Dissecting Serotonergic Control of Ingestion & Activity

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。5 -羟色胺系统的失调与这些疾病有关，这表明更好地了解5 -羟色胺对摄入和活动的调节对阐明其病理生理学具有重要意义。5 -羟色胺2c受体（5HT2CR）在5 -羟色胺摄入和活性的调节中起着重要作用，而5HT2CR调节的某些方面似乎是由黑素皮素系统介导的。这项工作的重点是通过描述5HT2CR和黑素皮质素通路在调节这些行为中的相互作用程度，来确定和理解5 -羟色胺调节摄入和活动的神经回路的功能。目的1。5HT2CR和MC4R同时中断的影响将用于识别依赖于黑素皮质素系统激活的5HT2CR调节的行为。目标2。参与摄入和活动协调调节的神经回路，其功能被这些突变破坏，将通过将fos样免疫反应性诱导与食物剥夺诱导的多动相关联来确定。目标3。假设5HT2CR在弓形下丘脑和腹侧下丘脑内侧的功能作用是不同的。这一假设将通过具体灭活这些区域的5HT2CR，并通过评估灭活对摄入模式和活动的影响来验证。目标4。通过选择性表达转基因跨神经元示踪剂鉴定其特定的神经连接，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学技术方面的培训，从而使候选人能够开发一种多学科方法，以小鼠为模型系统研究与精神病学相关的行为。此外，培训将培养候选人作为学术精神病学独立研究者的发展。

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.