Hippocampal Mechanisms of Stress-Induced Generalization of Negative Memories

压力引起的负面记忆泛化的海马机制

• 批准号: 10527326
• 负责人: Lynn Ren
• 金额: $ 3.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527326
• 关键词: Acetylcholine; Adult; Affect; Affective Symptoms; American; Animal Model; Anxiety Disorders; Association Learning; Basic Science; Behavior; Cells; Cognition; Cognitive deficits; Data; Depressive disorder; Development; Disease; Dorsal; Economic Burden; Episodic memory; Event; Exposure to; Fright; Future; Generalized Anxiety Disorder; Glutamates; Hippocampus; Human; Interview; Label; Major Depressive Disorder; Medial; Mediating; Memory; Memory impairment; Mental Depression; Modeling; Molecular; Mood Disorders; Mus; Muscarinic Acetylcholine Receptor; National Institute of Mental Health; Neurobehavioral Manifestations; Neurobiology; Neurons; Occupations; Output; Phenotype; Physicians; Population; Presynaptic Terminals; Process; Relapse; Research Domain Criteria; Rodent; Role; Scientist; Source; Specificity; Stress; Symptoms; System; Therapeutic; United States; Viral; career; cholinergic; clinically relevant; conditioned fear; conditioning; cost; disability; effective therapy; endophenotype; executive function; experience; experimental study; fear memory; genetic approach; memory encoding; memory process; neural circuit; neural correlate; neurobiological mechanism; neuromechanism; neurotransmission; new therapeutic target; novel; prevent; social; social defeat; stress reduction; theories; translational scientist

PROJECT SUMMARY ! Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) are debilitating and widespread disorders for which current treatments are unfortunately insufficient, particularly for associated cognitive symptoms. These cognitive symptoms, which include impairments of memory, executive function, and cognition, precede and predict the development of affective symptoms, thus they likely contribute to the development of associated affective symptoms. Given this, treating or preventing cognitive symptoms may prevent or lessen other symptoms of MDD and GAD. Unfortunately, our understanding of the neurobiological mechanisms underlying these cognitive symptoms is limited. A reliable and common cognitive deficit seen in MDD and GAD is overgeneralization of negative memories, defined as making sweeping conclusions based on a single past negative experience (e.g.: if I fail at this job interview, I will perform poorly on all my future interviews as well). Stress is known to promote generalization of negative memories; however, how this process occurs is not known. Thus, a better understanding of how stress alters neural circuits to promote generalization of negative memories is needed to elucidate the neural mechanisms underlying disease-relevant behaviors. On this basis, and consistent with NIMH's research domain criteria (RDoC) initiative, I propose to study the mechanisms of stress- induced generalization of negative memories (SIGNM) as an endophenotype of MDD and GAD. To this end, I developed an animal model for SIGNM by combining contextual fear conditioning with social defeat stress. I will use this model to elucidate cellular and molecular mechanisms of SIGNM. A promising candidate region is the dorsal hippocampus (DH) given (1) its role in associative learning, social memory, and episodic memory, (2) the fact that abnormal DH function has been implicated in generalization of memories in rodents and humans, and (3) that my pilot data shows that glutamatergic DH neurons mediate SIGNM. The DH is thought to encode contextual memories through organized ensembles of active neurons, commonly termed engram cells. Increased overlap of engram cells encoding different contextual memories is theorized to underlie increased generalizability between those contextual memories. Given this, increased overlap of neurons encoding negative event-associated and neutral contexts may provide a potential mechanism for SIGNM. I will explore this hypothesis in aim 1. To then explore circuit mechanisms of SIGNM, I will explore the contribution of DH glutamatergic outputs to RSC in SIGNM (Aim 2.) These projections are of promise as DH glutamatergic outputs to the RSC have been shown to mediate contextual fear memory processing. Next, as my pilot data shows that muscarinic acetylcholine receptors in the DH are necessary for SIGNM, I will then explore the role of cholinergic medial septum projections to the DH, the predominant source of DH acetylcholine, in SIGNM (Aim 3.) Upon completion of these experiments, I expect to have identified novel cellular and circuit mechanisms of SIGNM that can serve as RDoC for GAD and MDD, as well as novel therapeutic targets for these disorders.

项目摘要 呢 重度抑郁症（MDD）和广义焦虑症（GAD）令人衰弱和普遍 不幸的是，当前治疗的疾病不足，特别是相关认知的疾病 症状。这些认知症状包括记忆，执行功能和认知的损害， 先于并预测情感症状的发展，因此它们可能有助于发展 相关的情感症状。鉴于此，治疗或预防认知症状可能会阻止或减轻 MDD和GAD的其他症状。不幸的是，我们对神经生物学机制的理解 这些认知症状的基础受到限制。 MDD和GAD中看到的可靠且常见的认知缺陷 是对消极记忆的过度概括，定义为基于单个过去的大量结论 负面的经验（例如：如果我在这次面试中失败，我将来的所有面试也会表现不佳）。 已知压力会促进负记忆的概括。但是，该过程的发生方式尚不清楚。 因此，更好地理解压力如何改变神经回路以促进消极记忆的概括 需要阐明与疾病相关的行为的神经机制。在此基础上， 与NIMH的研究领域标准（RDOC）倡议一致，我建议研究应力机制 诱导的负记忆（SIGNM）作为MDD和GAD的内形型的概括。 为此，我通过将上下文恐惧调节与社会结合起来开发了一个动物模型 击败压力。我将使用此模型阐明Signm的细胞和分子机制。有希望的 候选地区是（DH）的背侧海马（1） 情节记忆，（2）DH功能异常与记忆的概括有关的事实 啮齿动物和人类，以及（3）我的试验数据表明，谷氨酸能DH神经元介导了Signm。 DH 被认为通过有效的主动神经元的有组织的合奏编码上下文记忆，通常称为 Engram单元格。理论上，编码不同上下文记忆的Engram单元格的重叠增加为基础 这些上下文记忆之间的推广性提高了。鉴于此，神经元的重叠增加 编码负面事件相关和中性环境可能会为Signm提供潜在的机制。我会 在AIM 1中探索这一假设。然后探索Signm的电路机制，我将探讨 DH谷氨酸能在Signm中向RSC输出​​（AIM2。）这些预测是有希望的 已显示出RSC的输出可以介导上下文恐惧记忆处理。接下来，作为我的飞行员数据 表明DH中有必要的毒蕈碱乙酰胆碱受体是Signm的必要条件，然后我将探索的作用 胆碱能的内侧隔膜投影对DH（DH的主要来源），在Signm中 3.）这些实验完成后，我希望已经确定了新型的细胞和电路机制 可以用作GAD和MDD的RDOC的Signm，以及这些疾病的新型治疗靶标。