Nicotinic Receptor Effects on Neurophysiology of Dorsolateral Prefrontal Cortex

烟碱受体对背外侧前额叶皮层神经生理学的影响

基本信息

批准号：
8423715
负责人：
MIN WANG
金额：
$ 31.91万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-10 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423715
关键词：
Acetylcholine Agonist Attention Attention deficit hyperactivity disorder Axon Behavioral Catecholamines Cells Cognition Cognition Disorders Cognitive Cues Data Dendritic Spines Development Disease Eye Movements Family Genetic Glutamates Goals Human Impaired cognition Location Memory impairment Mental disorders Monkeys N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Nicotine Dependence Nicotine Withdrawal Nicotinic Agonists Nicotinic Antagonists Nicotinic Receptors Nootropic Agents Patients Performance Pharmaceutical Preparations Physiological Physiology Play Positioning Attribute Prefrontal Cortex Presynaptic Terminals Primates Receptor Signaling Recurrence Research Rewards Rodent Schizophrenia Short-Term Memory Signal Transduction Substance abuse problem Synapses Therapeutic Therapeutic Agents Time Ventral Tegmental Area Vertebral column Work addiction cell fixation cholinergic clinically significant cognitive function comparative efficacy improved interest minimal risk neurochemistry neurophysiology neuropsychiatry operation receptor response sample fixation success therapeutic target transmission process vigilance

项目摘要

DESCRIPTION (provided by applicant): The proposed research will examine nicotinic receptor influences on dorsolateral prefrontal cortex (dlPFC) network physiology, with the goal of developing therapeutic agents to treat mental illness and nicotine addiction. Nicotinic agonists have great potential as cognitive enhancers if agents can be found that strengthen PFC without engaging subcortical addictive mechanisms. a4b2 and a7 nicotinic receptor subtypes are localized on presynaptic terminals in PFC, and a7 receptors are also post-synaptic on spines. a7 receptors are of particular interest, as they're genetically altered in some families with schizophrenia, and may not have reinforcing actions in the VTA. The proposed research will characterize the influence of a4b2 and a7 nicotinic receptors on dlPFC network physiology for the very first time. dlPFC networks excite each other via NMDA receptors to maintain persistent firing over the delay period in a working memory task. Aim 1 will characterize the effects of a4b2 agonists and antagonists on the responses of dlPFC neurons during performance of a spatial working memory task under control and distracting conditions, using iontophoretic application of drug during recording. Aim 2 will characterize the effects of a7 nicotinic agonists and antagonists, while Aim 3 will examine the interaction of nicotinic influences with NMDA receptor actions. Preliminary data indicate that a7 receptor stimulation enhances the task-related firing of both Delay and Fixation cells, and can rescue loss of firing from NMDA receptor blockade, encouraging the development of a7 agonists as cognitive enhancers.

描述（由申请人提供）：拟议的研究将检查烟碱受体对背侧前额叶皮层（DLPFC）网络生理学的影响，目的是开发治疗剂以治疗精神疾病和尼古丁成瘾。如果发现在不吸引皮层下成瘾的机制而加强PFC的情况下，烟碱激动剂作为认知增强剂具有很大的潜力。 A4B2和A7烟碱受体亚型位于PFC的突触前末端，A7受体也在刺上突触后。 A7受体特别令人感兴趣，因为某些精神分裂症的家庭在基因上改变了它们，并且可能不会在VTA中采取强化行动。拟议的研究将首次表征A4B2和A7烟碱受体对DLPFC网络生理学的影响。 DLPFC网络通过NMDA受体互相激发，以在工作内存任务中保持延迟期间的持续触发。 AIM 1将表征A4b2激动剂和拮抗剂对在控制和分散注意力条件下的空间工作记忆任务执行过程中DLPFC神经元在记录过程中的离子疗法应用的影响。 AIM 2将表征A7烟碱激动剂和拮抗剂的作用，而AIM 3将检查烟碱影响与NMDA受体作用的相互作用。初步数据表明，A7受体刺激增强了与任务相关的延迟和固定细胞的发射，并且可以从NMDA受体阻断中挽救发射的损失，从而鼓励将A7激动剂作为认知增强子的发展。