Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats

治疗 PTSD 和抑郁症：大鼠药物治疗和心理治疗的机制

• 批准号: 10250669
• 负责人: David A Morilak
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10250669
• 关键词: Acoustics; Affective; Afferent Pathways; Aftercare; Amygdaloid structure; Anhedonia; Animal Model; Attention; Beds; Behavior Therapy; Behavioral; Behavioral Mechanisms; Biological Models; Brain region; Brain-Derived Neurotrophic Factor; Cell Nucleus; Chronic; Chronic stress; Cognition; Cognitive; Collaborations; Combined Modality Therapy; Coping Behavior; Development; Dimensions; Disease; Dose; Down-Regulation; Extinction (Psychology); Family; Future; GABA-A Receptor; Goals; Grant; Healthcare; Hippocampus (Brain); Hour; Impairment; Investigation; Ketamine; Knowledge; Lateral; Lead; Measures; Medial; Mediating; Mental Depression; Mental disorders; Microinjections; Modality; Modeling; Neurobiology; Nucleus Accumbens; Pathology; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Protein Biosynthesis; Protocols documentation; Psychopharmacology; Psychotherapy; Quality of life; Rattus; Recording of previous events; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stress; Stress and Coping; Sucrose; System; Testing; Thalamic structure; Therapeutic; Therapeutic Agents; Therapeutic Effect; Treatment Efficacy; Veterans; associated symptom; behavior measurement; behavioral response; comorbid depression; comorbidity; designer receptors exclusively activated by designer drugs; drug candidate; effective therapy; efficacy testing; evidence base; flexibility; high risk; improved; learning extinction; military veteran; negative affect; neural circuit; neurobiological mechanism; neuromechanism; neutralizing antibody; novel; novel strategies; novel therapeutic intervention; novel therapeutics; preference; relating to nervous system; response; success; targeted agent; therapeutic evaluation; therapeutically effective; treatment response; treatment strategy

Current pharmacological treatments for PTSD and comorbid depression are inadequate. These stress- related psychiatric illnesses of high significance and impact to the veteran population, and finding more effective treatments would satisfy a tremendous gap in veterans’ health care. Evidence-based behavioral therapies, such as exposure therapy, are promising, but they also have limited efficacy. The lack of effective treatment arises, in part, from our lack of knowledge of the neurobiological mechanisms underlying these illnesses, the altered regulatory processes that lead to pathology, the neural systems that mediate the dimensions of cognition and adaptive coping behavior that are disrupted in these illnesses, and the mechanisms responsible for effective therapeutic response in any modality, pharmacological or behavioral. Such knowledge may inform a more targeted approach to increase therapeutic efficacy. To better study these processes, in the previous grant period we developed, validated and characterized extinction learning in rats as a model of exposure therapy in comorbid PTSD and depression. We demonstrated the efficacy of extinction in reversing behavioral and physiological deficits following chronic unpredictable stress. We showed that these effects were dependent upon activity in the medial prefrontal cortex (mPFC) during extinction for the therapeutic effects seen 24 hrs after treatment. And we showed that the therapeutic effects of extinction were dependent on the induction of de novo protein synthesis in the mPFC, which we believe represents the initiation of processes related to plasticity and changes in circuit function in this brain region. In this proposal for renewal, we will characterize the precise circuit-level plasticity and signaling mechanisms that underlie the therapeutic effects of extinction on a range of behavioral measures modeling different dimensions of comorbid PTSD and depression after chronic unpredictable stress exposure. In aim 1, using a virogenetic inhibitory DREADD strategy, we will investigate the role of specific efferent projections of the infralimbic (IL) and prelimbic (PL) sub-regions of mPFC to target regions that mediate specific behavioral response domains relevant to comorbid PTSD and depression, and to the therapeutic efficacy of exposure therapy. In aim 2, we will investigate the role of afferent projections to the IL and PL cortices arising from the mediodorsal thalamus and the ventral hippocampus in the therapeutic effects of extinction. We will also test the hypothesis that BDNF signaling during extinction, induced specifically by activity in ventral hippocampal afferent, initiates signal transduction processes in the mPFC necessary for the plasticity that is ultimately responsible for the beneficial behavioral effects seen 24 hours after extinction. With this knowledge, in aim 3, we will then test a rational adjunct treatment strategy combining a sub-effective extinction protocol with a sub- effective dose of a novel candidate pharmacotherapeutic agent, L-655,708, that activates signaling pathways and/or neural circuits convergent with those activated by extinction, to determine if this strategy can increase the efficacy of extinction. We have established the utility of the adjunct therapy strategy to detect enhanced efficacy using ketamine, an established therapeutic agent. The proposed investigation of potential therapeutic utility of L-655,708 is a high-risk high-gain undertaking, as the likelihood of success is less clear. L-655,708 is a selective negative allosteric modulator of the a5 subtype of the GABA-A receptor that is relatively specifically expressed in the ventral hippocampus, a major afferent to the IL cortex that we believe plays an important role in therapeutic efficacy after chronic stress. The ultimate goal of this research is to inform the development of more effective treatments for PTSD and comorbid depression, to improve the quality of life for veterans and their families. The PI and the MPI are well established VA investigators with a long history of productive collaboration and complementary expertise in stress neurobiology, psychopharmacology, animal models and systems neurobiology. They and their labs are ideally suited to the successful conduct of this project.

