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

下丘脑的高动态神经网络在调节体重和能量平衡中起着重要作用。这些控制电路根据机体的需要和身体周围燃料来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正在增加。为了更好地理解和对抗肥胖和相关的代谢紊乱，人们正在努力确定调节体重和能量稳态的控制机制。下丘脑室旁核（PVH）是一个重要的自主神经控制中心，它整合来自神经元、神经内分泌和自主通路的信号，调节自主神经过程，包括肾脏和心血管功能，以及应激反应。PVH对于控制能量平衡也是至关重要的。由于下丘脑的去甲肾上腺素能系统的操纵改变了摄食行为和食物摄入，我们想知道儿茶酚胺去甲肾上腺素是否是PVH中能量稳态调节神经元的直接调节剂。这个问题是特别相关的，因为最近对灵长类动物的研究表明，小脑座的去肾上腺素能神经元在处理奖励信息中起着关键作用。我们将分三步解决这个问题：首先，我们将通过在脑切片上进行穿孔膜片钳记录，分析去甲肾上腺素对已鉴定PVH神经元固有电生理特性的调节作用。其次，我们将使用细胞类型特异性转录组学来建立在不同类型PVH神经元中表达的肾上腺素能受体的清单，这些受体可能介导这些神经元的去肾上腺素能调节。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，以及它们如何促进NA的净调节作用。所提出的实验，将详细定义生物物理和细胞机制，介导调节不同PVH神经元类型的去甲肾上腺素。我们期望这些结果将促进我们对奖励和代谢信号如何在单细胞和回路水平上在这个突出的自主控制中心被处理的理解。

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.