A Two-Layer Biophysical Model of Cholinergic Neuromodulation in Olfactory Bulb

Abstract

Cholinergic inputs from the basal forebrain regulate multiple olfactory bulb (OB) functions including odor discrimination, perceptual learning, and short term memory. Previous studies have shown that nicotinic cholinergic receptor activation sharpens mitral cell chemoreceptive fields, likely via intraglomerular circuitry. Muscarinic cholinergic activation is less well understood, though muscarinic receptors are implicated in olfactory learning and in the regulation of synchronized oscillatory dynamics in hippocampus and cortex. To understand the mechanisms underlying cholinergic neuromodulation in OB, we developed a biophysical model of the OB neuronal network including both glomerular layer and external plexiform layer (EPL) computations and incorporating both nicotinic and muscarinic neuromodulatory effects. Our simulations show how nicotinic activation within glomerular circuits sharpens mitral cell chemoreceptive fields, even in the absence of EPL circuitry, but does not facilitate intrinsic oscillations or spike synchronization. In contrast, muscarinic receptor activation increases mitral cell spike synchronization and field oscillatory power by potentiating granule cell excitability and lateral inhibitory interactions within the EPL, but has little effect on mitral cell firing rates and hence will not sharpen olfactory representations under a rate metric. These results are consistent with the theory that EPL interactions regulate the timing, rather than the existence, of mitral cell action potentials, and perform their computations with respect to a spike timing-based metric. This general model suggests that the roles of nicotinic and muscarinic receptors in olfactory bulb are both distinct and complementary to one another, together regulating the effects of ascending cholinergic inputs on olfactory bulb transformations.

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

“…The GC model was adapted from that of Li and Cleland (2013), comprising four compartments (soma, radial dendrite, spine shaft, and spine body) and containing nine active ionic currents plus two ohmic leak currents. Detailed descriptions of compartmental dimensions can be found in Li and Cleland (2013). The values for the specific membrane resistance, membrane capacitance, and cytoplasmic (axial) resistivity were, respectively, R m ϭ 18 K⍀/cm 2 , C m ϭ 2 F/cm 2 , R a ϭ 80 ⍀·cm.…”

“…The reversal potentials for the I H and I CAN currents were E H ϭ Ϫ30 mV (Cadetti and Belluzzi 2001) and E CAN ϭ 10 mV (Inoue and Strowbridge 2008), respectively. Intracellular calcium was regulated by a simple first-order differential equation of the form (Li and Cleland 2013) …”

“…To examine how the modulatory effect of ACh and NE on GCs influences the firing patterns of MCs, a small microcircuit model consisting of 2 MCs and 30 GCs was developed. Importantly, the MCs were included as a metric to assess neuromodulatory effects on GCs; model MCs them- (Li and Cleland 2013) and utilized without modification. Each MC formed reciprocal dendrodendritic synapses with all GCs.…”

“…Muscarinic receptor activation increases the excitability of GCs by transforming a net afterhyperpolarization (AHP) following each spike into an afterdepolarization (ADP) (Pressler et al 2007;Smith and Araneda 2010). This ADP extends the period of activation of the GC, altering the balance of excitation and inhibition in the deeper bulbar layers and constraining MC action potential (AP) timing (Li and Cleland 2013;Pressler et al 2007). In concert, nicotinic and muscarinic cholinergic inputs depolarize MCs while enhancing both periglomerular inhibition of MC primary dendrites and GC inhibition of MC secondary dendrites (D'Souza and Vijayaraghavan 2012).…”

“…In concert, nicotinic and muscarinic cholinergic inputs depolarize MCs while enhancing both periglomerular inhibition of MC primary dendrites and GC inhibition of MC secondary dendrites (D'Souza and Vijayaraghavan 2012). The net effect of this cholinergic modulation improves the temporal precision of MC APs and increases the specificity of MC odor responses (de Almeida et al 2013;Li and Cleland 2013;Mandairon et al 2006).…”