalamus

Stressful stimuli trigger rapid and requisite changes that allow organisms to effectively cope with stress and restore homeostasis. While this response can be beneficial in the short term, prolonged exposure to stress can result in the disruption of numerous important physiological processes, including appetite regulation. The mechanisms underlying the link between stress and appetite; however, are poorly understood. The long term goal of my research program is to characterize the cellular, molecular, and synaptic mechanisms that underlie stress-induced alterations in food intake and metabolism. Numerous feeding circuits in the brain play an important role in regulating appetite and body weight, but no region is as fundamentally linked to stress and appetite as the dorsomedial nucleus of the hypothalamus (DMH). The DMH processes neural signals related to stress and satiety and I have recently demonstrated that stress triggers a functional rewiring of inhibitory synapses in the DMH such that presumed satiety neurons are inhibited. This is accomplished by alterations of two key signals that regulate neuronal communication in the DMH: endocannabinoids and nitric oxide. Much remains unknown, however, regarding the mechanisms by which stress influences synaptic function and endocannabinoid and nitric oxide signaling/interactions in the DMH. The behavioral consequences with respect to appetite regulation are also unknown. Thus, our short term objectives are threefold. First, we will use whole cell patch clamp electrophysiology to determine the effect of various stressors on synaptic transmission and changes in synaptic strength mediated by endocannabinoids and nitric oxide (Objective 1). Second, because endocannabinoids and nitric oxide interact to regulate neuronal communication in the DMH, we will study the mechanisms of these interactions and the effect of stress using electrophysiological and molecular (immunohistochemistry) techniques (Objective 2). Third, we will address the physiological consequences of endocannabinoid and nitric oxide administration in the DMH. Specifically, we will determine the effect of endocannabinoids and nitric oxide, and their interactions, in the DMH on food intake and body weight in naïve and stressed animals. (Objective 3). Together, these studies will provide important insight into the effect of stress on appetite regulation.

压力刺激会引发快速且必要的变化，使生物体能够有效应对压力并恢复体内平衡。虽然这种反应在短期内可能是有益的，但长期承受压力可能会导致许多重要生理过程的破坏，包括食欲调节。压力与食欲之间联系的机制；然而，人们对此知之甚少。我的研究计划的长期目标是表征压力引起的食物摄入和新陈代谢变化的细胞、分子和突触机制。大脑中的众多进食回路在调节食欲和体重方面发挥着重要作用，但没有哪个区域像下丘脑背内侧核（DMH）那样与压力和食欲有着如此根本的联系。 DMH 处理与压力和饱腹感相关的神经信号，我最近证明压力会触发 DMH 中抑制性突触的功能性重新布线，从而抑制假定的饱腹感神经元。这是通过改变 DMH 中调节神经元通讯的两个关键信号来实现的：内源性大麻素和一氧化氮。然而，关于压力影响 DMH 中突触功能以及内源性大麻素和一氧化氮信号传导/相互作用的机制，仍有许多未知之处。食欲调节方面的行为后果也是未知的。因此，我们的短期目标有三个。首先，我们将使用全细胞膜片钳电生理学来确定各种应激源对内源性大麻素和一氧化氮介导的突触传递和突触强度变化的影响（目标 1）。其次，由于内源性大麻素和一氧化氮相互作用来调节 DMH 中的神经元通讯，因此我们将使用电生理学和分子（免疫组织化学）技术研究这些相互作用的机制以及压力的影响（目标 2）。第三，我们将解决 DMH 中内源性大麻素和一氧化氮给药的生理后果。具体来说，我们将确定 DMH 中内源性大麻素和一氧化氮及其相互作用对幼稚和应激动物的食物摄入和体重的影响。 （目标 3）。总之，这些研究将为压力对食欲调节的影响提供重要的见解。