Nicotinic Receptor Effects on Neurophysiology of Dorsolateral Prefrontal Cortex

描述（由申请人提供）：拟议的研究将检查烟碱受体对背外侧前额叶皮层（dlPFC）网络生理学的影响，目的是开发治疗精神疾病和尼古丁成瘾的治疗药物。如果能发现能增强PFC而不涉及皮层下成瘾机制的药物，那么尼古丁激动剂作为认知增强剂具有很大的潜力。α_4 β_2和α_7烟碱受体亚型位于PFC的突触前末梢，α_7受体也位于突触后棘上。a7受体特别令人感兴趣，因为它们在一些精神分裂症家庭中发生了基因改变，并且可能对腹侧被盖区没有增强作用。这项研究将首次描述a4b2和a7烟碱受体对dlPFC网络生理学的影响。在工作记忆任务中，dlPFC网络通过NMDA受体相互激发，以在延迟期内保持持续放电。目的1将表征在控制和分心条件下，在记录期间使用药物的离子电渗应用的空间工作记忆任务的执行期间，a4b2激动剂和拮抗剂对dlPFC神经元的反应的影响。目的2将表征α 7烟碱激动剂和拮抗剂的作用，而目的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，α 7受体刺激增强了延迟细胞和固定细胞两者的任务相关放电，并且可以挽救NMDA受体阻断引起的放电损失，从而鼓励α 7激动剂作为认知增强剂的开发。

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.