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

目前的药物治疗PTSD和共病抑郁症是不够的。这些压力- 对退伍军人群体具有重要意义和影响的相关精神疾病，并找到更有效的方法 治疗将填补退伍军人医疗保健的巨大缺口。循证行为疗法，如 作为暴露疗法，是有希望的，但它们也具有有限的功效。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缺乏了解， 调节过程导致病理，神经系统介导的认知和 适应性应对行为在这些疾病中被破坏，以及负责有效应对的机制。 任何形式的治疗反应，药理学或行为。这样的知识可以告诉更多的人， 有针对性的方法，以提高治疗效果。为了更好地研究这些过程，在上一个赠款期， 我们开发、验证和表征了大鼠的消退学习，作为共病暴露疗法的模型， 创伤后应激障碍和抑郁症我们证明了灭绝在逆转行为和生理方面的功效。 慢性不可预测的压力后的赤字。我们发现，这些影响取决于活动， 消退期间的内侧前额叶皮质（mPFC），用于治疗后24小时观察到的治疗效果。和 我们发现，消退的治疗效果依赖于从头蛋白质合成的诱导， 在mPFC中，我们认为这代表了与可塑性和回路变化相关的过程的开始。 在这个大脑区域发挥作用。在这个更新的建议中，我们将描述精确的电路级可塑性 以及灭绝对一系列行为测量的治疗作用的信号机制 模拟慢性不可预测的压力暴露后共病PTSD和抑郁症的不同维度。 在目的1中，使用病毒发生抑制DREADD策略，我们将研究特异性传出蛋白的作用。 mPFC的边缘下（IL）和边缘前（PL）子区域向介导特异性免疫反应的靶区域的投射 与共病PTSD和抑郁症相关的行为反应领域，以及 暴露疗法在目标2中，我们将研究传入投射到IL和PL皮质的作用， 中背丘脑和腹侧海马的治疗效果。我们还将 测试这一假设，BDNF信号在灭绝过程中，特别是由腹侧海马的活动引起的， 传入，启动mPFC中的信号转导过程，这是可塑性所必需的， 负责灭绝后24小时看到的有益行为效果。有了这些知识，在目标3中， 然后，我们将测试一种合理的辅助治疗策略，该策略将次有效的消退方案与次有效的消退方案相结合， 激活信号通路的新型候选药物L-655，708的有效剂量 和/或神经回路与灭绝激活的神经回路会聚，以确定这种策略是否可以增加 灭绝的功效。我们已经建立了辅助治疗策略的效用，以检测增强的疗效 使用的是克他命一种公认的治疗药物对潜在治疗效用的拟议研究 L-655，708是一项高风险高收益的事业，因为成功的可能性不太清楚。L-655，708是一种选择性的 相对特异性表达的GABA-A受体α 5亚型的负变构调节剂 在腹侧海马，一个主要的传入IL皮质，我们认为在治疗中起着重要作用， 慢性应激后的疗效这项研究的最终目标是为更有效的开发提供信息 治疗创伤后应激障碍和共病抑郁症，以改善退伍军人及其家人的生活质量。 PI和MPI是成熟的VA调查员，具有长期的富有成效的合作历史， 在应激神经生物学、精神药理学、动物模型和系统方面的互补专业知识 神经生物学他们和他们的实验室非常适合这个项目的成功进行。

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.