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

• 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
• 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

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.

项目总结/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。特别是慢性压力往往导致适应不良的反应， 随后发展的精神障碍，如创伤后应激障碍（PTSD）和重大 抑郁症（MDD）。在这些疾病中观察到的一个核心症状是恐惧泛化增加， 其定义是将恐惧从条件性的、引起恐惧的刺激过度概括为新的、中性的刺激。 我们以前已经发现，单次注射（R，S）-氯胺酮，一种速效抗抑郁药， 保护小鼠免于应激诱导的抑郁样行为（Brachman等，2016年）和衰减学习 背景恐惧条件反射（CFC）后的恐惧（McGowan等人，2017年）。我们还发现，使用 上下文恐惧歧视（CFD）协议，（R，S）-氯胺酮降低恐惧泛化（Mastrodonato et 例如，2018年）。Denny实验室报道腹侧海马体（vHPC），特别是腹侧CA 3 （vCA 3）介导（R，S）-氯胺酮对减弱CFC范例中的习得性恐惧的作用。但如何 确切地说，（R，S）-氯胺酮调节vCA 3中的系综以减少恐惧泛化尚待探索。 这项研究计划将为揭示（R，S）-氯胺酮给药对恐惧的影响奠定基础 在vCA 3中使用体内微透析和体内Ca 2+成像的组合在整个CFD中进行概括。 这两种体内技术都将允许长期评估整个（R，S）的潜在变化。 氯胺酮给药和在行为表达期间（例如，害怕过度概括）。在目标1中，我将测试 谷氨酸、γ-氨基丁酸（GABA）和5-羟色胺（5-HT）的神经化学变化的假设， HT）可能介导（R，S）-氯胺酮对雄性和雌性小鼠恐惧泛化的影响。通过 使用体内微透析，我将确定与学习和记忆相关的神经递质是如何 在盐水（对照）注射和（R，S）-氯胺酮注射的小鼠中均有助于恐惧泛化。我将测试 假设vCA 3中的谷氨酸和5-HT持续增加，而GABA减少， 在盐水处理的小鼠中表达恐惧，但这种持续增加被（R，S）-氯胺酮减轻 治疗在Aim 2中，我将利用Insopix开发的nVoke微型显微镜进行体内Ca 2+成像 并将检验（R，S）-氯胺酮阻止vCA 3中兴奋性Ca 2+活性升高的假设 诱导的压力，从而减少恐惧泛化在男性和女性小鼠。对于目标2A，我将 可视化vCA 3兴奋性细胞中的Ca 2+瞬变。对于目标2B，我将在抑制性细胞中可视化Ca 2+瞬变。 vCA 3细胞。到目前为止，还没有利用体内Ca 2+成像或体内微透析研究的纵向研究。 还没有进行过恐惧泛化和/或（R，S）-氯胺酮给药。总的来说，我 该提案的目标是更好地了解（R，S）-氯胺酮如何改变神经递质和神经元 合奏，导致减少恐惧泛化，在创伤后应激障碍和抑郁症患者的核心症状。