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

目前对创伤后应激障碍和共病抑郁的药物治疗是不够的。这些压力- 相关精神疾病对退伍军人人群具有高度重要性和影响，并找到更有效的 治疗将填补退伍军人医疗保健方面的巨大缺口。循证行为疗法，如 作为暴露疗法，是有希望的，但它们的疗效也有限。出现了缺乏有效治疗的情况， 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，改变了的 导致病理的调节过程，调节认知和 在这些疾病中被破坏的适应性应对行为，以及有效的机制 任何形式的治疗反应，药理学或行为学。这样的知识可以让更多的人 有针对性地提高治疗效果。为了更好地研究这些过程，在上一次赠款期间 我们开发、验证和表征了大鼠的消退学习，作为一种并存的暴露治疗模型。 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上的有效性。 长期不可预测的压力带来的赤字。我们表明，这些影响依赖于脑组织中的活动 内侧前额叶皮质(MPFC)消退期间观察治疗24小时后的疗效。和 我们证明消退的治疗效果依赖于诱导从头合成蛋白质。 在mPFC中，我们认为它代表了与可塑性和电路变化相关的过程的启动 大脑这一区域的功能。在这份更新建议中，我们将描述精确的电路级塑性 以及在一系列行为指标上构成灭绝治疗效果的信号机制 模拟长期不可预测的压力暴露后共病的创伤后应激障碍和抑郁的不同维度。 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的作用 MPFC的下缘(IL)和前缘(PL)亚区向介导特定基因的靶区的投射 与共病的创伤后应激障碍和抑郁相关的行为反应领域，以及与治疗效果相关的 暴露疗法。在目标2中，我们将研究传入投射对IL和PL皮质产生的作用 从丘脑内侧和腹侧海马区的治疗效果中消退。我们还将 验证脑源性神经营养因子信号在消亡过程中的假设，该信号是由腹侧海马区的活动特异性地诱导的 传入，启动mPFC的信号转导过程，这是最终可塑性所必需的 对灭绝24小时后出现的有益行为影响负责。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，将亚有效消退方案与亚-有效治疗方案相结合 激活信号转导通路的新型候选药物L-655,708的有效剂量 和/或神经回路与那些因灭绝而激活的回路汇合，以确定这一策略是否可以增加 灭绝的功效。我们已经确定了辅助治疗策略的实用性，以检测增强的疗效。 使用氯胺酮，一种公认的治疗剂。拟议的潜在治疗效用的调查 L-655,708是一项高风险、高收益的项目，因为成功的可能性还不太清楚。L-655,708是一款精选 相对特异表达的GABA-A受体a5亚型的负变构调节剂 在腹侧海马区，IL皮质的主要传入神经，我们认为它在治疗中发挥着重要作用 慢性应激后的疗效。本研究的最终目的是为了通知更有效的发展 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都是老牌退伍军人管理局调查人员，有着长期的富有成效的合作历史和 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实施。

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.