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Dissecting the Contribution of the Ventral Hippocampus to (R,S)-Ketamine's Fear Buffering Effects

剖析腹侧海马对 (R,S)-氯胺酮恐惧缓冲效应的贡献

基本信息

批准号：
10319316
负责人：
Josephine McGowan
金额：
$ 4.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319316
关键词：
Address Affect Antidepressive Agents Anxiety Attenuated Award Behavior Behavioral Behavioral Assay Biological Buffers Complement Data Development Disease Enhancers Exposure to Female Fright Future Glutamates Goals Growth High-Throughput RNA Sequencing Hippocampus (Brain)Image Injections Institution Ketamine Knowledge Laboratories Latina Lead Learning Link Long-Term Effects Longitudinal Studies Major Depressive Disorder Measures Mediating Memory Mental Depression Mental disorders Mentors Microdialysis Microscopy Molecular Mus N-Methyl-D-Aspartate Receptors Neurons Neurosciences Neurotransmitters Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Positioning Attribute Post-Traumatic Stress Disorders Postdoctoral Fellow Predisposition Psychopathology Reporting Research Research Personnel Research Project Grants Retrieval Serotonin Shock Signal Transduction Stimulus Stress Symptoms Techniques Testing Training Work antidepressant effect awake behavioral response career comorbidity conditioned fear disability experience foot gamma-Aminobutyric Acid in vivo in vivo imaging insight large scale data male neurochemistry novel prevent resilience response skills stress disorder stress resilience stressor tool transcriptomics treatment-resistant depression

项目摘要

PROJECT SUMMARY / ABSTRACT Though stress is necessary for the adaptive survival of a species, stress exposure can also elicit maladaptive physiological and behavioral responses. Stress-induced maladaptive responses may lead to subsequent development of psychiatric disorders such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). A core symptom observed in these disorders is increased fear expression, as defined by heightened fear responses in the presence of stimuli associated with fear. We have previously discovered that a single injection of (R,S)-ketamine, a rapid-acting antidepressant, attenuates learned fear following contextual fear conditioning (CFC). We and others have reported that the ventral hippocampus (vHPC), specifically ventral CA3 (vCA3), mediates (R,S)-ketamine’s effects on attenuating learned fear. However, how exactly (R,S)-ketamine modulates the ensembles in vCA3 to decrease fear generalization is yet to be explored. It has additionally been shown that ventral CA1 (vCA1) contributes to fear behavior. Thus, this research plan will lay the groundwork to uncover the effects of (R,S)-ketamine administration on fear behavior using of in vivo microdialysis to complement and further explain the data already collected from in vivo Ca2+ imaging in vCA3 and vCA1. Overall, my goal for this proposal is to better understand how (R,S)-ketamine alters neurotransmitters and neuronal ensembles to buffer against heightened fear expression. My preliminary findings outlined in Aim 1 show that (R,S)-ketamine: 1) blunts responses to shocks during fear encoding specifically in vCA3; 2) differentially affects activity in ventral hippocampal regions CA3 and CA1; and 3) decreases correlated activity in the ventral hippocampus during both fear encoding and retrieval. Together, these findings lead me to my hypothesis that there are distinct changes in neurotransmitter content immediately following (R,S)-ketamine administration that are long-lasting and that blunt the experience of a fearful stressor. However, to test this hypothesis, I need to utilize in vivo microdialysis as outlined in Aim 2 to measure levels of glutamate, gamma-aminobutyric acid (GABA), and serotonin (5-HT) in vCA3 or vCA1 of male and female mice to understand how they potentially mediate (R,S)-ketamine’s effects. To date, no longitudinal studies utilizing in vivo Ca2+ imaging or in vivo microdialysis studies have yet been performed investigating (R,S)-ketamine effects on fear behavior. In Aim 3, I describe a postdoctoral research direction to accomplish my goal of understanding the biological substrates of stress resilience. I have gained experience in behavior, in vivo techniques, cellular and molecular neuroscience, and microscopy. However, I have yet to conduct techniques that manipulate circuits, or that probe the contribution of transcriptomic changes after drug treatment or with stress. Thus, I plan to address these gaps in my knowledge by finding a post-doctoral position that allows me to grow in these skills. In summary, this proposal will lead to the development of a diverse skillset in order to become a successful independent researcher in the psychiatric field.

项目概要/摘要虽然压力对于一个物种的适应性生存是必要的，但压力暴露也会引起适应不良生理和行为反应。压力引起的适应不良反应可能会导致后续的精神疾病的发展，例如创伤后应激障碍（PTSD）和重度抑郁症障碍（MDD）。在这些疾病中观察到的核心症状是恐惧表达增加，定义为当存在与恐惧相关的刺激时，恐惧反应会加剧。我们之前已经发现单次注射（R，S）-氯胺酮（一种速效抗抑郁药）可减轻情境后的习得性恐惧恐惧调节（CFC）。我们和其他人报告说，腹侧海马（vHPC），特别是腹侧 CA3 (vCA3)，介导 (R,S)-氯胺酮减轻习得性恐惧的作用。然而，究竟如何 (R,S)-氯胺酮调节 vCA3 中的整体以减少恐惧泛化仍有待探索。它有另外还显示腹侧 CA1 (vCA1) 会导致恐惧行为。因此，本研究计划将奠定为揭示 (R,S)-氯胺酮给药对体内恐惧行为的影响奠定了基础微透析补充并进一步解释从 vCA3 体内 Ca2+ 成像中已收集的数据和 vCA1。总的来说，我这个提案的目标是更好地理解 (R,S)-氯胺酮如何改变神经递质和神经元群可以缓冲高度的恐惧表达。我的初步目标 1 中概述的研究结果表明，(R,S)-氯胺酮：1) 减弱恐惧编码过程中对电击的反应特别是在 vCA3 中； 2) 对腹侧海马区 CA3 和 CA1 的活动有不同影响；和 3) 在恐惧编码和检索过程中减少腹侧海马的相关活动。一起，这些发现使我得出这样的假设：神经递质含量发生了明显的变化 (R,S)-氯胺酮给药后立即产生持久的效果，并减弱患者的体验可怕的压力源。然而，为了检验这一假设，我需要利用目标 2 中概述的体内微透析来测量 vCA3 或 vCA1 中谷氨酸、γ-氨基丁酸 (GABA) 和血清素 (5-HT) 的水平雄性和雌性小鼠，以了解它们如何潜在地介导（R，S）-氯胺酮的作用。迄今为止，没有利用体内 Ca2+ 成像或体内微透析研究的纵向研究尚未进行研究（R，S）-氯胺酮对恐惧行为的影响。在目标 3 中，我描述了一个博士后研究方向实现我了解压力恢复的生物基础的目标。我已经获得了以下方面的经验行为、体内技术、细胞和分子神经科学以及显微镜。然而，我还没有进行操纵电路的技术，或探测药物后转录组变化的贡献治疗或有压力。因此，我计划通过寻找博士后来弥补我的知识差距让我在这些技能上成长的职位。总而言之，该提案将导致开发多样化的技能，以成为精神病学领域成功的独立研究员。