Generative Biophysical Modeling of Dynamical Networks in the Olfactory System

  • Guoshi Li
  • Thomas A. Cleland
Part of the Methods in Molecular Biology book series (MIMB, volume 1820)


Generative models are computational models designed to generate appropriate values for all of their embedded variables, thereby simulating the response properties of a complex system based on the coordinated interactions of a multitude of physical mechanisms. In systems neuroscience, generative models are generally biophysically based compartmental models of neurons and networks that are explicitly multiscale, being constrained by experimental data at multiple levels of organization from cellular membrane properties to large-scale network dynamics. As such, they are able to explain the origins of emergent properties in complex systems, and serve as tests of sufficiency and as quantitative instantiations of working hypotheses that may be too complex to simply intuit. Moreover, when adequately constrained, generative biophysical models are able to predict novel experimental outcomes, and consequently are powerful tools for experimental design. We here outline a general strategy for the iterative design and implementation of generative, multiscale biophysical models of neural systems. We illustrate this process using our ongoing, iteratively developing model of the mammalian olfactory bulb. Because the olfactory bulb exhibits diverse and interesting properties at multiple scales of organization, it is an attractive system in which to illustrate the value of generative modeling across scales.

Key words

Generative model Compartmental model Olfactory bulb Subthreshold oscillations Network Gamma oscillations 



NIDCD grants R03 DC013872 to G.L., R01 DC014701 and R01 DC014367 to T.A.C.