目前针对 PTSD 和共病抑郁症的药物治疗是不够的。 对退伍军人群体具有重要意义和影响的相关精神疾病，并寻找更有效的方法 治疗将填补退伍军人医疗保健方面的巨大缺口，例如基于证据的行为疗法。 作为暴露疗法，它们很有希望，但它们的疗效也有限，因此缺乏有效的治疗方法。 部分原因是我们对这些疾病背后的神经生物学机制缺乏了解， 导致病理学的调节过程，介导认知和维度维度的神经系统 在这些疾病中被破坏的适应性应对行为，以及有效的机制 任何方式、药理学或行为方面的治疗反应都可以提供更多信息。 为了更好地研究这些过程，在之前的资助期内有针对性的方法来提高治疗效果。 我们开发、验证并表征了大鼠的消退学习，作为共病暴露疗法的模型 我们证明了消除在逆转行为和生理方面的功效。 我们发现，这些影响取决于长期不可预测的压力后的活动。 内侧前额皮质 (mPFC) 在消退期间观察治疗后 24 小时看到的治疗效果。 我们表明，消退的治疗效果依赖于蛋白质从头合成的诱导 在 mPFC 中，我们认为这代表了与可塑性和电路变化相关的过程的启动 在这个更新提案中，我们将描述精确的电路级可塑性。 和信号机制是灭绝对一系列行为测量的治疗作用的基础 对长期不可预测的压力暴露后共病 PTSD 和抑郁症的不同维度进行建模。 在目标 1 中，使用病毒发生抑制 DREADD 策略，我们将研究特定传出神经的作用 mPFC 的下边缘 (IL) 和前边缘 (PL) 子区域到介导特定功能的目标区域的投影 与共病 PTSD 和抑郁症以及治疗效果相关的行为反应领域 在目标 2 中，我们将研究传入投射对 IL 和 PL 皮质的作用。 来自内侧丘脑和腹侧海马的治疗作用也将消失。 检验以下假设：灭绝过程中 BDNF 信号传导是由腹侧海马区的活动专门诱导的 传入，启动 mPFC 中的信号转导过程，这是最终可塑性所必需的 有了这些知识，在目标 3 中，就可以看到灭绝后 24 小时内出现的有益行为影响。 然后，我们将测试一种合理的辅助治疗策略，将亚有效的灭绝方案与亚有效的灭绝方案相结合。 激活信号通路的新型候选药物治疗剂 L-655,708 的有效剂量 和/或神经回路与那些因灭绝而激活的神经回路融合，以确定该策略是否可以增加 我们已经建立了辅助治疗策略的实用性来检测增强的疗效。 使用氯胺酮（一种已确定的治疗剂）的潜在治疗效用的拟议研究。 L-655,708 是一项高风险高收益的项目，因为成功的可能性不太明确。L-655,708 是一项选择性项目。 相对特异表达的 GABA-A 受体 a5 亚型的负变构调节剂 位于腹侧海马体中，是 IL 皮层的主要传入神经，我们认为它在治疗中发挥着重要作用 这项研究的最终目标是为开发更有效的方法提供信息。 治疗创伤后应激障碍（PTSD）和共病抑郁症，以改善退伍军人及其家人的生活质量。 PI 和 MPI 都是经验丰富的 VA 调查员，有着悠久的富有成效的合作历史 压力神经生物学、精神药理学、动物模型和系统方面的互补专业知识 他们和他们的实验室非常适合该项目的成功实施。