Dissecting Serotonergic Control of Ingestion & Activity

剖析血清素的摄入控制

• 批准号: 6817361
• 负责人: Evan H. Goulding
• 金额: $ 17.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817361
• 关键词: behavioral /social science research tag; eating disorders; hypothalamus; laboratory mouse; neuroanatomy; neurons; neuropsychology; neuroregulation; nutrient intake activity; pathologic process; proopiomelanocortin; serotonin receptor

DESCRIPTION (provided by applicant): Evolutionary processes have led to neural systems coordinately regulating food intake and physical activity, and simultaneous perturbations of these behaviors are observed in mood and eating disorders. Dysregulation of serotonin systems has been implicated in these disorders, suggesting that a better understanding of serotonergic regulation of ingestion and activity has important implications for elucidating their pathophysiology. The serotonin 2c receptor (5HT2CR) plays an important role in serotonergic regulation of ingestion and activity, and some aspects of 5HT2CR regulation appear to be mediated by the melanocortin system. The focus of the proposed work is to identify and understand the function of the neural circuits through which serotonin regulates ingestion and activity by delineating the extent to which 5HT2CR and melanocortin pathways interact in regulating these behaviors. Aim 1. The effects of simultaneous disruption of 5HT2CR and MC4R will be used to identify behaviors regulated by 5HT2CR that depend on activation of the melanocortin system. Aim 2. Neural circuits involved in the coordinated regulation of ingestion and activity whose function is disrupted by these mutations will be identified by correlating induction of Fos-like immunoreactivity with food-deprivation induced hyperactivity. Aim 3. The functional roles of 5HT2CR in the arcuate and ventral medial hypothalamus are hypothesized to be distinct. This hypothesis will be tested by specifically inactivating 5HT2CR in each of these regions and by assessing the impact of inactivation on patterns of ingestion and activity. Aim 4. A better understanding of the functional role of 5HT2CR-expressing neurons in each of these regions will be obtained by identifying their specific neural connections using selective expression of a transgenic transneuronal tracer. This K08 Award will provide the candidate with training in quantitative behavioral analysis, mouse genomic manipulation, and neuroanatomic techniques, thereby allowing the candidate to develop a multi-disciplinary approach to the study of behaviors relevant to psychiatry using the mouse as a model system. In addition, the training will foster the candidate's development as an independent investigator in academic psychiatry.

描述（由申请人提供）：进化过程导致神经系统协调调节食物摄入和身体活动，并且在情绪和饮食失调中观察到这些行为的同时扰动。血清素系统失调与这些疾病有关，这表明更好地了解摄入和活动的血清素调节对于阐明其病理生理学具有重要意义。血清素 2c 受体 (5HT2CR) 在摄入和活动的血清素能调节中发挥着重要作用，5HT2CR 调节的某些方面似乎是由黑皮质素系统介导的。拟议工作的重点是通过描述 5HT2CR 和黑皮质素通路在调节这些行为中相互作用的程度，来识别和理解血清素调节摄入和活动的神经回路的功能。目标 1. 同时破坏 5HT2CR 和 MC4R 的效果将用于识别 5HT2CR 调节的行为，这些行为依赖于黑皮质素系统的激活。目标 2. 通过将 Fos 样免疫反应性的诱导与食物剥夺引起的多动症相关联，将鉴定参与协调调节摄入和活动的神经回路，其功能被这些突变破坏。目标 3. 假设 5HT2CR 在下丘脑弓状和腹内侧内侧的功能作用是不同的。该假设将通过在每个区域中特异性灭活 5HT2CR 并评估灭活对摄入和活动模式的影响来检验。目标 4. 通过使用转基因跨神经元示踪剂的选择性表达来识别这些区域中表达 5HT2CR 的神经元的特定神经连接，可以更好地了解这些区域中表达 5HT2CR 的神经元的功能作用。 K08 奖将为候选人提供定量行为分析、小鼠基因组操作和神经解剖技术方面的培训，从而使候选人能够开发一种多学科方法，使用小鼠作为模型系统来研究与精神病学相关的行为。此外，培训还将促进候选人作为学术精神病学独立研究者的发展。