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，并且在情绪和饮食障碍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-羟色胺能调节摄入和活动对阐明其病理生理学具有重要意义。5-羟色胺2c受体（5 HT 2CR）在摄食和活动的多巴胺能调节中起重要作用，并且5 HT 2CR调节的某些方面似乎是由黑皮质素系统介导的。拟议的工作的重点是确定和理解的神经回路的功能，通过5-羟色胺调节摄入和活动，划定在何种程度上5 HT 2CR和黑皮质素途径相互作用，在调节这些行为。目标1。5 HT 2CR和MC 4 R的同时破坏的影响将用于鉴定由5 HT 2CR调节的依赖于黑皮质素系统激活的行为。目标2.神经回路参与协调调节的摄入和活动，其功能被这些突变破坏，将确定相关诱导Fos样免疫反应性与食物剥夺诱导的多动症。目标3：下丘脑弓状核和腹内侧核中5 HT 2CR的功能作用被假设为是不同的。这一假设将通过特异性灭活这些区域中的每一个中的5 HT 2CR并通过评估灭活对摄入和活动模式的影响来进行测试。目标4。更好地了解在这些区域中的每一个的5 HT 2CR表达神经元的功能作用，将获得通过使用转基因transneuronal示踪剂的选择性表达确定其特定的神经连接。该K 08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，从而使候选人能够使用小鼠作为模型系统，开发多学科方法来研究与精神病学相关的行为。此外，培训将促进候选人作为学术精神病学独立调查员的发展。

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.