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：酒精是青少年使用的最广泛使用的药物之一，经常在狂欢中食用 饮酒方式。在这个关键的发育时期，暴饮暴食会导致持久的认知 有效治疗的障碍很少。青少年后被破坏的一个领域 暴饮暴食是行为灵活性，定义为适应不断变化的环境的能力。这 神经路的行为灵活性很复杂，但包括内侧前额叶皮层（MPFC），即 眶额皮质（OFC）和前岛皮层（AIC），所有区域都在被扰动的区域之一 青少年饮酒。更好地了解青少年酒精引起的基础神经机制 认知障碍并测试新的治疗范例，我们的实验室利用了青少年的大鼠模型 酒精暴露（青少年间歇性暴露或AIE）。我们已经确定了行为灵活性的缺陷 通过与对照组相比，通过暴露于AIE的大鼠的注意集合转移任务来衡量。此外，我们还有 最近确定了AIE诱导的会周神经元网（PNN）的变化，这是细胞外基质的一个成分 这优先围绕白蛋白（PV）中间神经元形成并调节其活性。 AIE被证明 MPFC和OFC中的PNN密度增加，并且较高比例的PV+中间神经元被包围 PNNS。此外，我们收集了初步数据，表明AIE导致PV+的比例较高 中间神经元在AIC中被PNN包围。由于这些改变的神经化学标记是在MPFC中发现的 OFC和AIC，它们可能是AIE后观察到的行为灵活性缺陷的基础。一个潜力 改善行为灵活性缺陷的策略是使用经颅交流刺激（TAC）， 人类使用的一种无创神经调节技术。 TACS已反向翻译，已经 证明可以恢复具有药物诱导损伤的大鼠的柔性行为。此外，已知TAC会改变 γ振荡，由PV中间神经元调节。但是，尚不清楚TACS是否治疗 将恢复青少年酒精引起的行为灵活性缺陷。此外，目前未知 TAC是否可以改变神经化学标记。该F32提案将：1）确定TACS是否治疗 使成年AIE暴露大鼠的PNN密度归一化； 2）确定TACS治疗是否恢复了酒精诱导的 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TAC的能力 改善酒精引起的行为灵活性缺陷，已知在人类中被破坏了 青少年暴饮暴食。这些目标产生的结果将奠定必要的 未来调查和赠款建议的基础，例如K99/R00申请。完成 拟议的研究将使我能够接受高度临床相关技术（TAC）的培训，并扩大我的 免疫组织化学和行为方面的专业知识，并这样做，准备我以解决重要问题 在酒精研究领域，我朝着成为一名独立研究员的目标。