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).

过度泛化是一种通常与创伤后应激有关的认知障碍 精神障碍以及情绪和焦虑障碍。在过去10年的赠款中，我们已经 积累的几条证据表明，齿状回(DG)参与了 一系列与负价感相关的行为，包括恐惧过度泛化，以及一些 抗抑郁药物对行为的影响。具体地说，我们和其他人已经表明 齿状回对于情景恐惧辨别学习至关重要，这是一种 已提出通过模式分离进行中介的学习，这是一种计算 相似经验转化为离散的非重叠神经的过程 申述。在当前的提案中，我们的目标是将这些行为和 通过表明DG对于模式分离是关键的生理研究路线，以及 模式分离缺陷是情绪中经常观察到的语境歧视缺陷的基础 和焦虑症。根据我们的初步结果，我们假设战略的目标是 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，成年的DG不仅包含发育成熟的婴儿 神经元，也有成人出生的神经元，通过一个被称为成人神经发生的过程产生。我们 另一些研究表明，成熟颗粒细胞(MGCs)和幼年出生的颗粒细胞 (AbGC)对情境恐惧歧视学习(CFD)至关重要。在建议的研究中，我们 将想象背景恐惧期间DG中abGC和mGC的活动 使用钙成像和微型显微镜(微型显微镜)进行辨别任务。 这项成像将在基线条件下(目标1)，在对abGC进行光遗传操作之后进行 调节DG活动(目标2)，以及在早期生活应激和成人对DG活动的操纵之后 (目标3)。