The early and lasting mechanisms underlying predator odor stressor-induced adaptations to alcohol interoceptive sensitivity

捕食者气味应激源诱导的酒精内感受敏感性适应的早期和持久机制

• 批准号: 10560497
• 负责人: Ryan Edward Tyler
• 金额: $ 1.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560497
• 关键词: Affect; Agreement; Alcohol consumption; Alcohol-Related Disorders; Alcohols; Animal Model; Attenuated; Behavioral; Brain; Clinical; Data; Development; Discrimination; Disease; Electrophysiology (science); Event; Exposure to; Foundations; Gene Expression; Glutamates; Individual; Literature; Mediating; Messenger RNA; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Odors; Optics; Organism; Output; Physiological; Post-Traumatic Stress Disorders; Procedures; Rattus; Receptor Gene; Receptor Signaling; Research; Research Personnel; Risk; Role; Satiation; Signal Transduction; Stimulus; Stress; Time; Training; Transcript; Water; alcohol comorbidity; alcohol effect; alcohol sensitivity; alcohol use disorder; antagonist; comparison control; drinking; drug discrimination; experimental study; functional adaptation; genetic approach; improved; optogenetics; prevent; skills; stressor; success

PROJECT SUMMARY/ABSTRACT Post-traumatic stress disorder (PTSD) can be precipitated by a traumatic stressor and is an enduring and debilitating disorder for which only limited treatment options exist. Furthermore, PTSD increases an individual’s likelihood to develop a co-morbid alcohol use disorder (AUD), demonstrating the importance of understanding the brain mechanisms underlying the relationship between stress and alcohol sensitivity. Alcohol interoceptive sensitivity refers to the subjective stimulus effects of alcohol on an organism. As such, interoceptive sensitivity has the potential to inform alcohol intake (i.e., signal satiety or drive more drinking). However, due to clinical limitations, little is known about brain mechanisms that underlie stressor-induced diminished sensitivity to alcohol. Therefore, we propose to use a well-established predator odor exposure (2,5‐dihydro‐2,4,5‐ trimethylthiazoline (TMT)) stressor model in rats that has demonstrated lasting behavioral consequences relevant to PTSD. Stress is associated with dysregulated cortical glutamate function. In agreement with the clinical stress literature, I find altered expression of mGlu receptor gene expression in the rat cortex following TMT exposure. Specifically, Grm3 (mGlu3) was downregulated in the prelimbic cortex (PrL) two days after TMT exposure. Additionally, several NMDA receptor gene transcripts (GriN2A, GriN2B, GriN2C, GriN2D, GriN3A, and GriN3B) were upregulated in the insular cortex (IC) 2 weeks after the TMT exposure. This is important as NMDA receptors modulate expression of the interoceptive effects of alcohol, and my preliminary data demonstrate diminished interoceptive sensitivity to alcohol in rats previously exposed to TMT at the same time point (2 weeks after TMT). Because the IC is involved in alcohol interoceptive processing and is one of the major outputs of the PrL, I hypothesize that plasticity induced by stress between PrL (mGlu3)IC circuitry triggers the NMDA-related brain changes in the IC that may underlie the blunted sensitivity to the interoceptive effects of alcohol. Aim 1 investigates the potential mechanisms that occur during the TMT stressor to promote the changes to alcohol interoceptive sensitivity. Exp 1.1 uses an mGlu3 negative allosteric modulator (NAM) to block mGlu3 receptor signaling in the PrL immediately prior to TMT exposure, and to determine if this treatment prevents the attenuated sensitivity to alcohol 2 weeks later. Exp. 1.2 uses a chemogenetic approach to silence glutamatergic projections from the PrL to the IC prior to TMT exposure, to assess if this treatment will prevent the blunted alcohol interoceptive sensitivity. Aim 2 investigates whether the NMDA receptor adaptations in the IC underlie the attenuated sensitivity to alcohol. Exp. 2.1 determines if TMT exposure produces NMDA receptor adaptation in optically evoked EPSC’s from IC neurons receiving projections from the PrL. Exp. 2.2 investigates the functional adaptations to IC NMDA receptors that underlie the attenuated sensitivity to alcohol. Together, these experiments will elucidate the early and lasting brain mechanisms that underlie stressor-induced adaptations to alcohol interoceptive sensitivity.

项目总结/文摘