Mechanisms of Stress-Enhanced Aversive Conditioning

摘要 认知功能障碍，包括不适当的概括（即，过度概括）的负面情节 记忆，是重性抑郁症的核心诊断标准，并被认为是严重抑郁症的关键决定因素。 情感症状因此，我们认为，研究记忆泛化的神经生物学可以 对抑郁症有相当大的转化影响。我们建议识别细胞和电路 机制subserving概括的负面背景（情节样）的记忆，使用新开发的 压力诱导泛化（stress-induced generalization，SIG）目标1将依赖于最新的方法，使我们能够 可视化和操纵编码特定和一般背景特征的神经元群体 回忆通过这些技术，我们希望确定压力是促进还是破坏了 这些神经元群体在记忆恢复过程中的重新激活。目标2将利用化学遗传学和 光遗传学方法，单独或结合神经元标记，以确定是否兴奋性 腹侧被盖区（VTA）到背侧海马（DH）的投射，其信号为负效价， 为SIG做贡献抑制这些预测预计将减少泛化，特别是在女性。 目标3将重点关注MS到DH预测的作用，我们怀疑这在SIG中发挥更突出的作用， 男性多于女性。除了目标2中使用的方法外，我们还将确定压力的影响， 胆碱能神经调节海马振荡和乙酰胆碱释放，我们将探讨 使用锰增强磁共振成像的应激介导的全球脑活动变化。 在这个项目的竞争中，我们希望已经确定了主要的细胞和电路（mal）适应性 由压力引起，导致负面背景记忆的持久概括。这些方法证明 有效逆转SIG可能是与以下相关的认知缺陷的新治疗的基础： 抑郁症和情感障碍。

ABSTRACT Cognitive dysfunction, including the inappropriate generalization (i.e., overgeneralization) of negative episodic memories, is a core diagnostic criterion of major depression, and is recognized as a key determinant of severe affective symptoms. For this reason, we believe that studying the neurobiology of memory generalization could have considerable translational impact for depression. We propose to identify the cellular and circuit mechanisms subserving generalization of negative context (episodic-like) memories using a newly developed paradigm of stress-induced generalization (SIG). Aim 1 will rely on most recent approaches that allow us to visualize and manipulate neuronal populations coding either specific and general features of context memories. Through these techniques, we expect to determine whether stress promotes or disrupts the reactivation of these neuronal populations during memory retrieval. Aim 2 will utilize chemogenetic and optogenetic approaches, alone or in combination with neuronal labeling, to determine whether excitatory ventral tegmental area (VTA) to dorsal hippocampus (DH) projections, which signal negative valence, contribute to SIG. Inhibition of these projections is expected to reduce generalization, especially in females. Aim 3 will focus on the role of MS to DH projections, which we suspect play a more prominent role in SIG in males than in females. In addition to the approaches used in Aim 2, we will determine the effects of stress and cholinergic neuromodulation on hippocampal oscillations and acetylcholine release, and we will explore the stress-mediated changes of global brain activity using manganese-enhanced magnetic resonance imaging. Upon competition of this project, we expect to have identified the main cellular and circuit (mal)adaptations induced by stress that result in lasting generalization of negative context memories. Approaches that prove effective in reversing SIG could be the foundation for novel treatments of cognitive deficits associated with depression and affective disorders.