Neural correlates of anxiety in 5-HT1AR knockout mice

描述（由申请人提供）：为了准备候选人在神经科学研究，培训和研究计划的独立职业生涯提出。该培训计划结合了正式的指导、教学、研讨会和会议，以促进获得：（1）与转基因小鼠的繁殖、维护以及行为和神经生理学特征有关的实验室技能;（2）创造性地思考如何利用精神疾病遗传模型的知识和能力;（3）在负责任地进行研究时接触到问题;及（4）在有效的实验室管理方面的经验。该研究计划需要评估5-羟色胺1A受体（5-HT 1AR）突变小鼠，这些小鼠具有增加的焦虑相关行为。了解导致这种表型的5-HT 1AR缺失的影响有可能有助于进一步定义焦虑症的神经生物学，并可能有助于确定抗焦虑治疗的新靶点。5-HT 1AR的表达在发育过程中需要在前脑中建立正常的焦虑样行为，这表明5-HT 1AR在生命早期起作用，以建立这些行为背后的神经元回路。该项目的目标是确定和表征与焦虑相关表型相关的5-HT 1A受体表达中断的神经生理学后果。将检验以下假设：（1）发育期间5-HT 1AR表达的缺乏导致海马功能失调，从而导致表型;以及（2）这种失调与完整小鼠中的先天性焦虑样行为相关。将从海马获得清醒的行为神经记录，其目的是：（1）评估5-HT 1AR敲除小鼠的海马活性;（2）评估具有仅在发育期间或仅在成年期表达的5-HT 1AR缺陷的前脑拯救的动物的海马活性;（3）通过行为和药理学操作研究海马活性与先天性焦虑之间的关系;（4）比较海马背侧区和腹侧区的神经生理学行为关系，这可能在先天性焦虑的介导中具有不同的参与。完成这些计划将提出与焦虑症相关的新的研究领域，并为候选人提供开发和表征其他精神疾病遗传模型所需的知识和经验。

DESCRIPTION (provided by applicant): To prepare the candidate for an independent career in neuroscience research, training and research plans are proposed. The training plan combines formal mentorship, didactics, seminars and meetings to facilitate the acquisition of: (1) laboratory skills related to the breeding, maintenance, and behavioral and neurophysiological characterization of genetically modified mice; (2) a fund of knowledge and ability to think creatively regarding genetic models of psychiatric disease how to exploit them; (3) exposure to issues in the responsible conduct of research; and (4) experience in effective laboratory management. The research plan entails the evaluation of serotonin 1A receptor (5-HT1AR) mutant mice, which have increased anxiety related behaviors. Understanding the effects of 5-HT1AR deletion that lead to this phenotype has the potential to help further define the neurobiology of anxiety disorders, and may help identify new targets for anxiolytic therapies. 5-HT1AR expression is required in the forebrain during development to establish normal anxiety-like behaviors, suggesting that the 5-HT1AR acts early in life to set up neuronal circuits underlying these behaviors. The goal of this project is to identify and characterize neurophysiological consequences of the disruption of 5-HT1A receptor expression that correlate with the anxiety-related phenotype. The following hypotheses will be tested: (1) the lack of 5-HT1AR expression during development results in functional dysregulation of the hippocampus, resulting in the phenotype; and (2) this dysregulation is relevant to innate anxiety-like behaviors in intact mice. Awake, behaving neural recordings will be obtained from the hippocampus, with these Aims: (1) evaluating hippocampal activity in 5-HT1AR knockout mice; (2) evaluating hippocampal activity in animals with a forebrain rescue of 5-HT1AR-deficiency expressed only during development or only in adulthood; (3) investigating the relationship between hippocampal activity and innate anxiety through behavioral and pharmacological manipulations; and (4) comparing neurophysiology behavior relationships across dorsal and ventral hippocampal regions, which may have differential involvement in the mediation of innate anxiety. Completing these plans will suggest new areas of investigation related to anxiety disorders, and provide the candidate with the knowledge and experience necessary to develop and characterize other genetic models of psychiatric illness.