Examining orexinergic modulation of the paraventricular nucleus of the thalamus as a novel therapeutic for PTSD and comorbid psychosis

检查丘脑室旁核的食欲素调节作为 PTSD 和共病精神病的新型治疗方法

基本信息

批准号：
10579193
负责人：
Hannah Elam
金额：
$ 1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2023-05-26
项目状态：
已结题

项目摘要

Project Abstract Post-traumatic stress disorder (PTSD) is a prevalent condition that afflicts approximately 8% of the United States population. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience symptoms of psychosis, such as hallucinations and delusions. Although the incidence of this comorbidity is high, treatment for PTSD and comorbid psychosis remains inadequate. However, recent work has demonstrated the antipsychotic potential of orexin receptor antagonists in a rodent model used to study PTSD. Selective and nonselective orexin receptor antagonists, when administered systemically, can alleviate psychosis-like neurophysiological and behavioral deficits in a rodent model used to study PTSD. Orexin receptors are expressed throughout the brain but the paraventricular nucleus of the thalamus (PVT) receives the highest concentration of orexin fibers, suggesting orexin receptor antagonists can significantly inhibit activity of the PVT. It has been shown that chemogenetic activation of projections from the PVT to the nucleus accumbens (NAc) increase dopamine neuron activity in the ventral tegmental area, which underlies psychosis-like behavior. Further, the PVT is a stress-sensitive region and discrete projections from the PVT to the NAc become activated following stressful events. Taken together, these data suggest that stress increases the activity of PVT NAc projections and this heightened activity results in an increase in downstream dopamine neuron activity. Orexin receptors are highly expressed within the PVT; therefore, it is further hypothesized that orexin receptor antagonists alleviate psychosis-like behavior by inhibiting the activity of PVT NAc projections following stress. In the current proposal two-day inescapable footshock will be used to induce stress-related pathophysiology in Sprague Dawley rats. Aim 1 will test the hypothesis that footshock stress-induced increases in the firing rate of PVT NAc projecting neurons are reversible by selective orexin receptor antagonists. Aim 2 will test the hypothesis that inhibition of PVT NAc projections will normalize stress-induced increases in dopamine neuron activity and reverse deficits in prepulse inhibition of startle. The proposed studies will examine the role of PVT NAc projections in mediating psychosis-like behavior and examine the direct effect of selective orexin receptor antagonists on PVT NAc projections, following stress. Ultimately this proposal aims to uncover novel therapeutic targets that will alleviate symptoms of psychosis associated with PTSD. My long-term goal is to become an independent neuroscientist that studies circuit-level alterations contributing to psychiatric disorders. The research plan described above will provide me with scientific training in techniques, such as fiber photometry and chemogenetics, that I will utilize throughout my career to examine and manipulate neuronal circuits. Further, I will present data gathered from these experiments at local and national conferences and enhance my science communication skills. This award will provide me with scientific and career development training that will prepare me for a productive postdoctoral fellowship and success as an independent researcher.

项目摘要创伤后应激障碍 (PTSD) 是一种普遍存在的疾病，困扰着大约 8% 的美国人口人口。除了该疾病的核心症状外，高达 64% 的人被诊断患有 PTSD 出现精神病症状，例如幻觉和妄想。虽然这种情况的发生合并症很高，对创伤后应激障碍（PTSD）和合并症精神病的治疗仍然不足。然而，最近的工作已经在用于研究 PTSD 的啮齿动物模型中证明了食欲素受体拮抗剂的抗精神病潜力。选择性和非选择性食欲素受体拮抗剂，当全身给药时，可以缓解用于研究创伤后应激障碍（PTSD）的啮齿动物模型中存在类似精神病的神经生理和行为缺陷。食欲素受体在整个大脑中表达，但丘脑室旁核 (PVT) 接收食欲素纤维浓度最高，表明食欲素受体拮抗剂可以显着抑制食欲素纤维的活性 PVT。研究表明，从 PVT 到伏隔核的投射的化学遗传学激活 (NAc) 增加腹侧被盖区的多巴胺神经元活性，这是精神病样行为的基础。此外，PVT 是一个应力敏感区域，从 PVT 到 NAc 的离散投影被激活发生应激事件后。综上所述，这些数据表明压力会增加 PVT NAc 的活性预测和这种增强的活动导致下游多巴胺神经元活动的增加。食欲素受体在 PVT 内高度表达；因此，进一步推测食欲素受体拮抗剂通过抑制压力后 PVT NAc 投射的活动来减轻精神病样行为。在当前的提案中，将使用两天不可避免的足部电击来诱发与压力相关的病理生理学斯普拉格道利鼠。目标 1 将检验以下假设：足部冲击应力引起的放电率增加 PVT NAc 投射神经元可通过选择性食欲素受体拮抗剂逆转。目标 2 将测试假设抑制 PVT NAc 投射将使压力诱导的多巴胺神经元增加正常化活性和逆转惊吓前脉冲抑制的缺陷。拟议的研究将探讨 PVT NAc 预测在调节精神病样行为中的作用并检查选择性食欲素的直接影响应激后PVT NAc 预测的受体拮抗剂。最终该提案旨在发现新颖的治疗目标将减轻与 PTSD 相关的精神病症状。我的长期目标是成为一名独立的神经科学家，研究回路水平的改变，到精神疾病。上述研究计划将为我提供科学的技术训练，例如纤维光度测定法和化学遗传学，我将在我的整个职业生涯中利用它们来检查和操纵神经元回路。此外，我将在地方和国家会议上展示从这些实验中收集的数据并提高我的科学沟通能力。该奖项将为我提供科学和职业发展培训将使我为获得富有成效的博士后奖学金和作为一名独立研究员的成功做好准备。