In an ever-changing environment, organisms evolved to filter information and focus on stimuli that are associated with relevant outcomes. Even the simplest animals assign valence to otherwise neutral stimuli in order to survive. A positive (rewarding) valence stimulus elicits approach, whereas a negative (aversive) valence stimulus supports avoidance behaviors. Decades of research revealed that some regions of the limbic system encode valence, including the nucleus accumbens (NAc), which is considered a prime candidate to interface valence and behavior. The NAc is mostly composed of GABAergic medium spiny neurons (MSNs), divided into those expressing dopamine receptor D1 and dynorphin, and those expressing D2 and enkephalin. D1 and D2 neurons were assumed to encode opposing valence, but recent data by us and others revealed this model to be overly simplistic. That is - to date, it is still not known how valence is encoded in this region. The main goal of this project is to determine how NAc neurons encode valence. Based on preliminary data, we hypothesize that valence is encoded by distinct patterns of MSN activity. These patterns differentially signal via GABA and opioids (dynorphin, enkephalin), triggering rewarding/aversive behaviors. To test this hypothesis, we will record neuronal activity of rodents performing tasks with opposing valences, in combination with time- and spatially-resolved analysis of opioidergic transmission, using newly-developed opioid fluorescent sensors. This information will then be used to mimic/block patterns of MSN activity and opioid events in order to show causality. This cutting-edge approach will unravel with unparalleled accuracy how NAc encodes valence, the role of endogenous opioids, and how these signals are decoded in the circuit to drive behavior. VALENCE is a frontier opening project that will answer long-standing questions in the field, deepening the knowledge on how the mammalian brain encodes rewarding and aversive events.
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