Noradrenergic modulation of identified, potentially energy homeostasis regulating neurons in the paraventricular nucleus of the hypothalamus

下丘脑中高度动态的神经元网络在体重和能量平衡的调节中起着重要作用。这些控制回路根据机体的需要和身体周围燃料源的可用性来调节食物摄入和能量消耗。能量摄入和消耗之间的不匹配可导致代谢紊乱，包括肥胖和2型糖尿病，其患病率在西方社会日益增加。为了更好地了解和对抗肥胖及其相关的代谢紊乱，人们越来越努力地定义调节体重和能量稳态的控制机制，下丘脑室旁核（paraventricular nucleus of hypothalamus，PVH）是一个重要的自主神经控制中心，它整合来自神经元、神经内分泌和自主神经通路的信号来调节自主神经过程，包括肾和心血管功能以及应激反应。PVH对于控制能量平衡也至关重要。由于操纵下丘脑的去甲肾上腺素能系统改变进食行为和食物摄入量，我们问是否儿茶酚胺去甲肾上腺素是一个直接调制器的能量稳态调节神经元的PVH。这个问题是特别相关的，因为最近在灵长类动物的研究表明，去甲肾上腺素能神经元的蜡样斑在处理的奖励information.We发挥了关键作用，将解决这个问题分三步：首先，我们将分析去甲肾上腺素的调制作用，确定PVH神经元的内在电生理特性进行穿孔膜片钳记录在大脑切片。其次，我们将使用细胞类型特异性转录组学来建立肾上腺素能受体的库存，这些受体在不同类型的PVH神经元中表达，并可能介导这些神经元的去甲肾上腺素能调节。第三，功能药理学将用于测试哪些表达的肾上腺素能受体是功能性的，以及它们如何有助于NA的净调节作用。拟议的实验，将详细定义的生物物理和细胞机制，介导的不同PVH神经元类型的调节去甲肾上腺素。我们希望这些结果将促进我们对奖励和代谢信号在这个突出的自主控制中心的单细胞和回路水平上是如何处理的理解。

Highly dynamic neuronal networks in the hypothalamus play an important role in the regulation of body weight and energy balance. These control circuits adjust food intake and energy expenditure according to the needs of the organism and the availability of fuel sources in the periphery of the body. Mismatch between energy intake and expenditure can cause metabolic disorders including obesity and type 2 diabetes mellitus, whose prevalence is increasing in Western societies. To better understand and counteract obesity and associated metabolic disorders, increasing efforts are being made to define the control mechanisms that regulate body weight and energy homeostasis.The paraventricular nucleus of hypothalamus (PVH) is an important autonomic control center, which integrates signals from neuronal, neuroendocrine, and autonomous pathways to regulate autonomic processes, including renal and cardiovascular functions, and stress responses. The PVH is also crucial for controlling the energy balance. Since manipulation of the noradrenergic system in the hypothalamus modifies feeding behavior and food intake, we ask whether the catecholamine noradrenalin is a direct modulator of energy homeostasis-regulatory neurons in the PVH. This question is of particular relevance, since recent studies in primates suggest that noradrenergic neurons of the locus cereuleus play a critical role in processing of reward information.We will address this question in three steps: First, we will analyze the modulatory effect of noradrenalin on intrinsic electrophysiological properties of identified PVH neurons by performing perforated patch clamp recordings in brain slices. Second, we will use cell type-specific transcriptomics to build an inventory of adrenergic receptors that are expressed in the different types of PVH neurons and potentially could mediate the noradrenergic modulation of these neurons. Third, functional pharmacology will be used to test which of the expressed adrenergic receptors are functional and how they contribute to the net modulatory effect of NA. The proposed experiments, will define in detail the biophysical and cellular mechanisms that mediate modulation of the different PVH neuron types by noradrenalin. We expect that these results will foster our understanding of how reward and metabolic signals are processed at the single-cell and circuit level in this prominent autonomic control center.