Harnessing Adult Hippocampal Neurogenesis to Enhance Learning and Modulate Mood

描述(由申请人提供)：该培训和研究奖项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，以了解神经回路是如何成为精神疾病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丰富背景经验，以及应用于小鼠认知和情绪研究的行为神经科学方面的严格培训。这项研究建议是基于越来越多的证据，即成年海马区神经发生对于特定形式的学习和调节抗抑郁药物的一些行为效应是必要的。具体目标是解决如何利用成年海马区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，可以在细胞自主的方式下增强成人神经发生的离散成分，候选人将测试增加成年出生神经元的数量或促进其成熟是否足以增强学习和赋予抗抑郁药物的行为效果。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年海马神经发生的离散成分以逆转认知缺陷和治疗抑郁症的治疗效果。为了实现这些目标，候选人制定了一项计划，将广泛的行为神经科学实践培训与正式指导、与经验丰富的调查人员的咨询和相关课程相结合。培训计划还将使应聘者获得翻译神经科学的框架，以便继续开发和测试以基础神经科学为基础并与精神疾病研究相关的新假说。相关性(见说明书)：拟议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认知障碍和治疗抑郁症的治疗效果。它可能导致开发针对抑郁症和认知缺陷的快速有效的新疗法，这些疗法针对成人海马神经发生的离散成分，并受到较少副作用的阻碍。

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.