Neural correlates of anxiety in 5-HT1AR knockout mice

描述(由申请人提供)：为使候选人在神经科学研究领域为独立的职业生涯做准备，提出了培训和研究计划。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)关于如何利用精神疾病的遗传模型的知识和能力的基金；(3)在负责任的研究中接触到问题；以及(4)有效的实验室管理经验。该研究计划需要对5-HT1AR突变小鼠进行评估，这些突变小鼠的焦虑相关行为增加。了解导致这种表型的5-HT1AR缺失的影响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。在发育过程中，前脑需要5-HT1AR的表达才能建立正常的焦虑样行为，这表明5-HT1AR在生命早期就会建立支持这些行为的神经元回路。该项目的目标是识别和表征与焦虑相关表型相关的5-HT1A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-HT1AR缺乏表达导致海马体功能失调，导致表型；(2)这种失调与完好小鼠的先天焦虑样行为有关。将从海马区获得清醒的行为神经记录，目的如下：(1)评估5-HT1AR基因敲除小鼠的海马区活动；(2)评估前脑挽救仅在发育期间或仅在成年期表达的5-HT1AR缺乏症动物的海马区活动；(3)通过行为和药物操作研究海马区活动与先天性焦虑之间的关系；以及(4)比较海马背和腹侧海马区的神经生理学行为关系，这可能参与调节先天焦虑的不同参与。完成这些计划将提出与焦虑症相关的新的研究领域，并为应聘者提供必要的知识和经验，以开发和表征其他精神疾病的遗传模式。

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.