funded by ANR/NSF-NIH Collaborative Research in Computational Neuroscience 2015-2019
The brain is the most complex organ in the body. Its billions of neurons make specific connections according to their genetic programs and neuronal activities. Precise yet plastic neuronal connections are required to decode and compute complex external signals coming from the environment and turn complex stimuli into appropriate behavioral or physiological responses. Among the external signals, odors are arguably the most complex. Tens of thousands of diverse volatile chemicals are detected by olfactory receptors (ORs), the largest family of G-protein coupled receptors (GPCRs), with each OR individually expressed in olfactory receptor neurons (ORNs). Combinatorial OR activation by an odorous agonist results in depolarization of each corresponding ORN, whose activity pattern is decoded in the brain, forming an olfactory percept. In addition to exogenous agonist stimulation, agonist-independent OR basal activity can also trigger neuronal activity.
In this project, we will uncover both agonist-dependent and agonist-independent molecular strategies of OR activation by modeling the atomic-level dynamic properties of ORs. Experimentally elucidating a structural change in an OR at the molecular level is currently not possible. No experimentally derived structure from nuclear magnetic resonance (NMR) or X-ray diffraction studies exists for ORs. Our collaborative team is in a good position to gain insight into how both agonist-dependent and agonist-independent basal activity are determined through a combination of in silico molecular modeling, in vitro functional assays, and ex-vivo electrophysiology.