Modified Project Summary/Abstract Section This project will be moved from the mentored phase institution (MIT) to the R00 institution (Rutgers University – New Brunswick). Responding to sensory information from the environment with appropriate motor actions requires at least two distinct cognitive abilities. While attentional engagement prioritizes behaviorally relevant sensory stimuli for processing, motor planning allows for selection of appropriate actions from a repertoire of possible movements. While the PFC has been widely implicated in guiding attention and motor planning, it is unclear if the same or distinct neural substrates underlie these functions. According to the ‘pre-motor theory of attention’, attention is an emergent property of networks that implement actions and, hence, the same set of neurons contribute to both attention and motor planning. However, recent evidence suggests that these functions are served by distinct cell types. In this application, I will test the hypothesis that distinct PFC cell-types target either the visual cortex or superior colliculus, a midbrain structure that coordinates motor behavior, to guide attentional modulation of sensory processing or motor planning, respectively. In Aim 1, I will use optogenetic inactivation to test the contribution of visual cortex, superior colliculus, or PFC to performance on a novel two-choice visual task with specific temporal epochs for attentional engagement or motor planning. (Aim 2a) Next, I will use projection-specific optogenetic inactivation to test the hypothesis that PFC cell-types that project to visual cortex contribute to attentional processing of visual stimuli, whereas cells projecting to superior colliculus contribute to motor planning. (Aim 2b) Using two-photon microscopy, I will measure the neural signatures of attentional engagement and motor planning in these two cell-types. (Aim 3a) In the independent phase of the award, I will use a disynaptic anatomical tracing strategy to test the hypothesis that the differential function of PFC outputs to the visual cortex or the superior colliculus arises from distinct set of presynaptic inputs received by these projection neuron populations. Using axonal calcium imaging and computational analyses, I will assess the representation of attentional engagement and motor planning in task responses of inputs to the PFC. (Aim 3b) In parallel, I will use optogenetic inactivation to test the functional contribution of inputs to coding of task variables by the two PFC projection neurons. Together, these studies will establish how interactions between long-range inputs and local microcircuits produce neural coding of task-related variables in specific PFC cell-types. My long-term career goal is to understand the neural circuit basis of cognitive function in mice using cutting-edge techniques for optical physiology. To facilitate this goal, I have received training in a variety of techniques including cellular neurophysiology, functional two-photon microscopy, and viral-based circuit tracing. During the mentored phase of this award, I received additional training in behavioral task design, projection-specific optogenetic manipulations, and computational methods for data analysis. This has equipped me with the tools necessary to probe the neural underpinnings of cognitive functions and launch my independent research career.

Dysregulation of attention and motor planning is implicated in various human disorders, including attention deficit hypersensitivity disorder (ADHD), dyspraxia, and apraxia caused by neurological damage. In this application, we will study cell type-specific PFC circuits that contribute to attention and motor planning. A thorough understanding of neural mechanisms underlying these cognitive abilities may clarify what goes awry during disease states and may help identify novel targets for therapeutic interventions for these ailments.