Examination of novel brain regional involvement in modulating sensitivity to alcohol

项目摘要/摘要 所有滥用药物都会产生独特的感觉/主观(即歧视性刺激)效应， 临床和临床前研究中的吸毒、寻求和复发。然而，神经回路 调节酒精的内感效应还有待确定。伏隔核核心(ACBC)， 一个已知的调节酒精相关行为的区域，也在调节歧视行为方面发挥着核心作用 酒精的刺激作用。因此，要开始建立调节内感效应的电路。 酒精，两个向ACBC投射的大脑区域将是拟议研究的焦点：岛叶 皮质(IC)和丘脑腹侧中线核群(RhRe)。尽管有牵连的角色 IC在加工内感线索和对酒精相关线索的反应中的功能调节作用 酒精诱导的内感效应到目前为止还没有被研究过。此外，RhRe被提议为 调节抑制、行为灵活性和动机，但它们在调节任何与药物有关的行为中的作用 尚未确定。然而，我们的初步数据表明，IC的化学生成失活 增加对酒精的敏感性和IC和RhRe的药物失活(独立)导致 部分“酒精样”的相互感觉效应，从而暗示了IC和RhRe在调节中的功能作用 酒精的歧视性刺激作用。因此，通过研究两个新的大脑区域(IC和 Re)和它们对ACBC的投射，这一应用程序建议研究潜在的神经电路 酒精诱导的内感状态。利用药物辨别的方法，将训练老鼠辨别 酒精和水，我们会在化学上灭活大脑区域和它们特定的进入ACBC的区域 检查对酒精的敏感性是否发生改变的投射。因此，目标1中的实验将确定 IC及其对ACBC的投射是否调节了酒精的辨别性刺激效应。目标2将 使用类似的方法来确定RhRe的作用及其对ACBC的预测。把这些放在一起 实验将证明两个新的大脑区域在调节内感受器中的功能作用 酒精的影响，同时识别与ACBC相关的潜在神经电路。通过在以下方面进行这些实验 同时，这种创新的方法能够向酒精领域通报以前没有牵连的区域 或未被充分研究，同时证明了酒精互感的重要性和神经生物学基础 状态/内部线索，从而帮助架起临床和临床前领域的桥梁。

PROJECT SUMMARY/ABSTRACT All drugs of abuse produce unique interoceptive/subjective (i.e., discriminative stimulus) effects that can impact drug-taking, seeking, and relapse in both clinical and preclinical studies. However, the neural circuitry modulating the interoceptive effects of alcohol has yet to be established. The nucleus accumbens core (AcbC), a region known to mediate alcohol-related behaviors, also plays a central role in modulating the discriminative stimulus effects of alcohol. Therefore, to begin to establish the circuitry modulating the interoceptive effects of alcohol, two brain regions with projections to the AcbC will be the focus of the proposed studies: the insular cortex (IC) and the rhomboid/reuniens ventral midline thalamic nuclei (RhRe). Despite the implicated role of the IC in processing interoceptive cues and responding to alcohol-related cues, its functional role in modulating alcohol-induced interoceptive effects has not been investigated to date. Additionally, the RhRe are proposed to modulate inhibition, behavior flexibility, and motivation, but their role in modulating any drug-related behaviors has yet to be determined. However, our preliminary data demonstrate that chemogenetic inactivation of the IC increases sensitivity to alcohol and pharmacological inactivation of IC and RhRe (independently) results in partial “alcohol-like” interoceptive effects, thus implicating a functional role for the IC and RhRe in modulating the discriminative stimulus effects of alcohol. Therefore, by investigating the two novel brain regions (IC and RhRe) and their projections to the AcbC, this application proposes to investigate the neural circuitry underlying alcohol-induced interoceptive states. Using drug discrimination methods, rats will be trained to discriminate alcohol vs. water, and we will chemogenetically inactivate the brain regions and their specific incoming AcbC projections to examine whether sensitivity to alcohol is altered. Thus, experiments in Aim 1 will determine whether IC and its projections to the AcbC modulate the discriminative stimulus effects of alcohol. Aim 2 will use a similar approach to determine the role of RhRe and its projections to the AcbC. Together these experiments will demonstrate a functional role for two novel brain regions in modulating the interoceptive effects of alcohol, while identifying potential AcbC-related neural circuitry. By conducting these experiments in parallel, this innovative approach has the ability to inform the alcohol field of regions not previously implicated or understudied while demonstrating the importance and neurobiology underlying alcohol interoceptive states/internal cues, thus helping bridge the clinical and preclinical fields.