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

Significance Statement

The mammalian olfactory bulb (OB), the first center of synaptic integration in the olfactory systems, receives massive cholinergic inputs from the basal forebrain and dense noradrenergic innervations from the locus coeruleus, both of which have profound effects on odor processing as well as olfactory learning and memory.  However, the effects of acetylcholine (ACh) and norepinephrine (NE) have not been clearly distinguished.  Given the important roles of cholinergic and noradrenergic modulation in the olfactory bulb, achieving clear functional dissociation among the roles of these two modulators is not trivial and is required for a mechanistic and integrated understanding of olfactory information processing in the brain.  Using detailed biophysical simulations of granule cells, the major interneurons in the olfactory bulb, both alone and embedded in a microcircuit with mitral cells (MCs), the principal output neurons of olfactory bulb, we demonstrated computationally for the first time that the effects of ACh and NE on olfactory bulb function are both distinct and functionally complementary to one another.  While ACh increases MC spike synchronization and sharpens MC firing rate representation, NE mainly modulates the neuronal signal-to-noise ratio (S/N) and can regulate cholinergic function.  Co-application of ACh and NE sharpens MC tuning, improves the S/N ratio and enhances spike synchronization among mitral cells.  Our main conclusions are that ACh is particularly important for odor discrimination and sensory information encoding via a spike-timing code, while NE is more important for odor detection.  Therefore, this work is significant in understanding the cholinergic and noradrenergic function in the olfactory bulb and offers important specific and testable hypotheses for future work.

Figure Legend: The effects of acetylcholine (ACh) and norepinephrine (NE) in the olfactory bulb are both distinct and complementary to each other.  ACh modulation increases mitral cell (MC) spike synchronization and sharpens odor representation by suppressing the weakly activated MCs.  By comparison, NE modulation increases the signal-to-noise (S/N) ratio by suppressing MC spontaneous activities.  Simultaneous activation of ACh and NE leads to highly synchronized MCs, large S/N ratio and highly tuned MC responses with little overlap between different odors.

 Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells. Global Medical Discovery

About the author

Dr. Guoshi Li is currently a postdoctoral research associate in the Department of Psychiatry at University of North Carolina at Chapel Hill.  His primary focus is to perform cutting edge computational neuroscience research.  He is currently working on two research projects: (1) Developing biophysically realistic models of the thalamocortical network to understand the cellular and circuit mechanisms underlying distinct states of oscillatory activities and how brain stimulation impacts the thalamocortical network dynamics; and (2) Extending an existing olfactory bulb network model (Li and Cleland, 2013) he developed previously to examine the dynamical mechanisms of external tufted cells in olfactory information processing.  His research in olfaction is funded by a NIH/NIDCD R03 grant.

Prior to joining the Frohlich lab at UNC, Dr. Li was a postdoctoral research associate in the Computational Physiology Lab at Cornell University directed by Dr. Thomas Cleland and Dr. Christiane Linster.  His postdoc research at Cornell focused on olfactory information processing in the olfactory bulb with a particular interest in cholinergic and noradrenergic neuromodulation and gamma oscillations.

Dr. Li obtained his PhD in Electrical Engineering from University of Missouri – Columbia in 2009 and MS in Mechanical Engineering from State University of New York at Buffalo in 2003.  His PhD research concentrated on understanding the neural mechanisms of fear learning and extinction using a computational modeling approach.  

About the author

Dr. Christiane Linster is a professor in the Department of Neurobiology and Behavior at Cornell University.  Her research focuses on the neural basis of sensory information processing, using olfaction as a model system. She is primarily interested in the relationship between perceptual qualities, as measured by behavioral experiments, and neural activity patterns, as observed electrophysiologically.  Her present work concerns how the central nervous system neuromodulators acetylcholine and noradrenaline, both of which have been implicated in memory deficits such as those symptomatic of Alzheimer’s disease, influence the representation and storage of olfactory information.  This approach necessitates coordinated behavioral and electrophysiological experiments based on predictive theories.

About the author

Dr. Thomas Cleland is an associate professor in the Department of Psychology at Cornell University.  His research concerns how complex cognitive and perceptual phenomena can arise from, and be regulated by, cellular and neural circuit properties. Primarily using the sense of smell (olfaction), Dr. Cleland investigates how learning, memory, expectation, and like processes shape the transformations performed on sensory inputs by relatively peripheral (i.e., experimentally accessible) cortical circuitry, and how these different transformations in turn influence behavior and subsequent learning.  He and his colleagues triangulate on these questions using a range of techniques including electrophysiology, pharmacology, behavior and behavior genetics, and biophysically constrained computational modeling.  In collaboration with colleagues in the College of Engineering, he also implemented circuit models of olfactory processing in neuromorphic digital chips.

Journal Reference

J Neurophysiol. 2015 Dec;114(6):3177-200.

Li G1, Linster C2, Cleland TA3. 

[expand title=”Show Affiliations”]
  1. Department of Psychology, Cornell University, Ithaca, New York; [email protected].
  2. Department of Neurobiology and Behavior, Cornell University, Ithaca, New York.
  3. Department of Psychology, Cornell University, Ithaca, New York; [/expand]


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 and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. 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 after potentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of after depolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication 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.

Copyright © 2015 the American Physiological Society.

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