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.

项目概要/摘要 创伤后应激障碍 (PTSD) 可由创伤性应激源引发，是一种持久且持续的疾病。 此外，创伤后应激障碍 (PTSD) 会增加个体的衰弱症状。 罹患共病酒精使用障碍 (AUD) 的可能性，证明了解的重要性 压力与酒精敏感性之间关系的大脑机制。 敏感性是指酒精对有机体的主观刺激作用，因此，内感受敏感性。 有可能告知摄入量（即发出饱腹感或促使更多饮酒），但由于临床原因。 局限性，对于压力源引起的敏感性降低的大脑机制知之甚少。 因此，我们建议使用成熟的捕食者气味暴露（2,5-二氢-2,4,5-）。 三甲基噻唑啉（TMT））大鼠应激模型已表现出持久的行为后果 与 PTSD 相关。压力与皮质谷氨酸功能失调有关。 临床应激文献中，我发现大鼠皮层 mGlu 受体基因表达发生改变 具体来说，两天后，Grm3 (mGlu3) 在前边缘皮层 (PrL) 中下调。 此外，还暴露了几种 NMDA 受体基因转录本（GriN2A、GriN2B、GriN2C、GriN2D、 TMT 暴露 2 周后，岛叶皮质 (IC) 中的 GriN3A 和 GriN3B 表达上调。 很重要，因为 NMDA 受体调节酒精内感受效应的表达，我的初步研究 数据表明，先前接触 TMT 的大鼠对酒精的内感受敏感性降低 时间点（TMT后2周）因为IC参与酒精内感受处理并且是其中之一。 PrL 的主要输出，我认为是由 PrL (mGlu3)IC 电路之间的应力引起的可塑性 触发 IC 中与 NMDA 相关的大脑变化，这可能是内感受敏感性减弱的原因 目标 1 研究 TMT 应激源促进的潜在机制。 Exp 1.1 使用 mGlu3 负变构调节剂 (NAM) 来改变酒精内感受敏感性。 在 TMT 暴露之前立即阻断 PrL 中的 mGlu3 受体信号传导，并确定这是否 实验 1.2 使用化学遗传学方法来预防 2 周后对酒精的敏感性减弱。 在 TMT 暴露之前沉默从 PrL 到 IC 的谷氨酸能投射，以评估这种治疗是否有效 目标 2 研究 NMDA 受体是否 IC 的适应是对酒精敏感性减弱的基础，这决定了是否 TMT 暴露。 在 IC 神经元的光学诱发 EPSC 中产生 NMDA 受体适应，接收来自 PrL. Exp. 2.2 研究了减毒后对 IC NMDA 受体的功能适应 这些实验将共同阐明影响酒精敏感性的早期和持久的大脑机制。 是压力源引起的对酒精内感受敏感性的适应的基础。