Cellular and Synaptic Physiology of the Dorsomedial Hypothalamus

应激刺激会引发快速和必要的变化，使有机体能够有效地应对压力并恢复动态平衡。虽然这种反应在短期内是有益的，但长期暴露在压力下可能会导致许多重要的生理过程被扰乱，包括食欲调节。然而，人们对压力和食欲之间联系的潜在机制知之甚少。我的研究计划的长期目标是描述压力引起的食物摄入和新陈代谢变化背后的细胞、分子和突触机制。大脑中的许多喂养回路在调节食欲和体重方面发挥着重要作用，但没有一个区域像下丘脑背内侧核(DMH)那样与压力和食欲联系在一起。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连接，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，关于应激影响DMH中突触功能、内源性大麻素和一氧化氮信号/相互作用的机制仍不清楚。与食欲调节有关的行为后果也是未知的。因此，我们的短期目标有三个方面。首先，我们将利用全细胞膜片钳电生理学来确定各种应激源对突触传递的影响以及由内源性大麻素和一氧化氮介导的突触强度的变化(目标1)。其次，由于内源性大麻素和一氧化氮在DMH中相互作用调节神经元通讯，我们将利用电生理和分子(免疫组织化学)技术研究这些相互作用的机制和应激的影响(目标2)。第三，我们将讨论内源性大麻素和一氧化氮在DMH中的生理后果。具体地说，我们将确定内源性大麻素和一氧化氮在DMH中对幼稚和应激动物的食物摄入量和体重的影响及其相互作用。(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。

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.