Effects of tACS on alcohol-induced cognitive and neurochemical deficits

摘要：酒精是青少年使用最广泛的毒品之一，而且经常在狂欢中消费 饮酒模式在这个关键的发育时期酗酒会导致持久的认知障碍。 几乎没有有效治疗方法的损伤。一个领域是中断后，青少年 酗酒是行为灵活性，定义为适应不断变化的环境的能力。的 行为灵活性的神经回路是复杂的，但包括内侧前额叶皮层（mPFC）， 眶额皮质（OFC）和前额叶皮质（aIC），所有这些区域都是受 青少年饮酒为了更好地了解青少年酒精诱导的神经机制， 认知障碍，并测试新的治疗模式，我们的实验室利用大鼠模型的青少年狂欢 酒精暴露（青少年间歇性暴露，或AIE）。我们已经发现了行为灵活性的缺陷 通过与对照组相比，暴露于AIE的大鼠的注意力转移任务来测量。此外，我们有 最近发现AIE诱导的神经元周围网（PNNs）的变化，PNNs是细胞外基质的一种成分 其优先在小清蛋白（PV）中间神经元周围形成并调节它们的活性。AIE显示， 增加mPFC和OFC中的PNN密度，并且更高比例的PV+中间神经元被 PNN。此外，我们收集的初步数据表明，AIE导致PV+的比例更高 aIC中被PNN包围的中间神经元。由于这些改变的神经化学标记物是在mPFC中发现的， OFC和aIC，它们可能支持AIE后观察到的行为灵活性缺陷。一个潜在 改善行为灵活性缺陷的策略是使用经颅交流电刺激（tACS）， 一种用于人类的非侵入性神经调节技术。tACS已被反向翻译， 在药物诱导的损伤中恢复灵活的行为。此外，已知tACS会改变 γ振荡，其由PV中间神经元调节。然而，目前尚不清楚tACS治疗是否 将恢复青少年酒精引起的行为灵活性缺陷。此外，目前还不清楚 tACS是否能改变神经化学标记物。本F32提案将：1）确定tACS治疗是否 使成年AIE暴露大鼠的PNN密度正常化;和2）确定tACS治疗是否恢复酒精诱导的PNN密度。 缺乏行为灵活性。在临床上，这些研究将具有影响力，因为它们测试了tACS的能力， 改善酒精引起的行为灵活性缺陷，这是已知的在人类以下被破坏 青少年酗酒这些目标产生的结果将奠定必要的 为将来的研究和拨款申请打下基础，例如K99/R 00申请。完成 拟议的研究将使我能够接受高度临床相关技术（tACS）的培训，并扩大我的 免疫组织化学和行为学方面的专业知识，并通过这样做，使我能够解决重要的问题 在酒精研究领域，我朝着成为一名独立调查员的目标前进。

ABSTRACT: Alcohol is one of the most widely used drugs by adolescents and is often consumed in a binge drinking pattern. Binge drinking alcohol during this critical developmental period can lead to lasting cognitive impairments for which there are few effective treatments. One domain that is disrupted following adolescent binge alcohol use is behavioral flexibility, defined as the ability to adapt behavior to a changing environment. The neurocircuitry underlying behavioral flexibility is complex but includes the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the anterior insula cortex (aIC), all regions that are among those perturbed by adolescent alcohol use. To better understand the neural mechanisms underlying adolescent alcohol induced cognitive impairments and to test novel treatment paradigms, our lab utilizes a rat model of adolescent binge alcohol exposure (adolescent intermittent exposure, or AIE). We have identified deficits in behavioral flexibility as measured by an attentional set shifting task in AIE-exposed rats compared to controls. Furthermore, we have recently identified AIE-induced changes in perineuronal nets (PNNs), a component of the extracellular matrix that preferentially forms around parvalbumin (PV) interneurons and modulates their activity. AIE was shown to increase PNN density in the mPFC and OFC, and a higher proportion of PV+ interneurons were surrounded by PNNs. Additionally, we have collected preliminary data suggesting that AIE leads to a higher proportion of PV+ interneurons surrounded by PNNs in the aIC. As these altered neurochemical markers are found in the mPFC, OFC, and aIC, they may underpin the observed deficits in behavioral flexibility following AIE. One potential strategy to improve deficits in behavioral flexibility is by using transcranial alternating current stimulation (tACS), a noninvasive neuromodulatory technique used in humans. tACS has been reverse translated and has been shown to restore flexible behavior in rats that have drug-induced impairments. Further, tACS is known to alter gamma oscillations, which are regulated by PV interneurons. However, it is not known whether tACS treatment will restore adolescent alcohol-induced deficits in behavioral flexibility. Additionally, it is currently unknown whether tACS can alter neurochemical markers. This F32 proposal will: 1) determine if tACS treatment normalizes PNN density in adult AIE-exposed rats; and 2) determine if tACS treatment restores alcohol-induced deficits in behavioral flexibility. Clinically, these studies will be impactful because they test the ability of tACS to ameliorate alcohol-induced deficits in behavioral flexibility, something known to be disrupted in humans following adolescent binge-alcohol consumption. The results generated from these Aims will lay the necessary groundwork for future investigations and grant proposals, such as a K99/R00 application. Completion of the proposed study will allow me to be trained in a highly clinically relevant technique (tACS), as well as expand my expertise in immunohistochemistry and behavior, and by doing so, prepare me to address important questions in the field of alcohol research as I progress towards my goal of becoming an independent investigator.