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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，约有8%的美国人患有这种疾病。人口除了这种疾病的核心症状外，高达64%的被诊断患有PTSD的人经历精神病的症状，如幻觉和妄想。虽然这种情况的发生率尽管PTSD和共病精神病的发病率很高，但对PTSD和共病精神病的治疗仍然不足。然而，最近的工作在用于研究PTSD的啮齿动物模型中证实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，可以减轻，精神病样神经生理和行为缺陷的啮齿动物模型用于研究创伤后应激障碍。食欲素受体在整个大脑中表达，但丘脑室旁核（PVT）接收受体。最高浓度的食欲素纤维，表明食欲素受体拮抗剂可以显著抑制食欲素纤维的活性。已经表明，从PVT到延髓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动，这是精神病样行为的基础。此外，PVT是一个应力敏感区，从PVT到NAc的离散投射被激活压力事件之后。综上所述，这些数据表明，压力增加了PVT NAc的活性这种增强的活性导致下游多巴胺神经元活性的增加。食欲素食欲素受体在PVT内高度表达;因此，进一步假设食欲素受体拮抗剂通过抑制压力后PVTNAc投射的活性来减轻精神病样行为。在目前的建议中，两天不可避免的足电击将用于诱导应激相关的病理生理学， Sprague道利大鼠。目的1将检验以下假设：足电击应力引起的 PVTNAc投射神经元可被选择性食欲素受体拮抗剂逆转。目标2将测试抑制PVTNAc投射将使应激诱导多巴胺神经元增加正常化的假设活动和扭转赤字的前脉冲抑制惊吓。拟议的研究将审查以下方面的作用： PVT-NAc投射介导精神病样行为并检查选择性食欲素的直接作用受体拮抗剂对PVT NAc预测，以下压力。最终，该提案旨在揭示新的治疗目标，将减轻与创伤后应激障碍相关的精神病症状。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，精神疾病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利用它们来检查和操作神经回路此外，我将在地方和国家会议上介绍从这些实验中收集的数据提高我的科学交流能力这个奖项将为我提供科学和职业发展培训，这将使我准备一个富有成效的博士后奖学金和成功的独立研究人员。