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

项目摘要/摘要 我们的建议是在非人类灵长类动物(NHP)中研究毒碱调节如何提高认知能力， 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支撑着这些 积极的影响。我们将特别为中央表达的正变构调节剂(PAM)制定基准 M_1受体，由范德比尔特药物发现中心开发。M1-PAM承诺克服 剂量限制副作用，避免激动剂过度刺激，限制依从性、有效性和耐受性 现有化合物。M1选择性调制可以是抗精神病药物，减少负面症状(例如，减少缺乏 动机)和改善精神分裂症患者的认知缺陷。M1-PAM可以通过以下方式实现这一目标 门控内源性胆碱能信号被认为调节谷氨酸和多巴胺能释放 前额叶皮质和纹状体。我们测试这些假设的工作机制，通过确定 M1 PAM作用的神经化学和电生理后果。 首先，我们将确定M1 PAM在增强认知、动机和行为方面的剂量反应效果 调节，比较它们与激动剂沙诺林和非选择性胆碱能药物多奈哌齐的效果。 我们将评估主要认知功能(注意力、工作记忆)、主要动机功能(努力 控制力、对损失的恢复能力)、认知灵活性(定势转移、坚持、奖励学习)、视觉空间问题 解决方案，以及当NHP参与触摸屏评估时捕获的行为视频的规则 在他们家的笼子里的售货亭。行为指标评估五个RDoC域，在单个会话中使用 一种新型的NHP多任务测试电池。我们将确定每个RDoC域的剂量-反应效率 分别阐明了广泛的M1 PAM如何增强认知-动机-行为功能，以及 DOMA域受到常规激动剂和非选择性胆碱能药物剂量限制副作用的影响。 第二，我们将确定细胞外乙酰胆碱浓度随药物剂量的变化， 多巴胺、5-羟色胺、谷氨酸、GABA和全身给药本身。我们在以下方面实现了这一点 在五个RDoC结构域上负荷不同的三个大脑区域并行的NHP，以确定剂量- 分别针对每个脑区的反应效果。对背外侧前额叶皮质进行评估以了解 M1 PAM如何调节谷氨酸和乙酰胆碱，从而支持认知RDoC结构。这个 评估纹状体以了解M1 PAM如何调节多巴胺以支持奖赏学习和认知 灵活性。对前扣带回皮质进行评估，以确定调节5-羟色胺和 谷氨酸调节努力--控制和动力。同时，神经放电活动被记录到 了解M1 PAM如何改变我们区分的不同中间神经元类型的放电和同步 电生理学的。总之，拟议的研究阐明了M1的工作机制和强度 PAMS与现有的剂量有限的药物制度相比较，从而为精神分裂症的治疗策略提供参考。

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.