An optogenetic investigation of CNS sensitization following alcohol withdrawal

酒精戒断后中枢神经系统敏化的光遗传学研究

• 批准号: 8835699
• 负责人: Gregory Erick Alberto
• 金额: $ 4.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835699
• 关键词: Alcohol Withdrawal Seizures; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; American; Animals; Antiepileptic Agents; Area; Automobile Driving; Basic Science; Behavioral; Calcium Channel; Calcium Channel Blockers; Cessation of life; Chronic; Clinical; Coupled; Depressed mood; Development; Disease; Economic Burden; Electrodes; Electrophysiology (science); Ensure; Epilepsy; Ethosuximide; Frequencies; Generations; Healthcare Systems; Hippocampus (Brain); Histology; Hour; Hypersensitivity; Individual; Intervention; Investigation; Kindling (Neurology); Link; Lorazepam; Measurement; Measures; Mediating; Mediator of activation protein; Mental Depression; Methods; Microscopy; Modeling; Mus; Nervous system structure; Neurons; Optics; Outcome; Pharmaceutical Preparations; Physicians; Population; Postdoctoral Fellow; Probability; Prophylactic treatment; Protein Isoforms; Recovery; Recruitment Activity; Relapse; Research; Research Personnel; Research Training; Risk; Role; Scientist; Seizures; Series; Severities; Site; Structure; T-Type Calcium Channels; Techniques; Testing; Thalamic structure; Time; Training; Transgenic Organisms; Translational Research; Trauma; United States; Withdrawal; Withdrawal Symptom; addiction; alcohol exposure; base; career; cost; efficacy testing; experience; gamma-Aminobutyric Acid; improved; insight; interdisciplinary approach; novel; novel strategies; optogenetics; problem drinker; public health relevance; relating to nervous system; research study; skills; social

DESCRIPTION (provided by applicant): The primary objective of this project is to characterize the T-type calcium channel (T-channel) mediated neuron and circuit sensitization that occurs in the setting of alcohol withdrawal (WD) and to determine the potential utility of specific T-channel blockers as therapy in WD. WD symptoms, including seizure, represent a major barrier to recovery for alcoholics, driving many to relapse. WD symptoms become more severe with subsequent WDs; likely due to rebound hyperexcitability following chronic CNS depression through GABA modulation by alcohol. Our lab has identified the T-channel isoform Cav3.2 as a potential mediator of WD hyperexcitability, and our findings suggest that T-channels may underlie the generation and propagation of WD seizures. I propose to investigate the T-channel mediated sensitization effects of WD by testing population sensitivity using a precise optogenetic stimulation paradigm in the presence or absence of T-channel blockers. Additionally, I will use an optogenetic seizure induction method to test the efficacy of the T-channel specific anti-epileptic drug ethosuximide against the standard WD seizure prophylaxis, lorazepam. Finally, I will identify the specific sites of sensitization in a proposed WD seizure network and test the effect of T-channel blockade on the responsiveness of the network. All of the following specific aims will employ chronic multi-site electrophysiology recording paired with optical stimulation of CA1 of the transgenic Thy1-ChR2 mouse. Specific Aim 1 will evaluate sensitization of thalamic and hippocampal neuron populations following WD by quantifying interictal spikes in kindled animals before and after WD. Specific Aim 2 proposes to use an optogenetic seizure induction paradigm following WD to determine the extent to which seizure spread, intensity, and threshold are modified by WD. While Specific Aim 3 will characterize network changes following WD by recording optogenetically evoked activity at multiple sites downstream of stimulation at a range of stimulation levels. T-channel blockers will be used in all experiments to distinguish T-channel mediated effects from those related to other mechanisms. This training plan proposes a multidisciplinary approach that includes optogenetics, electrophysiology, behavioral studies, and pharmacologic intervention to identify the T-channel mediated effects on neuron sensitivity following WD as well as to identify potential novel therapies for WD seizure. The approach to this study will provide training in optogenetic techniques, electrophysiology recording and analysis, behavioral studies, and histology and microscopy. With guidance and support from my advisor and research associates; this project will provide training for the pursuit of basic and translational research questions and generate insight into the burdens of alcoholism. Finally, a clinical training plan that encompasses the duration of my basic research training will ensure that I will be well-rounded in my career as a physician-scientist.

描述（由申请人提供）：该项目的主要目标是表征酒精戒断（WD）时发生的t型钙通道（t通道）介导的神经元和电路敏化，并确定特定t通道的潜在效用