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，包括负面情节的不当概括（即过度笼过） 记忆，是严重抑郁症的核心诊断标准，被认为是严重的关键决定因素 情感症状。因此，我们认为研究记忆概括的神经生物学可以 对抑郁症有很大的翻译影响。我们建议识别细胞和电路 使用新发展 应力诱导的概括（SIG）的范式。 AIM 1将依靠最近的方法，使我们能够 可视化和操纵神经元种群编码上下文的特定特征和一般特征 回忆。通过这些技术，我们希望确定压力是促进还是破坏 记忆回收过程中这些神经元种群的重新激活。 AIM 2将利用化学发生和 单独或与神经元标记结合使用光遗传学方法，以确定兴奋性是否 腹侧侧距区域（VTA）到背部海马（DH）投影，该预测信号为负价， 为SIG做出贡献。这些预测的抑制有望减少概括，尤其是在女性中。 AIM 3将侧重于MS对DH预测的作用，我们怀疑这在SIG中起着更为突出的作用 男性比女性。除了AIM 2中使用的方法外，我们还将确定压力和 海马振荡和乙酰胆碱释放的胆碱能神经调节，我们将探索 应力介导的全球大脑活动的变化使用锰增强的磁共振成像。 在该项目的竞争之后，我们希望已经确定了主要的细胞和电路（MAL）适应 由压力引起的，导致负面背景记忆的持续概括。证明的方法 有效扭转SIG可能是与与 抑郁和情感障碍。