Elucidating the mechanisms underlying ketamine-induced protection against fear overgeneralization

阐明氯胺酮诱导的针对恐惧过度概括的保护机制

基本信息

批准号：
9911605
负责人：
Josephine McGowan
金额：
$ 4.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911605
关键词：
Address Antidepressive Agents Anxiety Applications Grants Attenuated Behavior Behavioral Behavioral Assay Biological Assay Cells Chronic Chronic stress Data Development Discrimination Discrimination Learning Disease Environment Female Fright Functional disorder Glutamates Goals Hippocampus (Brain)Home environment Image Implant Injections Ketamine Knowledge Laboratories Lead Learning Long-Term Effects Longitudinal Studies Major Depressive Disorder Measures Mediating Memory Mental disorders Microdialysis Mus N-Methyl-D-Aspartate Receptors Neurons Neurotransmitters Patients Physiological Play Post-Traumatic Stress Disorders Protocols documentation Reporting Research Research Personnel Research Training Role Saline Serotonin Shock Stimulus Stress Symptoms Techniques Testing Treatment Efficacy Viral Virus Work antidepressant effect awake behavioral response calmodulin-dependent protein kinase II cell type cohort conditioned fear depressive symptoms design gamma-Aminobutyric Acid implantation in vivo lens male neurochemistry novel prevent public health relevance relating to nervous system response skills stress disorder stress resilience tool 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. Chronic stress in particular often leads to maladaptive responses, and 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 generalization, as defined by the overgeneralization of fear from a conditioned, fear-inducing stimulus to novel, neutral stimuli. We have previously discovered that a single injection of (R,S)-ketamine, a rapid-acting antidepressant, protects mice against stress-induced depressive-like behavior (Brachman et al., 2016) and attenuates learned fear following contextual fear conditioning (CFC) (McGowan et al., 2017). We have also found that, using a contextual fear discrimination (CFD) protocol, (R,S)-ketamine decreases fear generalization (Mastrodonato et al., 2018). The Denny laboratory has reported that the ventral hippocampus (vHPC), specifically ventral CA3 (vCA3), mediates (R,S)-ketamine's effects on attenuating learned fear in the CFC paradigm. However, how exactly (R,S)-ketamine modulates the ensembles in vCA3 to decrease fear generalization is yet to be explored. This research plan will lay the groundwork to uncover the effects of (R,S)-ketamine administration on fear generalization throughout CFD using a combination of in vivo microdialysis and in vivo Ca2+ imaging in vCA3. Both of these in vivo techniques will allow for chronic assessment of underlying changes throughout (R,S)- ketamine administration and during behavioral expression (e.g., fear overgeneralization). In Aim 1, I will test the hypothesis that neurochemical changes in glutamate, gamma-aminobutyric acid (GABA), and serotonin (5- HT) in vCA3 potentially mediate (R,S)-ketamine's effects on fear generalization in male and female mice. By using in vivo microdialysis, I will determine how neurotransmitters relevant to learning and memory are contributing to fear generalization in both saline (control)-injected and (R,S)-ketamine-injected mice. I will test the hypothesis that glutamate and 5-HT in vCA3 are persistently increased, while GABA is decreased, during expression of fear in saline-treated mice, but that this persistent increase is mitigated by (R,S)-ketamine treatment. In Aim 2, I will utilize nVoke minimicroscopes developed by Inscopix to perform in vivo Ca2+ imaging and will test the hypothesis that (R,S)-ketamine prevents the heightened excitatory Ca2+ activity in vCA3 induced by stress, and thus, decreases fear generalization in male and female mice. For Aim 2A, I will visualize Ca2+ transients in excitatory cells of vCA3. For Aim 2B, I will visualize Ca2+ transients in inhibitory cells of vCA3. To date, no longitudinal studies utilizing in vivo Ca2+ imaging or in vivo microdialysis studies have yet been performed for fear generalization and/or following (R,S)-ketamine administration. Overall, my goal for this proposal is to better understand how (R,S)-ketamine may alter neurotransmitters and neural ensembles, resulting in decreased fear generalization, a core symptom in PTSD and MDD patients.

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。特别是慢性压力通常会导致适应不良的反应，并且随后的精神疾病发展，例如创伤后应激障碍（PTSD）和主要抑郁症（MDD）。在这些疾病中观察到的核心症状是增加恐惧的概括，因为由从条件，恐惧的刺激到新颖的中性刺激的恐惧过度笼统的定义。我们以前已经发现（r，s） - 酮胺（一种快速作用的抗抑郁药）单一注射，保护小鼠免受压力引起的类似抑郁症的行为（Brachman等，2016），并减弱了学到的恐惧之后恐惧条件（CFC）（McGowan等，2017）。我们还发现，使用上下文恐惧歧视（CFD）方案，（R，S） - 酮胺减少了恐惧的概括（Mastrodonato et Al。，2018）。丹尼实验室报告说，腹侧海马（VHPC），特别是腹侧CA3 （VCA3），介导（R，S） - 酮胺对CFC范式中学到的恐惧的影响。但是，如何恰好（R，S） - 酮胺调节VCA3中的合奏以减少恐惧概括。该研究计划将奠定基础，以揭示（R，S） - 酮胺施用对恐惧的影响使用体内微透析和VCA3中体内Ca2+成像的组合，整个CFD的概括。这两种体内技术都将允许对整个（R，s） - 氯胺酮给药和行为表达期间（例如，恐惧过度笼统）。在AIM 1中，我将测试谷氨酸，γ-氨基丁酸（GABA）和5-羟色胺的神经化学变化的假设（5-- HT）在VCA3中可能介导（R，S） - 酮胺对雄性和雌性小鼠的恐惧概括的影响。经过使用体内微透析，我将确定与学习和记忆相关的神经递质如何在盐水（对照）注射和（R，S）注射小鼠的恐惧中有助于概括。我会测试 VCA3中谷氨酸和5-HT的假设持续增加，而GABA则减少，期间盐水处理的小鼠的恐惧表达，但是（R，S） - 酮胺会减轻这种持续增长治疗。在AIM 2中，我将利用Inscopix开发的NVOKE Minmimicimicroscopes在体内CA2+成像中执行并将检验以下假设：（R，S） - 酮胺可防止VCA3中兴奋的Ca2+活性的增强由压力诱导，从而减少雄性和雌性小鼠的恐惧概括。对于AIM 2A，我会可视化VCA3兴奋性细胞中的Ca2+瞬变。对于AIM 2B，我将可视化抑制性Ca2+瞬变 VCA3细胞。迄今尚未进行恐惧的概括和/或跟随（R，S） - 酮胺的给药。总的来说，我的该建议的目标是更好地了解（R，S） - 酮胺可能会改变神经递质和神经合奏，导致恐惧概括减少，是PTSD和MDD患者的核心症状。