Mechanisms of Stress-Enhanced Aversive Conditioning

压力增强厌恶性条件反射的机制

• 批准号: 10553724
• 负责人: Jelena Radulovic
• 金额: $ 61.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553724
• 关键词: Acetylcholine; Affect; Affective Symptoms; Behavior; Brain; Code; Cognitive deficits; Cues; Data; Development; Disease; Dorsal; Episodic memory; Female; Fiber; Foundations; Fright; Future; Genetic; Global Change; Hippocampus; Immediate-Early Genes; Impaired cognition; Impairment; Label; Magnetic Resonance Imaging; Major Depressive Disorder; Manganese; Measurement; Medial; Mediating; Memory; Mental Depression; Mood Disorders; Mus; NPAS4 gene; Negative Valence; Neuroanatomy; Neurobiology; Neurons; Photometry; Play; Population; Process; Recurrence; Retrieval; Review Literature; Role; Scopolamine; Severities; Signal Transduction; Source; Stress; Stressful Event; System; Techniques; Testing; Ventral Tegmental Area; Visualization; aversive conditioning; behavioral response; cholinergic; design; diagnostic criteria; episodic memory impairment; experience; experimental study; male; memory encoding; memory retrieval; neuroregulation; novel; optogenetics; promoter; social stress; stem; stress reduction; translational impact

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.

抽象的 认知功能障碍，包括对负面事件的不恰当概括（即过度概括） 记忆力是重度抑郁症的核心诊断标准，并被认为是重度抑郁症的关键决定因素。 情感症状。因此，我们相信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。我们建议识别蜂窝和电路 使用新开发的机制促进负面情境（情景式）记忆的泛化 压力诱导泛化（SIG）的范式。目标 1 将依赖最新的方法，使我们能够 可视化和操纵编码上下文的特定和一般特征的神经元群 回忆。通过这些技术，我们希望确定压力是否会促进或破坏 在记忆检索过程中这些神经元群的重新激活。目标 2 将利用化学遗传学和 光遗传学方法，单独或与神经元标记相结合，以确定是否兴奋 腹侧被盖区（VTA）到背侧海马（DH）的投影，表示负价， 为 SIG 做出贡献。抑制这些预测预计会减少泛化，特别是在女性中。 目标 3 将重点关注 MS 到 DH 预测的作用，我们怀疑这在 SIG 中发挥着更重要的作用 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压力的影响 胆碱能神经调节对海马振荡和乙酰胆碱释放的影响，我们将探讨 使用锰增强磁共振成像研究压力介导的全球大脑活动变化。 在该项目的竞争中，我们希望能够确定主要的细胞和电路（不良）适应 由压力引起，导致负面情境记忆的持久泛化。证明的方法 有效逆转 SIG 可能成为与认知缺陷相关的新疗法的基础 抑郁症和情感障碍。