CELL-TYPE SPECIFIC NEUROMODULATORY DYNAMICS UNDERLYING FLEXIBLE BEHAVIOR

At any moment, distinct combinations of neuromodulators are released throughout the brain, critically shaping circuit dynamics and behavior. These signals act in a cell-type–specific manner, differentially modulating neurons and astrocytes, through distinct signaling mechanisms that operate across diverse spatial and temporal scales. How such parallel neuromodulatory pathways are coordinated in vivo, and how their cell-type–specific effects are integrated to regulate complex behavior, remains largely unknown.
Here, we used multiplexed fiber photometry to simultaneously monitor neuromodulator release and cell-type–specific population activity in the mouse prefrontal cortex (PFC), a central hub for flexible and adaptive behavior. We recorded neuronal and astrocytic calcium activity alongside local neuromodulator dynamics using distinct G-protein-coupled Receptor Activation-Based (GRAB) sensors for the main neuromodulatory systems, including serotonin, norepinephrine, acetylcholine, and dopamine while freely behaving mice performed a cognitively-demanding automated rule-switching task.
Using this data, we characterized the dynamics of prefrontal neuromodulation and its relation to neuronal and astrocytic population activity at multiple timescales, ranging from event-locked responses to latent state modeling. We show that distinct neuromodulatory systems exhibit dissociable relationships with neuronal and astrocytic activity across behaviorally relevant events, contingency changes, and transitions between cognitive states.
Together, these findings delineate how major neuromodulatory inputs differentially relate to neuronal and astrocytic substrates to support adaptive behavior, offering a unified mapping of neuromodulator dynamics and cell-type–specific population activity during complex behavior.