Midbrain dopamine neurons display phasic responses to rewards and cues that predict rewards. During associative learning, when a sensory stimulus (such as a light flash or auditory tone) is paired with a reward, with training th sensory stimulus comes to predict the reward. This raises an interesting question. Since an animal receives a vast amount of sensory data at any given moment, what distinguishes the sensory information associated with a reward from other incoming information? One possibility is that neuromodulatory reward signals encoded by dopamine alter the representation of reward-predicting stimuli in sensory cortices (for instance, by preferentially enhancing the gain of neuronal responses elicited by reward-predicting stimuli), so that they can be differentiated from other sensory inputs. The cellular and circuit properties of the primary visual cortex (V1) have been extensively characterized; hence, it is an ideal model system to test the hypothesis that dopaminergic signaling modulates the gain of sensory information.
In Aim 1, channelrhodopsin-2 (ChR2) will be selectively expressed in dopamine neurons of the ventral tegmental area (VTA), which provides dopaminergic projections to the cortex. Fast-scan cyclic voltammetry (FSCV) will be used to establish the laminar profile of light-evoked dopamine release in V1. To test if dopamine signaling modulates the response properties of visually evoked activity, in-vivo single-unit and two-photon targeted cell-attached recordings from specific cell-types will be made. Neuronal responses to visual stimuli consisting of gratings at specific orientations will be recorded. In each animal, a randomly chosen orientation will be conditioned by pairing with optogenetic activation of dopaminergic fibers in V1 or of the ChR2- expressing cell bodies of dopamine neurons in the VTA. This experiment will establish whether pairing sensory input with local (optogenetic stimulation of V1) or global (VTA stimulation) dopaminergic signaling can modify the representation of visual stimuli, and how specific cell-types contribute to this modulation. After establishing the role of dopaminergic signaling in-vivo in Aim 2 mechanistic studies will be performed in-vitro. Different cell-types, especially molecularly-defined subtypes of inhibitory cells, make specific contributions to sensory processing. Hence, dopamine may preferentially recruit specific cell-types to exert its effects. In order to understand the cellular mechanisms of dopamine action, how dopamine impacts the intrinsic and synaptic properties of excitatory and subtypes of inhibitory cells will be determined Together, these studies will test the hypothesis that dopaminergic signals modify the encoding of sensory stimuli in V1 and will provide a solid groundwork for future work to investigate the role of dopamine signaling in the visual cortex during associative learning.

Public Health Relevance

Dysregulation of dopamine signaling is implicated in various disorders, including addiction and Parkinson's disease (PD). PD patients routinely present with visual dysfunction and visual cues associated with drug use can trigger relapse in subjects recovering from addiction; yet, the role of dopamine signaling in the visual cortex is entirely unknown. In this application, we will study the cell-type specific effects of dopamine on sensory processing in the visual cortex in hopes of uncovering novel pharmacological and gene therapy targets for the visual aspects of these ailments.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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Massachusetts Institute of Technology
Other Basic Sciences
Schools of Arts and Sciences
United States
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