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.

项目摘要 /摘要尽管对物种的自适应生存是必需的，但压力暴露也会引起适应不良的生理和行为反应。压力引起的不良适应反应可能导致随后的创伤性疾病（例如创伤后应激障碍（PTSD））和主要抑郁症的发展障碍（MDD）。在这些疾病中观察到的核心症状是增加恐惧表达，如在与恐惧相关的刺激的情况下，恐惧反应提高了。我们以前已经发现（r，s） - 酮胺的单一注射是一种快速作用的抗抑郁药，减轻了在上下文下学习的恐惧恐惧条件（CFC）。我们和其他人报告说，腹侧海马（VHPC），特别是腹侧CA3（VCA3），培养基（R，S） - 酮胺对衰减学习的恐惧的影响。但是，到底是怎么的（R，S） - 酮胺调节VCA3中的合奏以减少恐惧概括。它有另外，腹侧CA1（VCA1）有助于恐惧行为。那将是该研究计划揭示（R，S） - 酮胺施用对使用体内恐惧行为的影响的基础微透析以补充并进一步解释VCA3中体内Ca2+成像中已经收集的数据和VCA1。总体而言，我的这一建议的目标是更好地了解（R，S） - 酮胺如何改变神经递质和神经元合奏以缓冲恐惧表达。我的初步 AIM 1中概述的发现表明（R，S） - 酮胺：1）在恐惧编码期间对冲击的反应钝化 2）差异影响腹侧海马区域CA3和CA1的活性； 3）在恐惧编码和检索期间，腹侧海马的相关活性降低。一起，这些发现使我提出了我的假设，即神经递质含量有明显的变化紧随其后的（r，s） - 酮胺给药，持续持久，钝了恐惧的压力源。但是，为了检验这一假设，我需要使用AIM 2中概述的体内微透析谷氨酸，γ-氨基丁酸（GABA）和5-羟色胺（5-HT）的测量水平雄性和雌性小鼠了解它们如何介导（R，S） - 酮胺的作用。迄今为止，没有使用体内Ca2+成像或体内微透析研究的纵向研究尚未进行研究（R，S） - 酮胺对恐惧行为的影响。在AIM 3中，我描述了博士后研究方向实现我了解压力弹性的生物基质的目标。我有经验行为，体内技术，细胞和分子神经科学以及显微镜。但是，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压力。那就是我计划通过找到博士后来解决这些差距使我能够在这些技能中成长的位置。总而言之，该提议将导致发展多样化的技能，以成为精神病领域的成功独立研究人员。