Probing the neural representation of information acquired under the influence of midbrain dopamine transients

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Project Summary Learning associations between environmental stimuli and the reinforcing events they predict is necessary for survival. Animals and humans use these stimuli to learn where to acquire food, how to avoid predators, or where to find a mate. Learning associations between stimuli that do not predict appetitive or aversive events is equally important. While dopamine signaling was previously thought to only contribute to learning when there are changes in the value of a stimulus, recent work has found a role for dopamine neuron firing in forming more complex cognitive representations between neutral stimuli. Modern optogenetic techniques have allowed us to artificially stimulate dopamine neuron activity during a situation in which cues are present but normally “blocked” from producing learning under naturalistic conditions. The learning that results from this stimulation cannot be easily accounted for by reward prediction errors that only contain scalar quantities reflecting the value of future events, which dopamine was thought to be restricted to, and instead suggests dopamine drives the acquisition of associations between sensory events independent of value. While this artificial stimulation produces behavior that appears as if animals had learned normally, it is unknown how close the neural engram acquired under these conditions is to that learned naturally. Thus, the first goal of this proposal is to measure neural responses to stimuli that were learned under naturalistic versus artificially stimulated conditions. Single unit recording has yielded transformative information in the study of attention, visual processing, and learning, among others. While single unit recording unequivocally represents the output of a neuron, more recent tools such as calcium imaging that use genetically encoded calcium indicators that fluoresce in response to intracellular calcium are increasingly being used. Fluorescence is used to “infer” neural activity that may or may not be the same information recorded with a microelectrode. Critically, single-photon calcium signals have never been directly compared to electrophysiological signals in awake, behaving animals. I will subject separate groups of rats to the same behaviors while recording with calcium imaging or microelectrodes. The second goal of this project is to directly compare these two signals. I will assess real-time ensemble activity of the orbitofrontal cortex, a cortical target of the dopamine system that supports various forms of associative learning, during responding to normally versus artificially conditioned stimuli. I will test how closely the neural responses to artificially learned cues correspond to similar cues that have been learned about naturally. I will directly compare electrophysiological and single-photon calcium data. These experiments will pull from my strong background in learning theory and in-vivo calcium imaging I acquired in graduate school. Importantly, I will use this training to enhance my skillset in behavior, programming, and analysis. Findings from this research will uncover new information about the basic mechanisms of associate learning, and they will inform future interpretation of calcium imaging data.