Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dys-regulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism

Role of cholinergic receptors in prefrontal activity of nonhuman primates during an oculomotor rule-based working memory task

The ability to flexibly react to our dynamic environment is a cardinal component of cognition and our human identity. Millions across the globe are affected by disorders of cognition, affecting their ability to live independently. Prefrontal cortex is required for optimal cognitive functioning, but its circuitry is often disrupted in conditions of impaired cognition. In addition, the cholinergic system is vital to optimal executive function, but this is disrupted in a number of conditions, including Alzheimer’s disease and schizophrenia. The actions of cholinergic receptors were explored in this project with local application of cholinergic compounds onto prefrontal neurons as rhesus monkeys performed a rule-based saccadic task that requires working memory maintenance. The antisaccade task is a useful probe of prefrontal cortex function that elicits errors in neuropsychiatric conditions. Some prefrontal neurons respond to different task aspects of the antisaccade task, e.g., discharging preferentially for one task rule over the other (pro- or antisaccades), and are thought to be involved in the circuitry for correct behavioural responses. Chapter 2 explored the effect of general stimulation of cholinergic receptors on rhesus PFC neuronal activity during antisaccade performance. In Chapter 3, newly developed cholinergic receptor subtype-specific compounds were utilized to examine the actions of muscarinic M1 receptor stimulation on prefrontal activity. Cortical oscillations are emerging as an important aspect of cognitive circuitry, such as during working memory maintenance. Chapter 4 examined the influence of local cholinergic receptor stimulation and blockade on the power of local field potential in different frequency bands. This project characterized the role of cholinergic receptors in prefrontal cortical neurons that were actively involved in cognitive circuitry. This and future work on the cholinergic influence on prefrontal cortex will provide insights into the altered cognitive functioning in Alzheimer’s disease and schizophrenia, which are also affected by disrupted cholinergic systems

Investigating the Primate Prefrontal Cortex Correlates of Cognitive Deficits In the Ketamine Model of Schizophrenia

The World Health Organization has classified schizophrenia as one of the five leading causes of disability worldwide. Afflicting almost 1% of the world’s population, the disease’s greatest impact stems from its reduction in patients’ cognitive faculties. In order to better study these impairments, a pharmacological model has been developed using the NMDA antagonist, ketamine. This disease model successfully recreates the cognitive dysfunction of schizophrenia, allowing researchers to search for associated electrophysiological changes. In this project I examined the behavioural and neurophysiological effects of ketamine on non-human primates performing the anti-saccade task. Success in this task requires a degree of cognitive control over behaviour and previous studies have described poor performance in both patients with schizophrenia and healthy controls administered ketamine. Our intracranial recordings are localized in the prefrontal cortex (PFC), a region associated with many of the cognitive functions impaired in schizophrenia. The first study shows that neurons in the PFC exhibit selectivity for the task rule. This rule selectivity is lost after ketamine administration due to an indiscriminate increase in the neuronal firing rate. These changes were also associated with an increased error rate and longer reaction times. The second study shows that neurons in the PFC are also sensitive to the outcome of the trial, firing more for either correct or erroneous responses. Once again, selectivity is lost following ketamine administration and the neurons show increased, nonspecific activity. Lastly, we recorded the local field potential of the PFC and found changes in the oscillatory patterns during the anti-saccade task. Prior to ketamine there was a significantly stronger beta-band activity after correct trials compared to error trials, but this selective activity was lost due to an overall decrease in the outcome selective oscillatory events. These findings show that ketamine’s effect on the PFC is one of selectivity reduction. Patients with schizophrenia have been shown to require increased PFC activity but only reach moderate performance levels in cognitive challenges. It is possible that their brains suffer the same changes highlighted in this research. Although the signals are still present in their PFC, they are being lost amongst the noise