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

项目摘要 创伤后应激障碍(PTSD)是一种流行的疾病，困扰着大约8%的美国人 人口。除了精神障碍的核心症状外，高达%的人被诊断为创伤后应激障碍 体验精神错乱的症状，如幻觉和妄想。尽管这一事件的发生率 共患病率很高，创伤后应激障碍和共病精神病的治疗仍然不足。然而，最近的工作已经 在用于研究创伤后应激障碍的啮齿动物模型中展示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的啮齿动物模型中的精神病样神经生理和行为缺陷。食欲素 受体在整个大脑中都有表达，但丘脑室旁核(PVT)接受 最高浓度的增食欲素纤维，提示增食欲素受体拮抗剂能显著抑制 PVT。已经证明，从PVT到伏核的投射的化学发生激活。 (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是应力敏感区域，并且从PVT到NAC的离散投影被激活 紧跟着紧张的事件。综上所述，这些数据表明，压力增加了PVT NAC的活性 投射和这种高活性导致下游多巴胺神经元活性的增加。食欲素 受体在PVT中高表达；因此，进一步推测增食欲素受体 拮抗剂通过抑制应激后PVT NAC投射的活性来减轻精神病样行为。 在目前的提案中，将使用两天不可避免的足部电击来诱导与应激相关的病理生理学 Spraogue Dawley大鼠。目标1将检验以下假设：足底电击应激导致大鼠的射击率增加 PVT NAC投射神经元可被选择性增食欲素受体拮抗剂逆转。目标2将测试 假设抑制PVT NAC投射将使应激诱导的多巴胺神经元增加正常化 惊厥脉冲前抑制的活性和逆转缺陷。拟议的研究将审查 PVT-NAC投射在调节精神病样行为中的作用及其对选择性食欲素的直接影响 应激后PVT NAC投射上的受体拮抗剂。最终，这项提议的目的是揭示小说 治疗目标将缓解与创伤后应激障碍相关的精神障碍症状。 我的长期目标是成为一名独立的神经学家，研究电路水平的改变对 到精神错乱。上述研究计划将为我提供科学的技术培训， 例如纤维光度学和化学遗传学，我将在我的职业生涯中使用它们来检查和操纵 神经回路。此外，我将在地方和国家会议上介绍从这些实验中收集到的数据 并提高我的科学交流能力。这一奖项将为我的科学和职业发展提供 培训将为我成为一名富有成效的博士后研究员和作为一名独立研究员取得成功做好准备。

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.