Noradrenergic neuromodulation is complex, imposing intricate, nonlinear transformations on several aspects of neurons’ response properties and on the computational properties of the circuits in which they are embedded.  This new paper dissects the regulation of whole-cell computational properties in terms of the multiple concerted ion channel mechanisms that are directly affected by noradrenergic neuromodulation.

Li GL, Linster C, Cleland TA (2015)  Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.  Journal of Neurophysiology, preprint available online (doi:10.1152/jn.00324.2015).

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