  1. 1.
    Chen WR, Shen GY, Shepherd GM, Hines ML, Midtgaard J (2002) Multiple modes of action potential initiation and propagation in mitral cell primary dendrite. J Neurophysiol 88:2755–2764CrossRefPubMedGoogle Scholar
  2. 2.
    Pinching AJ, Powell TP (1971) The neuropil of the glomeruli of the olfactory bulb. J Cell Sci 9:347–377PubMedGoogle Scholar
  3. 3.
    Shepherd GM, Greer CA (1998) Olfactory bulb. In: Shepherd GM (ed) The synaptic organization of the brain, 4th edn. Oxford University Press, New YorkGoogle Scholar
  4. 4.
    Skinner FK (2013) Moving beyond type I and type II neuron types. F1000Res 2:19PubMedPubMedCentralGoogle Scholar
  5. 5.
    Colgin LL (2016) Rhythms of the hippocampal network. Nat Rev Neurosci 17:239–249CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nagayama S, Homma R, Imamura F (2014) Neuronal organization of olfactory bulb circuits. Front Neural Circuits 8:98CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Soucy ER, Albeanu DF, Fantana AL, Murthy VN, Meister M (2009) Precision and diversity in an odor map on the olfactory bulb. Nat Neurosci 12:210–220CrossRefPubMedGoogle Scholar
  8. 8.
    Cleland TA (2014) Construction of odor representations by olfactory bulb microcircuits. Prog Brain Res 208:177–203CrossRefPubMedGoogle Scholar
  9. 9.
    Cleland TA, Sethupathy P (2006) Non-topographical contrast enhancement in the olfactory bulb. BMC Neurosci 7:7CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mandairon N, Ferretti CJ, Stack CM, Rubin DB, Cleland TA, Linster C (2006) Cholinergic modulation in the olfactory bulb influences spontaneous olfactory discrimination in adult rats. Eur J Neurosci 24:3234–3244CrossRefPubMedGoogle Scholar
  11. 11.
    Cleland TA, Chen S-YT, Hozer KW, Ukatu HN, Wong KJ, Zheng F (2012) Sequential mechanisms underlying concentration invariance in biological olfaction. Front Neuroeng 4:21CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Banerjee A, Marbach F, Anselmi F, Koh MS, Davis MB, Garcia da Silva P, Delevich K, Oyibo HK, Gupta P, Li B, Albeanu DF (2015) An interglomerular circuit gates glomerular output and implements gain control in the mouse olfactory bulb. Neuron 87:193–207CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Igarashi KM, Ieki N, An M, Yamaguchi Y, Nagayama S, Kobayakawa K, Kobayakawa R, Tanifuji M, Sakano H, Chen WR, Mori K (2012) Parallel mitral and tufted cell pathways route distinct odor information to different targets in the olfactory cortex. J Neurosci 32:7970–7985CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fantana AL, Soucy ER, Meister M (2008) Rat olfactory bulb mitral cells receive sparse glomerular inputs. Neuron 59:802–814CrossRefPubMedGoogle Scholar
  15. 15.
    Lepousez G, Nissant A, Bryant AK, Gheusi G, Greer CA, Lledo PM (2014) Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons. Proc Natl Acad Sci U S A 111:13984–13989CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mandairon N, Linster C (2009) Odor perception and olfactory bulb plasticity in adult mammals. J Neurophysiol 101:2204–2209CrossRefPubMedGoogle Scholar
  17. 17.
    Pressler RT, Inoue T, Strowbridge BW (2007) Muscarinic receptor activation modulates granule cell excitability and potentiates inhibition onto mitral cells in the rat olfactory bulb. J Neurosci 27:10969–10981CrossRefPubMedGoogle Scholar
  18. 18.
    Inoue T, Strowbridge BW (2008) Transient activity induces a long-lasting increase in the excitability of olfactory bulb interneurons. J Neurophysiol 99:187–199CrossRefPubMedGoogle Scholar
  19. 19.
    Li G, Cleland TA (2013) A two-layer biophysical model of cholinergic neuromodulation in olfactory bulb. J Neurosci 33:3037–3058CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rall W, Shepherd GM (1968) Theoretical reconstruction of field potentials and dendrodendritic synaptic interactions in olfactory bulb. J Neurophysiol 31:884–915CrossRefPubMedGoogle Scholar
  21. 21.
    Lagier S, Carleton A, Lledo P-M (2004) Interplay between local GABAergic interneurons and relay neurons generates gamma oscillations in the rat olfactory bulb. J Neurosci 24:4382–4392CrossRefPubMedGoogle Scholar
  22. 22.
    Neville KR, Haberly LB (2003) Beta and gamma oscillations in the olfactory system of the urethane-anesthetized rat. J Neurophysiol 90:3921–3930CrossRefPubMedGoogle Scholar
  23. 23.
    Schoppa NE (2006) Synchronization of olfactory bulb mitral cells by precisely timed inhibitory inputs. Neuron 49:271–283CrossRefPubMedGoogle Scholar
  24. 24.
    Schoppa NE (2006) AMPA/kainate receptors drive rapid output and precise synchrony in olfactory bulb granule cells. J Neurosci 26:12996–13006CrossRefPubMedGoogle Scholar
  25. 25.
    Desmaisons D, Vincent JD, Lledo PM (1999) Control of action potential timing by intrinsic subthreshold oscillations in olfactory bulb output neurons. J Neurosci 19:10727–10737CrossRefPubMedGoogle Scholar
  26. 26.
    Li G, Cleland TA (2017) A coupled-oscillator model of olfactory bulb gamma oscillations. PLoS Comput Biol 13(11):e1005760CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    David F, Courtiol E, Buonviso N, Fourcaud-Trocmé N (2015) Competing mechanisms of gamma and beta oscillations in the olfactory bulb based on multimodal inhibition of mitral cells over a respiratory cycle. eNeuro 2.
