Unexpected lessons on neuromodulator action from imaging molecular signals
Yao Chen, Ph.D.
Department of Neurobiology
Harvard Medical School
Neuromodulators such as acetylcholine and dopamine have profound effects on neural circuits and behavior. However, how neuromodulator-induced molecular signals influence behavior represents an outstanding gap in our understanding of neuromodulator action. In order to go beyond the identity to the action of molecular signals, we need to know the subcellular and cellular specificity as well as temporal dynamics of neuromodulator-induced molecular signals. One of the major challenges to uncover these features is the lack of methods to dynamically monitor the molecular signals induced by G protein-coupled receptor (GPCR) activation with high spatial resolution. A critical intracellular integrator of GPCRs is protein kinase A (PKA). PKA activity is stimulated by Gαs-coupled and inhibited by Gαi-coupled neuromodulator receptors, and this push-pull relationship can bidirectionally modulate synaptic function as well as transcription. In order to monitor PKA activity in the brain, we modified a PKA activity sensor and developed optical approaches that enable quantitative analysis of endogenous GPCR signaling in brain tissue with two-photon fluorescence lifetime imaging microscopy. Using this reporter, we have found that, contrary to the canonical model of GPCR signaling, endogenous Gαq-coupled neuromodulator receptors elevate phosphorylation by PKA in the mouse hippocampus. I will present this discovery that highlights PKA as a central integrator of three major types of GPCR signals. Furthermore, I will share ongoing work suggesting that the same neuromodulator input (e.g. acetylcholine) can produce different PKA signals depending on the context of cellular physiology and animal experience. Finally, I will outline my future directions that aim to examine the spatial location, temporal dynamics and context dependence of neuromodulator-induced molecular signals, and how these features of molecular signaling contribute to cellular physiology and animal behavior.
host: Stan Froehner