Functional differentiation of cholinergic and noradrenergic modulation 2 in a biophysical model of olfactory bulb granule cells
چکیده
28 Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine 29 (NE), but the effects of these neuromodulators have not been clearly distinguished. We used 30 detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with 31 mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit 32 function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data 33 obtained from slice experiments; specifically, ACh reduced the conductance densities of the 34 potassium M-current IM and the calcium-dependent potassium current IAHP, whereas NE 35 nonmonotonically regulated the conductance density of an ohmic potassium current IKL. We 36 report that the effects of ACh and NE on granule cell physiology are distinct and functionally 37 complementary to one another. ACh strongly regulates granule cell firing rates and 38 afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When 39 combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and 40 persistent firing. In a microcircuit simulation developed to investigate the effects of GC 41 neuromodulation on mitral cell firing properties, ACh increased spike synchronization among 42 mitral cells whereas NE modulated the signal-to-noise ratio. Co-application of ACh and NE 43 both functionally improved the signal-to-noise ratio and enhanced spike synchronization among 44 mitral cells. In summary, our computational results support distinct and complementary roles for 45 ACh and NE in modulating olfactory bulb circuitry, and suggest that NE may play a role in the 46 regulation of cholinergic function. 47