Cholinergic Influences on Neuronal Physiology in Dorsolateral Prefrontal Cortex.

胆碱能对背外侧前额叶皮层神经元生理学的影响。

• 批准号: 9027155
• 负责人: MIN WANG
• 金额: $ 41.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027155
• 关键词: Acetylcholine; Address; Adverse effects; Agonist; Area; Arousal; Brain; Brain region; CHRM1 gene; Cells; Charge; Cognition; Cognition Disorders; Cognitive deficits; Combined Modality Therapy; Data; Dendritic Spines; Development; Disease; Dose; Drug Discovery Groups; Drug effect disorder; Etiology; Family; Glutamates; Grant; Hippocampus (Brain); Immunoelectron Microscopy; Impaired cognition; Ion Channel; Lead; Link; Mental disorders; Monkeys; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinics; N-Methyl-D-Aspartate Receptors; Neurons; Patients; Peripheral; Peripheral Nervous System; Physiology; Pilot Projects; Play; Positioning Attribute; Potassium Channel; Prefrontal Cortex; Primates; Protocols documentation; Pyramidal Cells; Receptor Gene; Receptor Signaling; Recurrence; Research; Role; Schizophrenia; Sensory; Short-Term Memory; Synapses; Synaptic Membranes; Testing; Therapeutic; Universities; Vertebral column; cholinergic; cigarette smoking; clinically relevant; cognitive function; density; desensitization; improved; novel; oculomotor; patient population; patient subsets; positive allosteric modulator; postsynaptic; public health relevance; receptor; receptor coupling; receptor expression; relating to nervous system; research study; therapeutic target; treatment strategy

 DESCRIPTION (provided by applicant): The pyramidal cell microcircuits of the primate dorsolateral prefrontal cortex (dlPFC) are gravely afflicted in schizophrenia. Research in monkeys has shown that these circuits excite each other through glutamatergic, NMDA receptor (NMDAR) synapses on dendritic spines to generate the persistent neural representations needed for working memory. Immunoelectron microscopy has revealed that both nicotinic-α7 receptors (nic- α7R), and muscarinic M1 receptors (M1R) are localized in dlPFC glutamate synapses within the post-synaptic density (PSD). During the previous tenure of this grant, we discovered that cholinergic stimulation of nic-α7R enhances neural representations in the primate dlPFC, and is permissive for NMDAR actions, rescuing neuronal firing from NMDAR blockade. As schizophrenia is associated with impaired NMDAR and nic-α7R signaling, these data encourage the development of nic-α7R agonists for the treatment of PFC cognitive deficits. However, this strategy has been hampered by the rapid desensitization of nic-α7R following stimulation, and by drug actions at peripheral nic-α7R. Thus, additional approaches are needed. Stimulation of M1R may have beneficial effects on dlPFC function similar to nic-α7R, and may provide a more tractable target since they are concentrated in brain areas relevant to cognition but are not as prevalent in the peripheral nervous system. As schizophrenia is associated with changes in the M1R gene (CHRM1) and with reduced M1R expression in dlPFC, these data have direct relevance to the etiology and treatment of this disease. In the proposed research, Aim 1 will examine whether stimulation of M1R, like nic-α7R, enhances the firing of dlPFC neurons in monkeys performing a working memory task, and whether M1R stimulation is permissive for NMDAR actions as suggested by their synaptic localization. We will also have the opportunity to test a novel, highly selective M1R positive allosteric modulator (PAM) created by Dr. Jeffrey Conn's Drug Discovery group at Vanderbilt University to see if this compound can enhance dlPFC neuronal firing and improve working memory following systemic administration in monkeys. Aim 2 will address the mechanism of M1R actions in dlPFC, examining the hypothesis that M1R act by closing KCNQ potassium channels (Kv7; also known as "M" channels), which are also localized within the PSD of layer III glutamate synapses, positioned to depolarize the synaptic membrane and facilitate NMDAR signaling when closed by M1R actions. Finally, Aim 3 will test whether the same neurons that respond to nic-α7R stimulation also respond to M1R, and if so, whether they have additive or synergistic interactions. Additive or synergistic actions of nic-α7R and M1R stimulation could lead to combined treatments that allow lower doses with fewer side effects, circumventing a major hurdle in the development of cholinergic therapeutics for cognitive disorders.

 描述（由适用提供）：原发性形成前额叶皮层（DLPFC）的锥体细胞微电路在精神分裂症中严重折磨。猴子的研究表明，这些电路通过谷氨酸能，NMDA受体（NMDAR）突触在树突棘上相互激发，以产生工作记忆所需的持久神经表示。免疫电子显微镜已经表明，烟碱-α7受体（NIC-α7R）和毒蕈碱M1受体（M1R）均位于后突触密度（PSD）内的DLPFC谷氨酸突触中。在该赠款的上一个任期期间，我们发现NIC-α7R的胆碱能刺激增强了灵长类动物DLPFC中的神经元表示，并且可以允许NMDAR作用，从而从NMDAR封锁中挽救了神经元射击。由于精神分裂症与NMDAR和NIC-α7R信号受损有关，因此这些数据鼓励开发NIC-α7R激动剂来治疗PFC认知缺陷。但是，刺激后NIC-α7R的快速脱敏以及在周围的NIC-α7R上的药物作用受到了阻碍。那需要其他方法。 M1R的刺激可能对类似于NIC-α7R的DLPFC功能具有有益的作用，并且由于它们集中在大脑中，因此可能会提供更容易拖动的靶标。与认知相关的领域，但在周围神经系统中不那么普遍。由于精神分裂症与M1R基因的变化（CHRM1）和DLPFC中M1R表达降低有关，因此这些数据与该疾病的病因学和治疗直接相关。在拟议的研究中，AIM 1将检查M1R（如NIC-α7R）的刺激是否会增强执行工作记忆任务的猴子中DLPFC神经元的发射，以及M1R刺激是否允许其突触定位所暗示的NMDAR动作。我们还将有机会测试由Jeffrey Conn博士在范德比尔特大学（Vanderbilt University）的药物发现小组创建的新型，高度选择性的M1R阳性变构调节剂（PAM），以查看该化合物是否可以增强DLPFC神经元点火并改善猴子全身性给药后的工作记忆。 Aim 2 will address the mechanism of M1R actions in dlPFC, examining the hypothesis that M1R act by closing KCNQ potassium channels (Kv7; also known as "M" channels), which are also localized within the PSD of layer III glutamate synapses, positioned to depolarize the synthetic membrane and facilitate NMDAR signaling when closed by M1R actions.最后，AIM 3将测试对NIC-α7R刺激反应的相同神经元是否也对M1R响应，如果是，它们是否已添加或协同相互作用。 NIC-α7R和M1R刺激的累加或协同作用可能导致合并的治疗方法，允许较低剂量具有更少的副作用，从而避免了认知疾病的胆碱能治疗的主要障碍。