Working memory and attention, both critical components of executive function and flexible, goal- driven behavior, are jointly impaired in multiple cognitive disorders, including Parkinson's disease, schizophrenia, and attention deficit hyperactivity disorder. Several decades of research have implicated the prefrontal cortex (PFC) in the control of attention and working memory. In spite of recent evidence indicating that the representation of visual information is modulated by the contents of working memory, little is known about the neural mechanisms underlying this modulation. This project aims to achieve a fundamental advance in our understanding of these mechanisms using very direct approaches: identifying PFC neurons involved in reciprocal connections with visual cortex, measuring dynamic changes in the strength of PFC inputs, and local pharmacological manipulations of neuronal activity. The ability of neuroscientists to describe the neural mechanisms giving rise to cognitive functions has long been hampered by the difficulty of combining anatomical and electrophysiological characterization of neurons.
Aim 1 will combine recent advances in online spike waveform discrimination, array recording, and custom hardware to produce a highly efficient, semi-automated system for the screening of connectivity between brain areas. This system will be developed in collaboration with data acquisition hardware company Neuralynx, and provide neurobiologists a high-throughput tool to study the connectivity of brain networks, significantly enhancing our ability to untangle functionally specific circuits. This system will be used to examine communication between PFC and visual cortex during working memory. Preliminary data indicate that working memory activity is the key characteristic of PFC neurons projecting to visual cortex. Next, how visual responses change based on the contents of working memory will be measured. Lastly, whether dopamine-mediated prefrontal activity is sufficient to drive these changes in visual processing will be directly tested using localized drug infusions.
Aim 2 examines the impact of spatial activity in prefrontal cortex on the maintenance of an object memory in visual cortex, and on memory performance. The contribution of dopaminergic prefrontal activity to the neural and behavioral correlates of object working memory will be causally tested. Together, these aims will provide a detailed mechanistic account of how the interactions between PFC and visual cortex depend upon the contents of working memory; such an understanding will provide insight into the interdependence of attention and working memory, and how working memory deficits are associated with impairments in the processing of visual information, as is often observed in mental illnesses.
By examining the role of prefrontal dopamine receptors in cognitive tasks, the proposed research will use a primate model to investigate how dopaminergic input to the prefrontal cortex, the core region in control of our goal-driven behavior, regulates the behavioral and neuronal correlates of visual working memory. Working memory impairments are observed in mental illnesses such as attention deficit hyperactivity disorder and schizophrenia. The proposed series of experiments will greatly expand our understanding of how imbalances in prefrontal dopamine can contribute to the deficits accompanying these mental disorders, which are thought to arise from an imbalance in prefrontal dopamine and are often treated with dopaminergic agents.
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