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

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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.