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: 9234977
• 负责人: ALAN FRAZER
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234977
• 关键词: Active Learning; Acute; Adverse event; Aftercare; Animal Model; Anisomycin; Antibodies; Apical; Attention; Attenuated; Behavior; Behavioral; Brain region; Brain-Derived Neurotrophic Factor; Cells; Chronic; Clozapine; Cognition; Cognitive; Cognitive Therapy; Cognitive deficits; Comorbidity; Coping Behavior; Cues; Data; Dendrites; Dendritic Spines; Development; Dimensions; Disease; Exposure to; Extinction (Psychology); Fright; Future; Glutamates; Goals; Human; Immunofluorescence Immunologic; Interneurons; Investigation; K 252a; Ketamine; Knowledge; Label; Lead; Learning; Link; Measures; Medial; Mediating; Mental Depression; Mental disorders; Microinjections; Modality; Modeling; NMDA receptor antagonist; Neurobiology; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Output; Oxides; Pathology; Patients; Pharmacogenetics; Pharmacotherapy; Phosphorylation; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Property; Protein Biosynthesis; Proteins; Psychotherapy; Pyramidal Cells; Rattus; Resistance; Ribosomal Protein S6; Role; Signal Pathway; Signal Transduction; Staining method; Stains; Stress; Stress and Coping; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Training; Translations; Treatment Efficacy; Ursidae Family; Vertebral column; Veterans; Viral Vector; Withdrawal; antidepressant effect; behavior test; calmodulin-dependent protein kinase II; cognitive enhancement; cognitive function; common symptom; comorbid depression; coping; density; depressed patient; effective therapy; evidence base; expectation; experience; flexibility; functional plasticity; hippocampal pyramidal neuron; improved; inhibitor/antagonist; insight; learning extinction; neurobiological mechanism; neuromechanism; neurotrophic factor; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; outcome prediction; promoter; relating to nervous system; response; selective expression; treatment effect; treatment response

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.

PTSD和抑郁症是严重的精神病患者，遭受退伍军人的疾病，并且经常是 合并。当前的药物和心理治疗不足，需要更有效的治疗方法。 缺乏对神经生物学机制的了解，阻碍了进步 病理和有效治疗这些疾病。我们已经使用了慢性不可预测的压力（CU） 在大鼠中产生行为变化，模拟了PTSD和抑郁症的几个共享维度，包括 认知灵活性的赤字，在内侧前额叶皮层（MPFC）中介导，并从活性转移到 被动应对行为，模型避免应对和PTSD常见的戒断症状 和抑郁。有了这个范式，我们使用恐惧灭绝学习证明了治疗作用 作为暴露疗法的新大鼠模型。灭绝是一个活跃的学习过程，可以改变对的期望 先前与不良事件配对的提示预测的负面结果。同样，暴露疗法， 认知行为疗法的形式是一种积极的学习过程，它改变了负面的期望 以前与压力丰富的经验或背景相关的提示所预测的结果。我们已经表明 CUS后的灭绝训练逆转了认知灵活性和应对行为的缺陷，在24小时后测试 治疗。现在，我们将使用该模型来研究心理治疗施加其神经机制 有益的效果。此外，我们将将灭绝疗法的机制与另一种具有 最近受到了NMDA受体拮抗剂氯胺酮的关注。氯胺酮具有快速的抗抑郁作用 在耐药患者和PTSD的早期研究中，也表现出了希望。但是，氯胺酮有很多 限制其作为治疗剂的潜在效用的不良品质。是否具有治疗作用的机制 可以识别，尤其是那些通过非药物治疗共享的人，可能有可能靶向 这些机制与负责其心理和成瘾性特性的机制分开。 因此，这两种截然不同的治疗方式共享的机制可能代表了潜在的重要 开发新型治疗策略的新目标。 MPFC的失调与 PTSD和抑郁症的病理学，MPFC是介导灭绝的关键组成部分 学习和认知灵活性。因此，我们将把调查集中在MPFC上。活性依赖性蛋白质 长期保留灭绝学习和涉及的信号通路是必需的 活性依赖性蛋白质合成也被氯胺酮激活。另外，灭绝和氯胺酮的影响 在治疗后24小时或更大的情况下，这意味着涉及神经可塑性，就像学习一样。因此， 我们的总体假设是，灭绝和氯胺酮治疗作用的基础机制涉及 内侧前额叶皮层中依赖活性的蛋白质合成，该皮质启动与塑性相关 增强认知灵活性和主动应对的过程。该假设的每个组成部分将是 以三个特定目的测试：目标1是使用药物遗传学测试MPFC中活动的必要性 DREADD在灭绝或氯胺酮治疗过程中选择性抑制MPFC的方法。目标2是测试 活性依赖性蛋白质合成在MPFC中的作用，通过在治疗过程中微注射选择性抑制剂。 我们将首先抑制BDNF信号传导，这是一种依赖活性的神经营养因子，启动信号级联 这会诱导蛋白质合成并激活核糖体蛋白S6，这是蛋白质翻译的成分。我们将 然后测试核糖体蛋白质合成抑制剂砷霉素的显微注射。目标3是检查功能 灭绝或氯胺酮治疗后MPFC中的结构可塑性，测量电气的变化 MPFC对兴奋性传入刺激的反应以及树突状脊柱密度的变化。结果的结果 项目将提供有关有益治疗的基础的共同和独特机制的洞察力 对PTSD和抑郁症的两种截然不同的治疗方法的影响，这可能表明新的治疗靶点。