The functions of dopamine signaling during sleep in memory

Project Summary Out of all daily experiences, salient ones are likeliest to leave long-lasting memories. A central neuronal population encoding different aspects of salient experiences, including rewarding and aversive stimuli, reward- predictive cues and behavioral choices, is the ventral tegmental area dopamine (VTA-DA) neurons. While the role of VTA-DA neurons in online coding of salience is well-established, whether and how VTA-DA neurons are involved in offline consolidation of these experiences into long-term memory is considerably less understood. In particular, despite pharmacological evidence that dopaminergic activity during sleep is required for memory formation, and physiological evidence that VTA representations of food stimuli can show a form of reactivation, there are still large knowledge gaps regarding the experience dependence of VTA-DA neuronal activity during sleep, the integration of VTA-DA activity with hippocampal (HC)-dependent memory consolidation processes, the causal role of VTA-DA neuronal activity in memory consolidation and the neural circuitry involved. Our overarching hypothesis is that VTA-DA activity during sleep is critically involved in the consolidation of recent salient experiences into long-term memories via reactivation of salient facets of waking experience, bidirectional communication with the HC and modulation of dopamine release in downstream target structures. We will test this hypothesis using optical and electrophysiological recordings of neural activity and closed-loop optogenetic manipulations of specific neural circuits in freely behaving, learning and sleeping mice. Guided by strong preliminary data, we will first test which facets of waking experience are reactivated by VTA-DA neurons during sleep and how and when this reactivation manifests at the population, ensemble and single-cell levels. Next, we will determine the causal relationship between VTA-DA neuronal activity and HC sharp-wave ripples during sleep. Finally, we will determine the memory function of dopamine release at major target regions during sleep, using recording and inactivation paradigms. These experiments will provide fundamental new insight regarding the role of VTA-DA neurons in consolidation of salient experiences. These findings will shed light on the neural mechanisms underlying a key cognitive function, and 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.