MCH Modulation of Neurotransmission in the LH area

描述（由申请人提供）： 在这个建议中，黑色素浓集激素（MCH）的调节和功能的外侧下丘脑（LH）在细胞水平上的作用和机制将被解决。LH在摄食调节中起关键作用，被认为是摄食中枢。食物摄入的调节在能量平衡的体内平衡中是至关重要的.不平衡的能量积累导致肥胖。MCH是一种环状19-氨基酸肽。来自系统、形态学和分子生物学研究的大量证据表明，MCH参与摄食调节。然而，很少有证据表明MCH在LH神经元细胞水平的生理作用。此外，关于MCH和其他神经肽如何在LH神经元中相互作用的证据很少。此外，关于LH区的细胞生理学以及神经元和神经元组织的特性的数据很少。本研究拟采用电生理学方法（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下丘脑神经元和急性脑片进行研究。待检验的主要假设是MCH作为一种抑制性神经肽调节LH中的神经元活性。以下假设将被检验：1. MCH抑制活性依赖性基因转录。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LH切片中的谷氨酸能和GABA能突触传递。4.将记录LH切片中MCH反应神经元的表征和组织。这项建议将开始弥合进食调节的分子研究和系统研究之间的差距，以造福肥胖和肥胖相关疾病患者。申请人先前在表征新发现的神经肽下丘脑泌素/食欲素的细胞生理学方面的工作是他追求理解LH中神经传递的长期目标的旅程的第一步。这项研究计划的资金对于申请人继续这门课程很重要。职业发展计划也记录在本建议书中。

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.