Effects of tACS on alcohol-induced cognitive and neurochemical deficits

tACS 对酒精引起的认知和神经化学缺陷的影响

• 批准号: 10825849
• 负责人: Emily Sullivan
• 金额: $ 7.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2025-07-17
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825849
• 关键词: Address; Adolescent; Adult; Alcohol consumption; Alcohols; Animal Model; Animals; Anterior; Applications Grants; Attention; Behavior; Behavioral; Brain; Brain region; Cephalic; Clinical; Cocaine; Cognitive; Complex; Consumption; Data; Disease; Environment; Exhibits; Extracellular Matrix; Female Adolescents; Functional Magnetic Resonance Imaging; Future; Goals; Histologic; Human; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Impairment; Individual; Insula of Reil; Interneurons; Investigation; Knowledge; Learning; Life; Male Adolescents; Manuscripts; Measures; Medial; Mediating; Mental Depression; Modeling; Neurons; Outcome; Parvalbumins; Pattern; Perfusion; Pharmaceutical Preparations; Prefrontal Cortex; Rattus; Reporting; Research; Research Personnel; Rest; Schizophrenia; Stress; Structure; Substance Use Disorder; Synapses; Techniques; Testing; Training; Translating; adolescent alcohol exposure; adolescent binge drinking; adolescent drug use; alcohol research; behavior measurement; binge drinking; clinically relevant; comparison control; critical developmental period; density; effective therapy; experimental study; flexibility; improved; memory retrieval; neural; neural circuit; neurochemistry; neuromechanism; neuroregulation; novel; pre-clinical; substance use treatment; success; underage drinking

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.

摘要：酒精是青少年最广泛使用的药物之一，并且经常在暴饮暴食时饮用。 饮酒模式。在这个关键的发育时期暴饮暴食可能会导致持久的认知障碍 几乎没有有效治疗方法的损伤。青春期后被破坏的一个领域 酗酒是行为灵活性，定义为使行为适应不断变化的环境的能力。这 行为灵活性背后的神经回路很复杂，但包括内侧前额叶皮层 (mPFC)、 眶额皮质 (OFC) 和前岛叶皮质 (aIC)，所有受干扰的区域 青少年饮酒。为了更好地了解青少年酒精诱发的神经机制 认知障碍并测试新的治疗范例，我们的实验室利用青少年暴饮暴食的大鼠模型 酒精暴露（青少年间歇性暴露，或 AIE）。我们发现了行为灵活性的缺陷 通过与对照组相比，AIE 暴露大鼠的注意力转移任务来测量。此外，我们还有 最近发现 AIE 诱导的神经元周围网 (PNN) 发生变化，PNN 是细胞外基质的一个组成部分 优先在小清蛋白 (PV) 中间神经元周围形成并调节其活动。 AIE 被证明 增加 mPFC 和 OFC 中的 PNN 密度，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+ 比例更高 aIC 中的中间神经元被 PNN 包围。由于这些改变的神经化学标记物是在 mPFC 中发现的， OFC 和 aIC，它们可能会加剧 AIE 后观察到的行为灵活性缺陷。一种潜力 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 已被反向翻译并已 显示可以恢复因药物引起的损伤的大鼠的灵活行为。此外，已知 tACS 会改变 伽马振荡，由 PV 中间神经元调节。然而，尚不清楚 tACS 治疗是否有效。 将恢复青少年酒精引起的行为灵活性缺陷。另外，目前尚不清楚 tACS 是否可以改变神经化学标志物。该 F32 提案将：1) 确定 tACS 治疗是否有效 使成年 AIE 暴露大鼠的 PNN 密度正常化； 2) 确定 tACS 治疗是否可以恢复酒精诱导的 行为灵活性的缺陷。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，这是已知的人类行为灵活性缺陷 青少年酗酒。这些目标产生的结果将奠定必要的基础 为未来的调查和资助提案（例如 K99/R00 申请）奠定基础。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，并扩展我的能力 免疫组织化学和行为方面的专业知识，并通过这样做，让我做好解决重要问题的准备 在酒精研究领域，我正在朝着成为一名独立研究者的目标前进。