Circuits underlying overgeneralization

过度概括是一种认知障碍，通常与创伤后应激有关 以及情绪和焦虑障碍。在过去的10年里，我们 积累了几条证据表明，齿状回（DG）有助于 一系列负效价相关的行为，包括恐惧过度概括，以及一些 抗抑郁药物对行为的影响。具体来说，我们和其他人已经表明， 齿状回对于情境恐惧辨别学习是至关重要的， 学习已经提出了由模式分离，计算 类似的经验被转化为离散的非重叠神经网络的过程。 表示。在目前的提案中，我们的目标是将这些行为和 生理研究表明，DG是关键的模式分离， 模式分离的缺陷是在情绪中经常观察到的背景辨别缺陷的基础。 和焦虑症根据我们的初步结果，我们假设， 改善DG中的模式分离将有利于情绪的治疗， 焦虑症 与大多数其他大脑区域不同，成年人的DG不仅包含成熟的发育中出生的 神经元，但也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 其他研究表明，成熟颗粒细胞（mGCs）和年轻的成体颗粒细胞 （abGCs）对于情境恐惧辨别学习（CFD）至关重要。在拟议的研究中， 我将在背景恐惧期间对DG中的abGC和mGC的活动进行成像 通过使用钙成像和微型显微镜（微型镜）进行辨别任务。 该成像将在abGC的光遗传学操作之后在基线条件（目标1）下进行 调节DG活性（目的2），并在早期生活应激和成年后DG活性的操作 (Aim 3）。

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).