Deciphering the role of VTA dopaminergic signaling in memory consolidation during sleep

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Project Summary/Abstract Of all life experiences, salient ones are the likeliest to be remembered. The storage of experiences into long- term memory is thought to depend on post-learning consolidation processes occurring during sleep. While much is known on how spatial and sensory information is incorporated into memory, the mechanisms through which salient aspects of experiences are linked to other components of a memory are still largely unknown. A central neuronal population implicated in encoding salience is the ventral tegmental area dopamine (VTADA) neurons. VTADA neurons encode, and are necessary for the formation of, both positive and negative valence associations, and are anatomically and functionally connected with brain regions implicated in memory consolidation. Prior research and our preliminary data suggest that VTADA neuronal activity during sleep is experience-dependent, yet whether the activation of VTADA neurons during sleep has a causal role in memory consolidation, the specific components of waking experiences that affect VTADA neuronal activity during sleep and the integration of VTADA neuronal activity with hippocampal-dependent memory consolidation processes are largely unknown. We hypothesize that activity in VTADA neurons during sleep plays a critical role in linking salient aspects of experiences to other aspects of a memory trace. We propose to elucidate the determinants, contents and time-course of experience-dependent activity and reactivation events in VTADA neurons during sleep (Aim 1) and causally interrogate the function of VTADA neuronal activity during sleep in processes of memory consolidation (Aim 2). To achieve these aims, we have developed an innovative approach that combines ensemble-level calcium imaging, electrophysiological recordings, optogenetic manipulations and various learning tasks in freely behaving and sleeping mice. Our findings will provide fundamental new insight regarding the integration of information encoded in multiple brain regions into coherent multifaceted memories during sleep. Moreover, our research could promote the development of new therapeutic approaches for various psychiatric disorders that are associated with a combination of dysregulated dopamine signaling and impaired memory. The training plan we have developed, which draws on the skills and expertise of my various sponsors, as well as the strengths of the research environment at the University of Michigan, will provide me with comprehensive and rigorous training as I develop into an independent researcher.