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

创伤后应激障碍和抑郁症是困扰退伍军人的严重精神疾病，而且经常 同病相怜。目前的药物和心理疗法是不够的，需要更有效的治疗。 由于缺乏对潜在的神经生物学机制的了解，进展受到阻碍。 这些疾病的病理和有效治疗。我们使用了慢性不可预测的压力(CUS)来 在模拟创伤后应激障碍和抑郁的几个共同维度的大鼠中产生行为变化，包括 由内侧前额叶皮质(MPFC)调节的认知灵活性缺陷，以及从活跃到 消极应对行为，它模拟了创伤后应激障碍常见的回避性应对和戒断相关症状 和抑郁症。在这个范例中，我们展示了恐惧消退学习的治疗效果。 作为一种新的暴露疗法的大鼠模型。灭绝是一个主动的学习过程，它改变了人们对 由先前与不良事件配对的线索预测的负面结果。同样，暴露疗法，一种 认知行为疗法是一种主动的学习过程，可以改变对负面情绪的预期 由先前与紧张经历或背景相关的线索所预测的结果。我们已经证明了 CUS后的消退训练逆转认知灵活性和应对行为的缺陷，24小时后进行测试 治疗。我们现在将使用这个模型来研究心理治疗发挥作用的神经机制。 有益的效果。此外，我们将比较消亡疗法和另一种疗法的机制。 最近受到关注的是NMDA受体拮抗剂氯胺酮。氯胺酮具有快速的抗抑郁作用 在耐药患者中，创伤后应激障碍的早期研究也显示出希望。然而，氯胺酮有很多 限制其作为治疗剂的潜在用途的不良特性。其治疗作用的机制 可以被识别，特别是那些由非药物治疗所共有的，可能有可能靶向 这些机制与导致其精神分裂和上瘾的机制是分开的。 因此，这两种非常不同的治疗模式共享的机制可能代表潜在的重要 开发新的治疗策略的新靶点。MPFC的调节失调与 创伤后应激障碍和抑郁的病理机制，而mPFC是调节消退的回路中的关键组成部分 学习和认知灵活性。因此，我们将把重点放在mPFC上。活性依赖蛋白 合成对于消亡学习的长期保持是必需的，而信号通路参与了 依赖活性的蛋白质合成也被氯胺酮激活。此外，灭绝和氯胺酮的影响 在治疗后24小时或更长时间明显，这意味着神经可塑性参与，就像在学习中一样。因此， 我们的总体假设是消退和氯胺酮的治疗效果的潜在机制包括 内侧前额叶皮质的活性依赖性蛋白质合成，启动可塑性相关 增强认知灵活性和积极应对的过程。这一假设的每个组成部分都将是 测试有三个具体目标：目标1是使用药物遗传学测试mPFC活性的必要性 DREADD方法在消退或氯胺酮处理期间选择性地抑制mPFC。目标2是测试 在治疗过程中通过微量注射选择性抑制剂，活性依赖的蛋白质合成在mPFC中的作用。 我们将首先抑制BDNF信号，这是一种启动信号级联反应的活性依赖神经营养因子 诱导蛋白质合成并激活核糖体蛋白S6，这是蛋白质翻译的一个组成部分。我们会 然后测试微量注射核糖体蛋白合成抑制剂山奈素。目标3是检查功能 和mPFC在消光或氯胺酮处理后的结构可塑性，测量电的变化 MPFC对兴奋性传入刺激的反应以及树突棘密度的变化。这样做的结果 该项目将提供对有益治疗背后的共同和独特机制的洞察 两种截然不同的治疗方法对创伤后应激障碍和抑郁症的影响，这可能会提出新的治疗靶点。

PTSD and depression are serious psychiatric disorders afflicting the veteran population, and are frequently comorbid. Current pharmaco- and psychotherapies are inadequate, and more effective treatments are needed. Progress has been hampered by a lack of understanding of the neurobiological mechanisms underlying the pathology and effective treatment of these disorders. We have used chronic unpredictable stress (CUS) to produce behavioral changes in rats that model several shared dimensions of PTSD and depression, including a deficit of cognitive flexibility, mediated in the medial prefrontal cortex (mPFC), and a shift from active to passive coping behavior, which models avoidant coping and withdrawal-related symptoms common to PTSD and depression. With this paradigm, we have demonstrated therapeutic effects using fear extinction learning as a novel rat model of exposure therapy. Extinction is an active learning process that modifies expectations of negative outcome predicted by cues previously paired with an adverse event. Similarly, exposure therapy, a form of cognitive behavioral therapy, is an active learning process that changes expectations of negative outcome predicted by cues previously associated with a stressful experience or context. We have shown that extinction training after CUS reverses the deficits in cognitive flexibility and coping behavior, tested 24 hr after treatment. We will now use this model to investigate neural mechanisms by which psychotherapy exerts its beneficial effect. Further, we will compare the mechanisms of extinction therapy with another therapy that has received recent attention, the NMDA receptor antagonist, ketamine. Ketamine has rapid antidepressant effects in treatment-resistant patients, and early studies in PTSD also show promise. However, ketamine has many undesirable qualities that limit its potential utility as a therapeutic agent. If mechanisms for its therapeutic effect can be identified, especially those shared by a non-pharmacological treatment, it may be possible to target those mechanisms separately from the ones responsible for its psychotomimetic and addictive properties. Thus, mechanisms shared by these two very different treatment modalities may represent potentially important new targets for the development of novel therapeutic strategies. Dysregulation of the mPFC is implicated in the pathology of PTSD and depression, and the mPFC is a critical component in the circuitry mediating extinction learning and cognitive flexibility. Thus we will focus our investigations on the mPFC. Activity-dependent protein synthesis is required for the long-term retention of extinction learning, and signaling pathways involved in activity-dependent protein synthesis are also activated by ketamine. Also, effects of extinction and ketamine are evident 24 hr or more after treatment, implying that neural plasticity is involved, as it is in learning. Thus, our overall hypothesis is that mechanisms underlying the therapeutic effects of extinction and ketamine involve activity-dependent protein synthesis in the medial prefrontal cortex, which initiates plasticity-related processes that enhance cognitive flexibility and active coping. Each component of this hypothesis will be tested in three specific aims: Aim 1 is to test the necessity of activity in the mPFC using a pharmacogenetic DREADD approach to selectively inhibit the mPFC during extinction or ketamine treatment. Aim 2 is to test the role of activity-dependent protein synthesis in the mPFC, by microinjecting selective inhibitors during treatment. We will first inhibit BDNF signaling, an activity-dependent neurotrophic factor that initiates a signaling cascade that induces protein synthesis and activates ribosomal protein S6, a component of protein translation. We will then test microinjection of the ribosomal protein synthesis inhibitor, anisomycin. Aim 3 is to examine functional and structural plasticity in the mPFC after extinction or ketamine treatment, measuring changes in the electrical response in mPFC to excitatory afferent stimulation, and changes in dendritic spine density. The results of this project will provide insight into the common and unique mechanisms underlying the beneficial therapeutic effects of two very different treatments for PTSD and depression, which may suggest new therapeutic targets.