Spike Timing Defects and State Representation Impairments in Nonhuman Primates

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PROJECT SUMMARY: PROJECT 1 The purpose of PROJECT 1 is to use nonhuman primates to examine prefrontal local circuit and distributed network impairments associated with state representation dysfunctions of relevance to individuals with psychosis. PROJECT 1 will relate synaptically mediated functional interactions between neurons in prefrontal networks to computations that support state representation processes. In Aim 1, we will quantify functional neural interactions by measuring temporal correlations in the timing of action potentials (‘spikes’) imposed by synaptic interactions between the neurons. In Aim 2, we will disrupt those interactions by pharmacologically blocking NMDA receptors (NMDAR), which induces a period of transient cognitive impairment during which monkeys commit similar patterns of behavioral errors during the DPX decision-making task as do people with schizophrenia. We will record neural activity in prefrontal cortex and anatomically connected brain areas (posterior parietal cortex and the dorsal striatum) concurrently during the period of cognitive impairment, while monkeys perform the DPX and Bandit tasks, which allow us to index state estimation, state learning, and state stability processes. We will discover how reducing NMDAR synaptic transmission alters functional interactions between neurons in prefrontal networks, leading to computational failures in state representation processes. To provide a bridge to neural signals that we can record in humans, we will record neural signals that reflect brain activity at the microscale (single neuron action potentials), mesoscale (local field potentials within a cortical area) and macroscale (local field potentials and EEG across cortical areas) from prefrontal cortex and connected structures simultaneously. We will use causal discovery analysis to identify the parameters that can be found with more limited neurophysiological techniques available in humans (for PROJECTS 3 and 4). As PROJECT 4 identifies specific cognitive training regimens that improve state estimation and state stability in individuals with early psychosis, PROJECT 1 will back-translate these paradigms to monkeys to identify training-induced changes in attractor network parameters at the neurophysiological (micro-, meso- and macro- circuit) levels.