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（由申请人提供）：灵长类动物背外侧前额皮质（dlPFC）的锥体细胞微电路在精神分裂症中受到严重影响。对猴子的研究表明，这些回路通过树突棘上的谷氨酸能 NMDA 受体 (NMDAR) 突触相互兴奋，产生工作记忆所需的持久神经表征。免疫电镜显示烟碱-α7 受体 (nic-α7R) 和毒蕈碱 M1 受体 (M1R) 均位于突触后密度 (PSD) 内的 dlPFC 谷氨酸突触中。在该资助的上一个任期内，我们发现 nic-α7R 的胆碱能刺激增强了灵长类动物 dlPFC 中的神经表征，并且允许 NMDAR 动作，从而从 NMDAR 阻断中拯救神经元放电。由于精神分裂症与 NMDAR 和 nic-α7R 信号传导受损有关，这些数据鼓励开发 nic-α7R 激动剂来治疗 PFC 认知缺陷。然而，该策略受到刺激后 nic-α7R 快速脱敏以及外周 nic-α7R 的药物作用的阻碍。因此，需要额外的方法。与 nic-α7R 类似，刺激 M1R 可能对 dlPFC 功能产生有益影响，并且可能提供更容易处理的目标，因为它们集中在与认知相关的大脑区域，但在周围神经系统中并不普遍。由于精神分裂症与 M1R 基因 (CHRM1) 的变化以及 dlPFC 中 M1R 表达的减少有关，因此这些数据与该疾病的病因和治疗具有直接相关性。在拟议的研究中，目标 1 将检查 M1R 的刺激（如 nic-α7R）是否会增强执行工作记忆任务的猴子中 dlPFC 神经元的放电，以及 M1R 刺激是否允许 NMDAR 动作（如突触定位所表明的那样）。我们还将有机会测试范德比尔特大学 Jeffrey Conn 博士的药物发现小组创建的一种新型、高度选择性的 M1R 正变构调节剂 (PAM)，看看这种化合物在猴子全身给药后是否可以增强 dlPFC 神经元放电并改善工作记忆。目标 2 将解决 dlPFC 中 M1R 作用的机制，检验 M1R 通过关闭 KCNQ 钾通道（Kv7；也称为“M”通道）发挥作用的假设，该通道也位于第 III 层谷氨酸突触的 PSD 内，当 M1R 作用关闭时，其定位是使突触膜去极化并促进 NMDAR 信号传导。最后，Aim 3 将测试对 nic-α7R 刺激做出反应的相同神经元是否也对 M1R 作出反应，如果是，它们是否具有加性或协同相互作用。 nic-α7R 和 M1R 刺激的相加或协同作用可能会导致联合治疗，从而降低剂量，减少副作用，从而绕过认知障碍胆碱能疗法开发的主要障碍。