Neural correlates of anxiety in 5-HT1AR knockout mice

描述（由申请人提供）：为使候选人能够独立从事神经科学研究，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、行为和神经生理特征相关的实验室技能；(2)对精神疾病的遗传模型有丰富的知识和创造性的思考能力，如何利用这些模型；(3)在负责任的研究行为中了解问题；(4)具有有效的实验室管理经验。该研究计划需要评估5-羟色胺1A受体（5-HT1AR）突变小鼠，这些小鼠具有增加的焦虑相关行为。了解5-HT1AR缺失导致这种表型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疗法的新靶点。5-HT1AR在发育过程中需要在前脑中表达，以建立正常的焦虑样行为，这表明5-HT1AR在生命早期就起作用，建立这些行为背后的神经回路。该项目的目标是确定和表征与焦虑相关表型相关的5-HT1A受体表达中断的神经生理学后果。本文将检验以下假设：(1)发育过程中缺乏5-HT1AR表达导致海马功能失调，从而导致表型；(2)这种失调与完整小鼠的先天性焦虑样行为有关。从海马体获得清醒时的行为神经记录，目的如下：(1)评估5-HT1AR基因敲除小鼠的海马体活动；(2)评估仅在发育期间或仅在成年期表达5- ht1ar缺失的前脑救援动物的海马活动；(3)通过行为学和药理学研究海马活动与先天焦虑的关系；(4)比较海马背侧区和腹侧区的神经生理行为关系，这些区域可能在先天焦虑的中介中有不同的参与。完成这些计划将为焦虑障碍相关的研究开辟新的领域，并为候选人提供必要的知识和经验，以发展和表征其他精神疾病的遗传模型。

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.