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）是一种普遍的疾病，大约占美国的8％人口。除了疾病的核心症状外，多达64％的被诊断为PTSD的人经历精神病的症状，例如幻觉和妄想。虽然这是合并症很高，对PTSD的治疗和合并症的精神病仍然不足。但是，最近的工作有在用于研究PTSD的啮齿动物模型中，证明了Orexin受体拮抗剂的抗精神病药潜力。选择性和非选择性的Orexin受体拮抗剂，如果系统地给药，可以减轻用于研究PTSD的啮齿动物模型中的精神病样神经生理和行为缺陷。 OREXIN 受体在整个大脑中表达，但丘脑（PVT）的室室核接收浓度最高的Orexin纤维，建议Orexin受体拮抗剂可以显着抑制 Pvt。已经表明，从PVT到伏核的投影的化学发生激活（NAC）增加腹侧段盖区域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的离散投影被激活跟随压力事件。综上所述，这些数据表明应力增加了PVT NAC的活性预测和这种增强的活性导致下游多巴胺神经元活性的增加。 OREXIN 受体在PVT中高度表达；因此，进一步假设Orexin受体拮抗剂通过抑制压力后PVT NAC预测的活性来减轻精神病样行为。在目前的提案中，两天不可避免的脚印将用于诱导与压力有关的病理生理学 Sprague Dawley老鼠。 AIM 1将检验以下假设，即脚并触发压力引起的点火率增加 PVT NAC投射神经元可通过选择性Orexin受体拮抗剂可逆。 AIM 2将测试假设抑制PVT NAC投影将使应激诱导的多巴胺神经元增加吸气抑制的活性和反向缺陷。拟议的研究将研究 PVT NAC介导类似精神病行为的NAC预测并检查选择性Orexin的直接作用压力下，PVT NAC投影的受体拮抗剂。最终，该提议旨在发现小说可以减轻与PTSD相关的精神病症状的治疗靶标。我的长期目标是成为一个独立的神经科学家，研究电路级变更有助于到精神疾病。上述研究计划将为我提供技术的科学培训，例如纤维光度法和化学遗传学，我将在整个职业生涯中利用它来检查和操纵神经元电路。此外，我将在本地和国家会议上介绍这些实验中收集的数据并提高我的科学沟通能力。这个奖项将为我提供科学和职业发展培训将使我为富有成效的博士后奖学金和作为独立研究人员的成功做好准备。