MCH Modulation of Neurotransmission in the LH area

描述(由申请人提供)： 在这项提案中，黑色素浓缩激素(MCH)在细胞水平上对外侧下丘脑(LH)的调节和功能的作用和机制将被讨论。在摄食调节中，黄体生成素起着关键作用，一直被认为是摄食中心。食物摄入量的调节在能量平衡的动态平衡中至关重要。能量积累不平衡会导致肥胖。MCH是一种由19个氨基酸组成的环状多肽。来自系统、形态和分子生物学研究的大量证据表明，MCH参与了摄食调节。然而，在细胞水平上，关于MCH在黄体生成素神经元中的生理作用的证据很少。此外，关于促黄体生成素和其他神经肽如何在黄体生成素神经元中相互作用的证据也很少。此外，关于LH区的细胞生理学以及神经元的特性和神经元组织的数据也很少。在本方案中，将使用电生理方法(包括细胞外记录、全细胞电压和电流钳记录)、免疫细胞化学和数字钙成像技术对培养的大鼠神经元和急性下丘脑片进行研究。需要检验的主要假设是，MCH作为一种抑制神经肽来调节黄体生成素中的神经元活动。我们将检验以下假设：1.MCH抑制依赖活性的基因转录。2.MCH通过不同的信号通路抑制电压依赖性钙通道亚型的功能。3.MCH抑制黄体生成素脑片的谷氨酸能和GABA能突触传递。4.将记录黄体生成素脑片中MCH反应神经元的特征和组织。这项提议将开始弥合分子研究和系统研究之间的差距，这些研究旨在调节喂养，使那些患有肥胖症和肥胖相关疾病的人受益。申请人之前在表征新发现的神经肽--下丘脑素/食欲素的细胞生理学方面所做的工作，是他追求了解黄体生成素神经传递这一长期目标的第一步。这项研究计划的资金对申请者继续这门课程很重要。这份建议书中还记录了一项职业发展计划。

DESCRIPTION (provided by applicant): In this proposal, the role and mechanism of melanin-concentrating hormone (MCH) in the regulation and function of the lateral hypothalamus (LH) at the cellular level will be addressed. In feeding regulation LH plays a key role and has been considered as a feeding center. The regulation of food intake is crucial in energy- balance homeostasis. Unbalanced energy accumulation leads to obesity. MCH is a cyclic 19-amino-acid peptide. A substantial body of evidence from systemic, morphological and molecular biological studies suggests that MCH is involved in feeding regulation. However, there is little evidence as to the physiological role of MCH in LH neurons at the cellular level. Also there is little evidence as to how MCH and other neuropeptides interact in LH neurons. Furthermore, there is little data about the cellular physiology as well as properties of neurons and neuronal organization in the LH area. In this proposal, electrophysiological methods (including extracellular recording, whole-cell voltage and current clamp recording), immunocytochemistry and digital calcium imaging will be employed in cultured neurons and acute hypothalamic slices from rats. The chief hypothesis to be tested is that MCH acts as an inhibitory neuropeptide to modulate neuronal activity in the LH. The following hypotheses will be examined: 1. MCH depresses the activity-dependent gene transcription. 2. MCH inhibits the function of voltage-dependent calcium channel subtypes via distinct signaling pathways. 3. MCH depresses glutamatergic and GABAergic synaptic transmission in the LH slices. 4. Characterization and organization of MCH responding neurons in LH slices will be documented. This proposal will begin to bridge the gap between molecular research and systemic studies on the regulation of feeding to benefit those suffering from obesity and obesity-related diseases. The applicant's previous work in characterizing the cellular physiology of the newly discovered neuropeptide hypocretin/orexin is the first step in his journey to pursue his long-term goal of understanding neurotransmission in the LH. The funding of this research proposal is important for the applicant to continue this course. A career development plan is also documented in this proposal.