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:
- 金额:$ 1万
- 依托单位:
- 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
- 来源:
- 关键词:AdultAntipsychotic AgentsAwardBehaviorBehavioralBindingBrainBrain regionCellsCognitive deficitsCommunicationComplexControl AnimalCoupledDataDelusionsDiagnosisDiseaseDopamineDoseElectrodesElectrophysiology (science)Enterobacteria phage P1 Cre recombinaseEventFellowshipFiberFunctional disorderG alpha q ProteinGeneticGoalsHallucinationsHypothalamic structureIncidenceIndividualIontophoresisLabelLateralLigandsMeasuresMedialMediatingMental disordersNeuronsNeuropeptidesNucleus AccumbensOpticsPathologicPathologyPathway interactionsPatientsPatternPeptidesPhotometryPopulationPost-Traumatic Stress DisordersPostdoctoral FellowPrefrontal CortexProductivityPsychosesRattusResearchResearch PersonnelRodent ModelRoleScienceSignal TransductionSiteSprague-Dawley RatsStressStressful EventStructure of paraventricular nucleus of thalamusSymptomsSynapsesSystemTechniquesTestingTherapeuticTherapeutic EffectTrainingUnited StatesVentral Tegmental AreaVirusWorkantagonistcareercareer developmentcomorbiditydesigner receptors exclusively activated by designer drugsdopamine systemdopaminergic neuronexperienceexperimental studyextracellularhypocretinin vivoneuronal circuitryneurophysiologynew therapeutic targetnovel therapeuticsorexin 1 receptororexin Aorexin Borexin B receptorpharmacologicprepulse inhibitionreceptorreduce symptomsskillssuccesssymposiumtraumatic event
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
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Increased Presynaptic Dopamine Synthesis Capacity Is Associated With Aberrant Dopamine Neuron Activity in the Methylazoxymethanol Acetate Rodent Model Used to Study Schizophrenia-Related Pathologies.
- DOI:10.1093/schizbullopen/sgac067
- 发表时间:2022-01
- 期刊:
- 影响因子:0
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