Chandramouli Chandrasekaran, Ph.D. - US grants

? DESCRIPTION (provided by applicant): 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.

Abstract: The objective of the proposed research is to understand the diverse lamina-specific neurons, and connections between the dorsolateral prefrontal cortex (DLPFC) and the rostral aspect of the dorsal premotor cortex (PMdr) during decision-making. Decision-making refers to our ability to choose and perform appropriate actions based on sensory cues and context to achieve behavioral goals. Pressing the brakes to stop the car in response to a red light or choosing what dress to wear are common decisions that we make in our everyday life. Disrupted activity in brain areas such as the DLPFC and PMdr contribute to the impairments in decision-making observed in mental illness. Our past work and other research has provided some insight into the involvement of DLPFC and PMdr in decision-making and that these areas are strongly interconnected. However, we currently do not understand 1) the relationship between biophysical properties and morphological structure, and in vivo decision-related activity of neurons in different layers of these brain areas, and 2) whether the connections between DLPFC and PMdr are feedforward, feedback or lateral (both feedforward and feedback). We address these open questions by using a multimodal approach that combines in vivo neurophysiology in DLPFC and PMdr of behaving monkeys, decoding and granger causality analysis, optical stimulation of DLPFC inputs to PMdr, tract tracing experiments and in vitro single neuron electrophysiology and morphometry in slices from the same subjects. Our first aim uses laminar multi-contact electrodes to investigate neuronal responses across layers of PMdr, and DLPFC while monkeys perform a novel decision-making task that separates perceptual decisions from action selection. We will investigate if in vivo differences are related to differences in biophysical and morphological properties of these neurons with in vitro whole-cell patch-clamp recordings of lamina-specific neurons in PMdr slices. In Aim 2, we examine the granger causality between the local field potentials recorded simultaneously in DLPFC and PMdr to understand whether DLPFC sends a feedforward driving input or a modulating feedback input. We combine these in vivo experiments with anatomical tracing experiments in DLPFC to understand the bidirectional laminar pattern of DLPFC and PMdr connections. In Aim 3, we will inject an opsin in DLPFC and stimulate the anterograde fibers in PMdr in vivo to causally investigate whether the pattern of activity induced in PMdr by stimulation of DLPFC is consistent with feedforward, feedback, or lateral connections. To obtain a more detailed understanding of the pattern of inputs from DLPFC to PMdr, we will investigate in vitro synaptic responses of these PMdr neurons in layers 3 and 5 to optical stimulation of afferent DLPFC fibers and localize the morphological compartments of PMdr neurons to which DLPFC afferent fibers provide inputs. Impact: This project will elucidate the in vivo and in vitro laminar dynamics within and interactions between two critical, clinically relevant brain areas. Such data is a prerequisite for future development of circuit- level therapeutics for mental illness and brain machine interfaces for recovery following brain injury.