Muscarinic modulation of RDoC constructs in primate behavior and fronto-striatal circuits

灵长类行为和额纹状体回路中 RDoC 结构的毒蕈碱调节

• 批准号: 10599997
• 负责人: Thilo Womelsdorf
• 金额: $ 73.8万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599997
• 关键词: Acetylcholine; Address; Affect; Agonist; Anhedonia; Animals; Anterior; Antipsychotic Agents; Area; Attention; Behavior; Behavior assessment; Behavioral; Benchmarking; Binding; Brain; Chemicals; Choline; Cholinergic Agents; Clinical; Cognition; Cognitive; Cognitive deficits; Complement; Complex; Consensus; Corpus striatum structure; Data; Dopamine; Dose; Dose Limiting; Drug Compounding; Drug Modulation; Drug usage; Electrophysiology (science); Fingerprint; Glutamates; Home; Human; Interneurons; Lead; Learning; MATRICS Consensus Cognitive Battery; Macaca mulatta; Measures; Mediating; Mental disorders; Microdialysis; Motivation; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Muscarinics; Neuromodulator; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phase; Prefrontal Cortex; Primates; Problem Solving; Process; Psychoses; Regulation; Research; Research Domain Criteria; Rest; Rewards; Sampling; Schizophrenia; Serotonin; Short-Term Memory; Signal Transduction; Solid; Symptoms; Synapses; Task Performances; Testing; Therapeutic Index; Training; Up-Regulation; Visuospatial; affective disturbance; attentional control; behavior prediction; cell type; cholinergic; cingulate cortex; cognitive enhancement; cognitive function; cognitive task; cognitive testing; design; donepezil; drug action; drug discovery; extracellular; flexibility; frontal lobe; gamma-Aminobutyric Acid; improved; in vivo; insight; memory process; multitask; neural; neurochemistry; neurophysiology; nonhuman primate; novel; novel therapeutics; positive allosteric modulator; receptor; receptor density; resilience; response; side effect; skills; touchscreen; treatment strategy; xanomeline

PROJECT SUMMARY / ABSTRACT Our proposal investigates in the nonhuman primate (NHP) how muscarinic modulation enhances cognition, motivation and behavioral regulation and which neurochemical and cell-type specific mechanisms underlie these positive effects. We specifically will benchmark a positive allosteric modulator (PAM) for the centrally expressed muscarinic M1 receptor, developed at the Vanderbilt Center for Drug Discovery. M1-PAMs promise to overcome dose-limiting side effects and avoid agonist overstimulation that limit compliance, efficacy, and tolerability of existing compounds. M1 selective modulation can be antipsychotic, reduce negative symptoms (e.g. reduce lack of motivation) and ameliorate cognitive deficits in patients with schizophrenia. M1-PAMs may achieve this by gating intrinsic cholinergic signaling which is believed to regulate glutamatergic and dopaminergic release in the prefrontal cortex and striatum. We test these hypothesized working mechanisms by determining the neurochemical and electrophysiological consequences of M1 PAM action. First, we will determine the dose-response efficacy of M1 PAMs to enhance cognition, motivation, and behavioral regulation, comparing their effects to the agonist Xanomeline and the non-selective cholinergic drug Donepezil. We will assess primary cognitive functions (attention, working memory), primary motivational functions (effort control, resilience to loss), cognitive flexibility (set shifting, perseveration, reward learning), visuospatial problem solving, and the regulation of behavior video-captured when NHPs engage with the touchscreen assessment Kiosk in their home cages. The behavioral metrics evaluate five RDoC domains, tested in single sessions using a novel Multi-Task Test Battery for NHP. We will determine dose-response efficacy for each RDoC domain separately which clarifies how broad M1 PAMs enhance cognitive-motivational-behavioral functions and which domains suffer from dose-limiting side effects with a conventional agonist and a nonselective cholinergic drug. Second, we will determine the drug-dose dependent changes of extracellular concentrations of Acetylcholine, Dopamine, Serotonin, Glutamate, GABA, and of the systemically administered drug itself. We achieve this in NHPs in parallel in three brain areas that load differently on the five RDoC domains to determine the dose- response efficacy for each brain area separately. The dorsolateral prefrontal cortex is assessed to understand how M1 PAMs regulate glutamate and acetylcholine implicated to support cognitive RDoC constructs. The Striatum is assessed to understand how M1 PAMs regulate dopamine to support reward learning and cognitive flexibility. The anterior cingulate cortex is assessed to determine dose-efficacy for modulating serotonin and glutamate to mediate effort-control and motivation. Simultaneously, neural spiking activity is recorded to understand how M1 PAMs alter firing and synchronization of different interneuron types that we distinguish electrophysiologically. Together, the proposed studies elucidate the working mechanisms and strength of M1 PAMs relative to existing dose-limited drug regime and thereby inform treatment strategies for schizophrenia.

项目摘要 /摘要 我们的建议在非人类灵长类动物（NHP）中调查了毒蕈碱调节如何增强认知， 动机和行为调节以及哪些神经化学和细胞类型的特定机制是这些基础 积极影响。我们专门将为中央表达的阳性变构调节剂（PAM）基准测试 毒蕈碱M1受体在范德比尔特药物发现中心开发。 M1-PAM有望克服 剂量限制副作用并避免过度刺激的激动剂过度刺激，从而限制了依从性，功效和耐受性 现有化合物。 M1选择性调节可以是抗精神病药，减少负面症状（例如，减少缺乏 精神分裂症患者的动机和改善认知缺陷。 M1-PAM可以通过 门控固有的胆碱能信号传导，据信，它可以调节谷氨酸能和多巴胺能释放 前额叶皮层和纹状体。我们通过确定这些假设的工作机制来测试这些假设的工作机制 M1 PAM作用的神经化学和电生理后果。 首先，我们将确定M1 PAM的剂量反应功效以增强认知，动机和行为 调节，将它们的作用与激动剂的Xanomeline和非选择性胆碱能药物多奈奈旋齐尔进行了比较。 我们将评估主要的认知功能（注意，工作记忆），主要动机功能（努力 控制，对损失的韧性），认知灵活性（设置转移，毅力，奖励学习），视觉空间问题 解决NHP与触摸屏评估互动时的求解以及行为视频捕获的调节 售货亭在他们的笼子里。行为指标评估了五个RDOC域，并在单个会话中使用 NHP的新型多任务测试电池。我们将确定每个RDOC域的剂量反应功效 单独阐明了广泛的M1 PAM如何增强认知动机行为的功能以及哪些功能 常规激动剂和非选择性胆碱能药物具有限制剂量的副作用。 其次，我们将确定乙酰胆碱细胞外浓度的药物剂量依赖性变化， 多巴胺，5-羟色胺，谷氨酸，GABA和系统施用的药物本身。我们实现了 NHP在三个大脑区域并联，在五个RDOC结构域上负载不同，以确定剂量 每个大脑区域的响应功效。评估背侧外侧前额叶皮层以了解 M1 PAMS如何调节谷氨酸和乙酰胆碱与支持认知RDOC构建体有关的含量。这 评估纹状体以了解M1 PAM如何调节多巴胺以支持奖励学习和认知 灵活性。评估前扣带回皮层以确定调节5-羟色胺和 谷氨酸介导努力控制和动力。同时，将神经尖峰活动记录到 了解M1 PAM如何改变我们区分的不同中间神经元类型的触发和同步 电生理学。共同提出的研究阐明了M1的工作机制和强度 PAM相对于现有剂量有限的药物制度，从而为精神分裂症提供了治疗策略。