Harnessing Adult Hippocampal Neurogenesis to Enhance Learning and Modulate Mood

该培训和研究奖的长期目标是使候选人能够建立一个独立的研究计划，将小鼠遗传学与行为神经科学相结合，以了解神经回路如何成为精神疾病的病因机制和治疗的底物。该奖项的指导阶段将补充候选人在发育神经生物学，分子生物学和小鼠遗传学方面的广泛背景经验，并在行为神经科学方面进行严格的培训，以应用于小鼠的认知和情感研究。这项研究计划是基于越来越多的证据，这些证据表明成年海马神经发生对于特定形式的学习和介导抗抑郁药的一些行为效应是必要的。具体目标解决如何利用成年海马神经发生来增强学习和调节情绪。通过使用新的遗传功能获得策略，可以以细胞自主的方式增强成人神经发生的离散成分，候选人将测试增加成年神经元的数量或增强其成熟是否足以增强学习并赋予抗抑郁药的行为效应。这些实验将揭示成年出生的神经元如何有助于模式分离，这是齿状回编码的基本特征，以及齿状回在情绪调节中的功能。从翻译的角度来看，这些实验将有助于确定刺激成人海马神经发生的离散组件，以扭转认知缺陷和治疗抑郁症的治疗效果。为了实现这些目标，候选人制定了一个计划，将行为神经科学的广泛实践培训与正式的指导，与经验丰富的调查人员的咨询和相关课程相结合。该培训计划还将使候选人获得转化神经科学的框架，以便继续开发和测试基于基础神经科学和与精神疾病研究相关的新假设。相关性（参见说明）：这项拟议中的研究将有助于确定刺激成年海马神经发生对改善精神疾病中的认知障碍和治疗抑郁症的治疗影响。它可能会导致抑郁症和认知缺陷的快速作用的新疗法的发展，目标成人海马神经发生的离散组件，并受到较少的副作用。

DESCRIPTION (provided by applicant): The long-term objective of this training and research award is to enable the candidate to establish an independent research program that integrates mouse genetics with behavioral neuroscience to understand how neural circuits are substrates for etiological mechanisms and treatment of psychiatric illnesses. The mentored phase of this award will complement the candidate's extensive background experience in developmental neurobiology, molecular biology and mouse genetics with a rigorous training in behavioral neuroscience as applied to the study of cognition and emotion in mice. The research proposal is predicated upon growing evidence that implicates adult hippocampal neurogenesis as necessary for specific forms of learning and mediating some of the behavioral effects of antidepressants. The Specific Aims address how adult hippocampal neurogenesis may be harnessed to enhance learning and modulate mood. Through the use of novel genetic gain-of-function strategies with which discrete components of adult neurogenesis can be enhanced in a cell-autonomous manner, the candidate will test if increasing the number or enhancing the maturation of adult-born neurons is sufficient to enhance learning and confer the behavioral effects of antidepressants. These experiments will reveal how adult born neurons contribute to pattern separation, a fundamental feature of encoding in the dentate gyrus, and to the functions of the dentate gyrus in mood regulation. From a translational standpoint, these experiments will help determine the therapeutic impact of stimulating discrete components of adult hippocampal neurogenesis to reverse cognitive deficits and for treatment of depression. To accomplish these goals, the candidate has developed a plan that combines extensive practical training in behavioral neuroscience with formal mentorship, consultations with experienced investigators and relevant coursework. The training program will also enable the candidate to acquire a framework in translational neuroscience so as to continue to develop and test novel hypotheses that are grounded in basic neuroscience and relevant to the study of mental illnesses. RELEVANCE (See instructions): The proposed research will help determine the therapeutic impact of stimulating adult hippocampal neurogenesis for ameliorating cognitive impairments in psychiatric disorders and for treatment of depression. It may result in the development of fast acting novel treatments for depression and cognitive deficits that target discrete components of adult hippocampal neurogenesis and are encumbered by fewer side-effects.