Neuromodulatory GPCRs implement boolean logic gates

Neuromodulators act on a large family of G protein-coupled receptors (GPCRs) that, despite great diversity, are all coupled to one of three G proteins to initiate intracellular signaling cascades. We hypothesize that this “fan-in” architecture between diverse GPCRs and redundant second messengers allows neurons to implement boolean logic gates via GPCR interactions, such that neurons can condition the cellular effects of neuromodulation on the combined activity of multiple neuromodulators. In this proposal, we will measure and manipulate the dynamics of multiple neuromodulators in the striatum and frontal cortex while also monitoring downstream intracellular signals such as cAMP, to identify the logic of neuromodulatory interactions in different genetic and projection-specific cell types. We will leverage our lab’s unique behavioral approach, which includes high-throughput behavioral training of rats performing a sophisticated decision-making task and well-validated behavioral models to relate neuromodulatory dynamics and downstream biochemical signaling to precise algorithmic computations for behavior. This ambitious program will pioneer an innovative conceptual framework for neuromodulation and yield novel insights into how multiple neuromodulators interact to support complex cognitive behaviors.