  28. 28.
    Osinski BL, Kay LM (2016) Granule cell excitability mediates gamma and beta oscillations in a model of the dendrodendritic microcircuit. J Neurophysiol 116:522–539CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hayar A, Karnup S, Shipley MT, Ennis M (2004) Olfactory bulb glomeruli: external tufted cells intrinsically burst at theta frequency and are entrained by patterned olfactory input. J Neurosci 24:1190–1199CrossRefPubMedGoogle Scholar
  30. 30.
    Hayar A, Karnup S, Ennis M, Shipley MT (2004) External tufted cells: a major excitatory element that coordinates glomerular activity. J Neurosci 24:6676–6685CrossRefPubMedGoogle Scholar
  31. 31.
    Najac M, De Saint Jan D, Reguero L, Grandes P, Charpak S (2011) Monosynaptic and polysynaptic feed-forward inputs to mitral cells from olfactory sensory neurons. J Neurosci 31:8722–8729CrossRefPubMedGoogle Scholar
  32. 32.
    Gire DH, Franks KM, Zak JD, Tanaka KF, Whitesell JD, Mulligan AA, Hen R, Schoppa NE (2012) Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path. J Neurosci 32:2964–2975CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Marr D, Poggio T (1977) From understanding computation to understanding neural circuitry. Neurosciences Res Prog Bull 15:470–488Google Scholar
  34. 34.
    Harrison TA, Scott JW (1986) Olfactory bulb responses to odor stimulation: analysis of response pattern and intensity relationships. J Neurophysiol 56:1571–1589CrossRefPubMedGoogle Scholar
  35. 35.
    Wellis DP, Scott JW, Harrison TA (1989) Discrimination among odorants by single neurons of the rat olfactory bulb. J Neurophysiol 61:1161–1177CrossRefPubMedGoogle Scholar
  36. 36.
    Meredith M (1986) Patterned response to odor in mammalian olfactory bulb: the influence of intensity. J Neurophysiol 56:572–597CrossRefPubMedGoogle Scholar
  37. 37.
    Aungst JL, Heyward PM, Puche AC, Karnup SV, Hayar A, Szabo G, Shipley MT (2003) Centre-surround inhibition among olfactory bulb glomeruli. Nature 426:623–629CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cleland TA, Johnson BA, Leon M, Linster C (2007) Relational representation in the olfactory system. Proc Natl Acad Sci U S A 104:1953–1958CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Koch C (1998) Biophysics of computation: information processing in single neurons. Oxford University Press, New YorkGoogle Scholar
  40. 40.
    Koch C, Segev I (eds) (1999) Methods in neuronal modeling: from ions to networks. Bradford, Cambridge, MAGoogle Scholar
  41. 41.
    Gerstner W, Kistler WM, Naud R, Paninski L (2014) Neuronal dynamics: from single neurons to networks and models of cognition. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  42. 42.
    Rubin DB, Cleland TA (2006) Dynamical mechanisms of odor processing in olfactory bulb mitral cells. J Neurophysiol 96:555–568CrossRefPubMedGoogle Scholar
  43. 43.
    Sethupathy P, Rubin DB, Li G, Cleland TA (2013) A model of electrophysiological heterogeneity in periglomerular cells. Front Comput Neurosci 7:49CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rall W (1959) Branching dendritic trees and motoneuron membrane resistivity. Exp Neurol 1:491–527CrossRefPubMedGoogle Scholar
  45. 45.
    Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117:500–544CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Peace ST, Johnson BC, Li G, Kaiser M, Fukunaga I, Schaefer AT, Molnar AC, Cleland TA (2017) Coherent olfactory bulb gamma oscillations arise from coupling independent columnar oscillators. BioRxiv.
  47. 47.
    Shen GY, Chen WR, Midtgaard J, Shepherd GM, Hines ML (1999) Computational analysis of action potential initiation in mitral cell soma and dendrites based on dual patch recordings. J Neurophysiol 82:3006–3020CrossRefPubMedGoogle Scholar
  48. 48.
    Chen WR, Shepherd GM (1997) Membrane and synaptic properties of mitral cells in slices of rat olfactory bulb. Brain Res 745:189–196CrossRefPubMedGoogle Scholar
  49. 49.
    Xiong W, Chen WR (2002) Dynamic gating of spike propagation in the mitral cell lateral dendrites. Neuron 34:115–126CrossRefPubMedGoogle Scholar
  50. 50.
    Bhalla US, Bower JM (1993) Exploring parameter space in detailed single neuron models: simulations of the mitral and granule cells of the olfactory bulb. J Neurophysiol 69:1948–1965CrossRefPubMedGoogle Scholar
  51. 51.
    Davison AP, Feng J, Brown D (2000) A reduced compartmental model of the mitral cell for use in network models of the olfactory bulb. Brain Res Bull 51:393–399CrossRefPubMedGoogle Scholar
  52. 52.
    Bathellier B, Lagier S, Faure P, Lledo P-M (2006) Circuit properties generating gamma oscillations in a network model of the olfactory bulb. J Neurophysiol 95:2678–2691CrossRefPubMedGoogle Scholar
  53. 53.
