Cognitive impairments related to stroke, schizophrenia, aging, and autism are characterized by the inability to select appropriate actions based on environment or circumstances. This process, termed goal-directed behavior, involves applying a learned rule to a sensory stimulus to decide on an abstract behavioral goal and to select the appropriate motor action to achieve the goal. To illustrate, encountering a red light when driving, results in a sequence of neural responses across several areas of your brain, which make you press the brakes (an action) with your foot to stop the car (a goal). Lesion and physiological studies implicate several cortical and subcortical circuits in this process. However, we currently have a quite limited understanding of the relative contributions of these circuits, circuit organization and the dynamical mechanism(s) that results in goal- directed behavior. My long-term goal is a research career focused on answering these questions with special emphasis on cortical circuits. This specific proposal focuses on understanding circuit organization and temporal dynamics in the dorsal premotor cortex (PMd) and the dorsolateral prefrontal cortex (DLPFC), two areas implicated in goal-directed behavior. During the K99 phase, I will focus on examining the functional circuit organization of PMd perpendicular (e.g. across the different layers of cortex) and parallel to the cortical surface. I will also examine th relationship between PMd activity and behavior on single trials. In the R00 phase, I will first tes the hypothesis that PMd and DLPFC are involved in different aspects of goal-directed behavior. Specifically, we postulate that PMd mediates the selection of action (e.g. pressing brakes) whereas PFC networks are involved in using the behavioral rule to process the sensory stimulus and decide on the behavioral goal (e.g. stop vs. go). I will then examine circuit organization in DLPFC during goal-directed behavior. In order to be able to answer these questions, the proposal introduces several innovative experimental approaches and techniques: 1) a reaction time discrimination task with a rich parametric red- green checkerboard stimulus, reaching as the behavioral report, and a task design separating out behavioral goals from performed actions, 2) laminar electrodes that allow simultaneous measurement of activity across several depths, 3) two-photon calcium imaging which allows recording with single neuron resolution from populations of neurons, 4) single trial analysis of relationship between population neural data and behavior. The significance of this research is that it will provide an understanding of the circuit organization and dynamics of premotor and prefrontal circuits mediating goal-directed behavior in a primate. This understanding in a primate when combined with tools for precise circuit manipulation might lead to circuit level therapeutics for patients suffering from psychiatrc and neurological disorders. It is also expected to guide the design and ideal placement of electrode arrays to decode cognitive and motoric components of goal-directed behavior thus enabling robust brain-machine interfaces for patients suffering from paralysis.
Stroke, psychiatric disorders and degenerative neural diseases impact the frontal and premotor cortex disrupting our remarkable and effortless ability to perform appropriate motor actions on the basis of learned sensory cues and the context to achieve goals. My research focuses on providing an in-depth understanding of the circuit organization and mechanism by which these circuits mediate this goal-directed behavior. An understanding of circuit organization and dynamics when combined with newly developed tools for precise circuit manipulation is expected to provide circuit level therapeutics and guide the design of the next generation of brain-machine interfaces for patient populations.
