Circuits underlying overgeneralization

过度概括的电路

• 批准号: 10585706
• 负责人: Rene Hen
• 金额: $ 39.98万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-07 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585706
• 关键词: Adult; Anxiety Disorders; B-Lymphocytes; Behavior; Behavioral; Brain region; Calcium; Cells; Development; Discrimination; Discrimination Learning; Exercise; Exposure to; Freezing; Fright; Gene Expression; Grant; Hippocampus; Hyperactivity; Image; Impaired cognition; Impairment; Learning; Light; Maps; Measures; Mediating; Microscope; Mood Disorders; Mus; Negative Valence; Neurons; Opsin; Pattern; Pharmaceutical Preparations; Physiological; Population; Post-Traumatic Stress Disorders; Process; Publishing; Research; System; Testing; Therapeutic; Time; adult neurogenesis; antagonist; antidepressant effect; dentate gyrus; early life stress; endophenotype; experience; experimental study; granule cell; improved; neural; neurogenesis; neuromechanism; optogenetics; pharmacologic; young adult

Overgeneralization is a cognitive impairment commonly associated with post-traumatic stress disorder as well as mood and anxiety disorders. Over the past 10 years of this grant, we have accumulated several lines of evidence indicating that the dentate gyrus (DG) contributes to a range of negative valence related behaviors including fear overgeneralization, as well as to some of the behavioral effects of antidepressant medications. Specifically, we and others have shown that the dentate gyrus is critical for contextual fear discrimination learning, a form a learning that has been proposed to be mediated by pattern separation, a computational process by which similar experiences are transformed into discrete non-overlapping neural representations. In the current proposal we aim at bringing together these behavioral and physiological lines of research by showing that the DG is critical for pattern separation and that deficits in pattern separation underlie the contextual discrimination deficits often observed in mood and anxiety disorders. Based on our preliminary results we hypothesize that strategies aimed at improving pattern separation in the DG will be beneficial for the treatment of mood and anxiety disorders. Unlike most other brain regions, the adult DG contains not only mature developmentally-born neurons but also adult-born neurons generated via a process termed adult neurogenesis. We and others have shown that both mature granule cells (mGCs) and young adult-born granule cells (abGCs) are critical for contextual fear discrimination learning (CFD). In the proposed studies we will image the activity of both abGCs as well as mGCs in the DG during a contextual fear discrimination task by using calcium imaging and miniature microscopes (miniscopes). This imaging will be done in baseline conditions (Aim 1), after optogenetic manipulation of abGCs to modulate DG activity (Aim 2), and after early life stress and adult manipulations of DG activity (Aim 3).

过度概括是一种通常与创伤后应激相关的认知障碍 障碍以及情绪和焦虑障碍。在过去 10 年的拨款中，我们 积累了几行证据表明齿状回（DG）有助于 一系列与负价相关的行为，包括恐惧过度概括，以及某些 抗抑郁药物的行为影响。具体来说，我们和其他人已经表明 齿状回对于情境恐惧歧视学习至关重要，这是一种形式 学习被提议通过模式分离来调节，模式分离是一种计算方法 将相似的经历转化为离散的、不重叠的神经网络的过程 交涉。在当前的提案中，我们的目标是将这些行为和 生理学研究表明，DG 对于模式分离至关重要，并且 模式分离的缺陷是情绪中经常观察到的情境辨别缺陷的基础 和焦虑症。根据我们的初步结果，我们假设策略旨在 改善 DG 中的模式分离将有利于治疗情绪和 焦虑症。 与大多数其他大脑区域不同，成人 DG 不仅包含成熟的发育出生 神经元，也包括通过称为成人神经发生的过程产生的成人出生的神经元。我们 等人已经表明，成熟颗粒细胞（mGC）和年轻的成年颗粒细胞 （abGC）对于情境恐惧歧视学习（CFD）至关重要。在拟议的研究中，我们 将在情景恐惧期间对 DG 中的 abGC 和 mGC 的活动进行成像 使用钙成像和微型显微镜（微型显微镜）进行辨别任务。 该成像将在 abGC 光遗传学操作后在基线条件下完成（目标 1） 调节 DG 活动（目标 2），以及在早期生活压力和成人操纵 DG 活动之后 （目标 3）。