Hippocampal Mechanisms of Stress-Induced Generalization of Negative Memories

项目总结 好了！ 严重抑郁障碍(MDD)和广泛性焦虑障碍(GAD)是令人衰弱和普遍的 令人遗憾的是，目前的治疗方法不足以治疗这些疾病，特别是相关的认知障碍 症状。这些认知症状包括记忆、执行功能和认知障碍， 在情感性症状的发展之前和预测，因此他们可能有助于发展 相关的情感症状。鉴于此，治疗或预防认知症状可能会预防或减轻 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 这些认知症状的潜在原因是有限的。MDD和GAD患者常见的可靠认知缺陷 是对负面记忆的过度泛化，定义为根据单一的过去做出概括性的结论 负面经历(例如：如果我这次面试不及格，我在未来的所有面试中也会表现不佳)。 众所周知，压力会促进负面记忆的泛化；然而，这个过程是如何发生的还不清楚。 因此，对压力如何改变神经回路以促进负面记忆泛化有了更好的理解 是阐明疾病相关行为背后的神经机制所必需的。在此基础上，以及 根据NIMH的研究领域标准(RDoC)倡议，我建议研究压力的机制-- 负性记忆诱导泛化(SIGNM)是MDD和GAD的一种内表型。 为此，我为SIGNM开发了一个动物模型，将情景恐惧条件反射与社交相结合 战胜压力。我将使用这个模型来阐明SIGNM的细胞和分子机制。一个有希望的人 候选区域是背侧海马区，因为它(1)在联想学习、社会记忆和 情景记忆，(2)记忆的泛化与异常的DH功能有关。 啮齿动物和人类，以及(3)我的试点数据显示，谷氨酸能DH神经元介导SIGNM。卫生署 被认为是通过有组织的活跃神经元集合来编码语境记忆，通常被称为 英格拉姆细胞。编码不同语境记忆的印迹细胞重叠增加的理论基础是 提高了这些上下文记忆之间的概括性。有鉴于此，神经元的重叠增加 对否定的事件相关上下文和中性上下文进行编码可以为SIGNM提供潜在的机制。这就做 在目标1中探索这一假设。为了随后探索SIGNM的电路机制，我将探索 在SIGNM(目标2)中向RSC输出DH谷氨酸能。这些预测是有希望的，因为DH谷氨酸能 RSC的输出已经被证明可以调节背景恐惧记忆的处理。接下来，作为我的试点数据 证明了胆碱型乙酰胆碱受体是信号转导所必需的，接下来我将探讨其作用。 内侧隔区胆碱能投射至去甲肾上腺素的主要来源--去甲肾上腺素 3.)在完成这些实验后，我希望能识别出新的细胞和电路机制 SIGNM可作为GAD和MDD的RDoC，以及这些疾病的新治疗靶点。

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.