Mechanisms of Stress-Enhanced Aversive Conditioning

摘要 认知功能障碍，包括对消极情节的不适当概括(即过度概括) 记忆是抑郁症的核心诊断标准，被认为是严重抑郁症的关键决定因素 情绪性症状。出于这个原因，我们认为研究记忆概括的神经生物学可以 对抑郁症有相当大的转化影响。我们建议识别细胞和电路 使用新开发的一种新技术实现负面情境(情节样)记忆泛化的机制 应激诱导概括范式(SIG)。目标1将依赖于最新的方法，使我们能够 可视化和操控编码特定和一般上下文特征的神经元群体 回忆。通过这些技术，我们希望确定压力是促进还是破坏 在记忆恢复过程中这些神经元群体的重新激活。目标2将利用化学发生和 光遗传学方法，单独或结合神经元标记，以确定兴奋性 腹侧被盖区(VTA)到背侧海马区(DH)的投射是负价的信号， 为SIG做出贡献。抑制这些投射预计会减少泛化，特别是在女性中。 AIM 3将侧重于MS到DH的投射，我们怀疑它在SIG中起着更突出的作用 男性多于女性。除了目标2中使用的方法外，我们还将确定压力和 胆碱能神经对海马区振荡和乙酰胆碱释放的调节作用，我们将探讨 使用锰增强磁共振成像的应激介导的全球大脑活动的变化。 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)适配 由压力引起的，这会导致负面背景记忆的持久概括。证明了这些方法 有效逆转SIG可能是新的治疗与高血压相关的认知障碍的基础 抑郁和情感障碍。

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.