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: 10620164
• 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/10620164
• 关键词: Acoustics; Affective; Afferent Pathways; Aftercare; Amygdaloid structure; Anhedonia; Animal Model; Attention; Beds; Behavior Therapy; Behavioral; 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; Family; Future; GABA-A Receptor; Goals; Grant; Healthcare; Hippocampus; Hour; Impairment; Investigation; Ketamine; Knowledge; Lateral; Measures; Medial; Mediating; Mental Depression; Mental disorders; Microinjections; Modality; Modeling; Neurobiology; Nucleus Accumbens; Pathology; Pharmacological Treatment; Pharmacotherapy; Physiological; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Productivity; Protein Biosynthesis; Protocols documentation; Psychopharmacology; Psychotherapy; Quality of life; Rattus; Recording of previous events; Research; Research Personnel; Role; Signal Induction; 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; neural circuit; neurobiological mechanism; neuromechanism; neutralizing antibody; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; preference; 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.

PTSD和合并症抑郁症的当前药物治疗不足。这些应力 - 相关的精神病疾病具有高意义和对退伍军人人口的影响，并发现更有效 治疗将满足退伍军人医疗保健的巨大差距。基于证据的行为疗法，这样 作为暴露疗法，这是有望的，但它们的有效性也有限。缺乏有效的治疗， 在某种程度上，由于我们对这些疾病背后的神经生物学机制的了解不足 导致病理学的调节过程，介导认知和介导的神经系统 这些疾病中破坏的自适应应对行为以及负责有效的机制 在任何形态，药物或行为方面的治疗反应。这样的知识可能会更多地告知 有针对性的方法提高治疗效率。为了更好地研究这些过程，在上一个赠款期间 我们在大鼠中开发，验证和表征的扩展学习是合并症的暴露疗法的模型 PTSD和抑郁症。我们证明了扩展在逆转行为和生理学方面的效率 慢性不可预测的压力后的缺陷。我们表明这些影响取决于活动 治疗后24小时的治疗作用的延伸期间内侧前额叶皮层（MPFC）。和 我们表明，扩展的治疗作用取决于从头蛋白质的诱导 在MPFC中，我们认为这代表了与可塑性和电路变化有关的过程的主动性 在这个大脑区域的功能。在此续订建议中，我们将表征精确的电路级可塑性 以及延伸对一系列行为措施的治疗作用的基础的信号传导机制 在慢性不可预测的压力暴露后，对合并症PTSD和抑郁的不同维度进行建模。 在AIM 1中，使用病毒式抑制性无助战略，我们将研究特定有效的作用 MPFC对媒体特定区域的MPFC的注射（IL）和前比（PL）子区域的预测 与合并症PTSD和抑郁症相关的行为反应域，以及与治疗效率 暴露疗法。在AIM 2中，我们将调查传入项目对IL和PL Cortices的作用 从延伸的治疗作用中，来自培养基丘脑和腹海马。我们也会 检验延伸过程中BDNF信号传导的假设，该假设是通过腹侧海马活动专门诱导的 传入，在MPFC中启动信号转导过程的可塑性最终所需的可塑性 负责扩展后24小时看到的有益行为影响。有了这些知识，在AIM 3中， 然后，我们将测试合理的辅助治疗策略，该策略结合了次有效的扩展方案与亚下 新型候选药物治疗剂L-655,708的有效剂量激活信号通路 和/或神经回路与扩展激活的电路，以确定此策略是否可以增加 扩展的功效。我们已经建立了辅助治疗策略的实用性，以检测提高效率 使用氯胺酮，已建立的治疗剂。提出的对潜在治疗效用的调查 L-655,708是一项高风险的高级事业，因为成功的可能性还不太清楚。 L-655,708是一种选择性 GABA-A接收器的A5亚型的负变构调节剂相对表达 在腹侧海马，我们认为在治疗中起着重要作用的IL皮层的主要影响力 慢性应激后有效。这项研究的最终目标是告知开发更有效。 PTSD和合并抑郁症的治疗方法，以改善退伍军人及其家人的生活质量。 PI和MPI是成熟的VA调查人员，具有悠久的产品协作历史和 压力神经生物学，心理药理学，动物模型和系统的完全专业知识 神经生物学。他们和他们的实验室非常适合该项目的成功行为。

项目成果

Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats.

• DOI: 10.1038/s41386-021-01171-7
• 发表时间: 2022-01
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Paredes D;Knippenberg AR;Morilak DA
• 通讯作者: Morilak DA