    Brea JN, Kay LM, Kopell NJ (2009) Biophysical model for gamma rhythms in the olfactory bulb via subthreshold oscillations. Proc Natl Acad Sci U S A 106:21954–21959CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Shao Z, Puche AC, Kiyokage E, Szabo G, Shipley MT (2009) Two GABAergic intraglomerular circuits differentially regulate tonic and phasic presynaptic inhibition of olfactory nerve terminals. J Neurophysiol 101:1988–2001CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    McQuiston AR, Katz LC (2001) Electrophysiology of interneurons in the glomerular layer of the rat olfactory bulb. J Neurophysiol 86:1899–1907CrossRefPubMedGoogle Scholar
  56. 56.
    Kosaka K, Kosaka T (2005) Synaptic organization of the glomerulus in the main olfactory bulb: compartments of the glomerulus and heterogeneity of the periglomerular cells. Anat Sci Int 80:80–90CrossRefPubMedGoogle Scholar
  57. 57.
    Kosaka K, Kosaka T (2007) Chemical properties of type 1 and type 2 periglomerular cells in the mouse olfactory bulb are different from those in the rat olfactory bulb. Brain Res 1167:42–55CrossRefPubMedGoogle Scholar
  58. 58.
    Kiyokage E, Pan YZ, Shao Z, Kobayashi K, Szabo G, Yanagawa Y, Obata K, Okano H, Toida K, Puche AC, Shipley MT (2010) Molecular identity of periglomerular and short axon cells. J Neurosci 30:1185–1196CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Isaacson JS, Strowbridge BW (1998) Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20:749–761CrossRefPubMedGoogle Scholar
  60. 60.
    Cang J, Isaacson JS (2003) In vivo whole-cell recording of odor-evoked synaptic transmission in the rat olfactory bulb. J Neurosci 23:4108–4116CrossRefPubMedGoogle Scholar
  61. 61.
    Pinato G, Midtgaard J (2003) Regulation of granule cell excitability by a low-threshold calcium spike in turtle olfactory bulb. J Neurophysiol 90:3341–3351CrossRefPubMedGoogle Scholar
  62. 62.
    Balu R, Larimer P, Strowbridge BW (2004) Phasic stimuli evoke precisely timed spikes in intermittently discharging mitral cells. J Neurophysiol 92:743–753CrossRefPubMedGoogle Scholar
  63. 63.
    Cadetti L, Belluzzi O (2001) Hyperpolarisation-activated current in glomerular cells of the rat olfactory bulb. Neuroreport 12:3117–3120CrossRefPubMedGoogle Scholar
  64. 64.
    Le Jeune H, Aubert I, Jourdan F, Quirion R (1995) Comparative laminar distribution of various autoradiographic cholinergic markers in adult main olfactory bulb. J Chem Neuroanat 9:99–112CrossRefPubMedGoogle Scholar
  65. 65.
    Schoppa NE, Westbrook GL (1999) Regulation of synaptic timing in the olfactory bulb by an A-type potassium current. Nat Neurosci 2:1106–1113CrossRefPubMedGoogle Scholar
  66. 66.
    Carnevale NT, Hines ML (2006) The neuron book. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  67. 67.
    Bower JM, Beeman D (2003) The book of GENESIS: exploring realistic neural models with the GEneral NEural SImulation System, Internet edition.
  68. 68.
    Ray S, Bhalla US (2008) PyMOOSE: interoperable scripting in Python for MOOSE. Front Neuroinform 2:6PubMedPubMedCentralGoogle Scholar
  69. 69.
    Vanier MC, Bower JM (1999) A comparative survey of automated parameter-search methods for compartmental neural models. J Comput Neurosci 7:149–171CrossRefPubMedGoogle Scholar
  70. 70.
    Druckmann S, Banitt Y, Gidon A, Schurmann F, Markram H, Segev I (2007) A novel multiple objective optimization framework for constraining conductance-based neuron models by experimental data. Front Neurosci 1:7–18CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Rall W (1967) Distinguishing theoretical synaptic potentials computed for different soma-dendritic distributions of synaptic input. J Neurophysiol 30:1138–1168CrossRefPubMedGoogle Scholar
  72. 72.
    Jack JJB, Noble D, Tsien RW (1975) Electric current flow in excitable cells. Clarendon Oxford, Oxford, UKGoogle Scholar
  73. 73.
    Destexhe A, Mainen ZF, Sejnowski TJ (1994) An efficient method for computing synaptic conductances based on a kinetic model of receptor binding. Neural Comput 6:14–18CrossRefGoogle Scholar
  74. 74.
    Wang XJ, Buzsáki G (1996) Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci 16:6402–6413CrossRefPubMedGoogle Scholar
  75. 75.
    Huang L, Ung K, Garcia I, Quast KB, Cordiner K, Saggau P, Arenkiel BR (2016) Task learning promotes plasticity of interneuron connectivity maps in the olfactory bulb. J Neurosci 36:8856–8871CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Moreno MM, Bath K, Kuczewski N, Sacquet J, Didier A, Mandairon N (2012) Action of the noradrenergic system on adult-born cells is required for olfactory perceptual learning. J Neurosci 32:3748–3758CrossRefPubMedGoogle Scholar
  77. 77.
    Gheusi G, Lledo PM (2014) Adult neurogenesis in the olfactory system shapes odor memory and perception. Prog Brain Res 208:157–175CrossRefPubMedGoogle Scholar
  78. 78.
    Beshel J, Kopell N, Kay LM (2007) Olfactory bulb gamma oscillations are enhanced with task demands. J Neurosci 27:8358–8365CrossRefPubMedGoogle Scholar
  79. 79.
    Doucette W, Restrepo D (2008) Profound context-dependent plasticity of mitral cell responses in olfactory bulb. PLoS Biol 6:e258CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychologyCornell UniversityIthacaUSA
  2. 2.Department of PsychiatryUniversity of North CarolinaChapel HillUSA

Personalised recommendations