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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