Abstract
In neural integrators, transient inputs are accumulated into persistent firing rates that are a neural correlate of short-term memory. Integrators often contain two opposing cell populations that increase and decrease sustained firing as a stored parameter value rises. A leading hypothesis for the mechanism of persistence is positive feedback through mutual inhibition between these opposing populations. We tested predictions of this hypothesis in the goldfish oculomotor velocity-to-position integrator by measuring the eye position and firing rates of one population, while pharmacologically silencing the opposing one. In complementary experiments, we measured responses in a partially silenced single population. Contrary to predictions, induced drifts in neural firing were limited to half of the oculomotor range. We built network models with synaptic-input thresholds to demonstrate a new hypothesis suggested by these data: mutual inhibition between the populations does not provide positive feedback in support of integration, but rather coordinates persistent activity intrinsic to each population.
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02 May 2007
panels c and d
Notes
*NOTE: In the version of this article initially published, the labels for the x-axes in figure 8, panels c and d are incorrect. The correct labels should be “Rate, left”. This error has been corrected in the HTML and PDF versions of the article.
References
Taube, J.S. & Bassett, J.P. Persistent neural activity in head direction cells. Cereb. Cortex 13, 1162–1172 (2003).
Mazurek, M.E., Roitman, J.D., Ditterich, J. & Shadlen, M.N. A role for neural integrators in perceptual decision making. Cereb. Cortex 13, 1257–1269 (2003).
Major, G. & Tank, D. Persistent neural activity: prevalence and mechanisms. Curr. Opin. Neurobiol. 14, 675–684 (2004).
Lopez-Barneo, J., Darlot, C., Berthoz, A. & Baker, R. Neuronal activity in prepositus nucleus correlated with eye movement in the alert cat. J. Neurophysiol. 47, 329–352 (1982).
McFarland, J.L. & Fuchs, A.F. Discharge patterns in nucleus prepositus hypoglossi and adjacent medial vestibular nucleus during horizontal eye movement in behaving macaques. J. Neurophysiol. 68, 319–332 (1992).
Aksay, E., Baker, R., Seung, H.S. & Tank, D.W. Anatomy and discharge properties of pre-motor neurons in the goldfish medulla that have eye position signals during fixations. J. Neurophysiol. 84, 1035–1049 (2000).
Romo, R., Brody, C.D., Hernandez, A. & Lemus, L. Neuronal correlates of parametric working memory in the prefrontal cortex. Nature 399, 470–473 (1999).
Miller, P., Brody, C.D., Romo, R. & Wang, X.J. A recurrent network model of somatosensory parametric working memory in the prefrontal cortex. Cereb. Cortex 13, 1208–1218 (2003).
Shadlen, M.N. & Newsome, W.T. Neural basis of a perceptual decision in the parietal cortex (area LIP) of the rhesus monkey. J. Neurophysiol. 86, 1916–1936 (2001).
Huk, A.C. & Shadlen, M.N. Neural activity in macaque parietal cortex reflects temporal integration of visual motion signals during perceptual decision making. J. Neurosci. 25, 10420–10436 (2005).
McCrea, R.A. & Horn, A.K. Nucleus prepositus. Prog. Brain Res. 151, 205–230 (2005).
Escudero, M., de La Cruz, R.R. & Delgado-Garcia, J.M. A physiological study of vestibular and prepositus hypoglossi neurones projecting to the abducens nucleus in the alert cat. J. Physiol. (Lond.) 458, 539–560 (1992).
Aksay, E., Baker, R., Seung, H.S. & Tank, D.W. Correlated discharge among cell pairs within the oculomotor horizontal velocity-to-position integrator. J. Neurosci. 23, 10852–10858 (2003).
Machens, C.K., Romo, R. & Brody, C.D. Flexible control of mutual inhibition: a neural model of two-interval discrimination. Science 307, 1121–1124 (2005).
Hanks, T.D., Ditterich, J. & Shadlen, M.N. Microstimulation of macaque area LIP affects decision-making in a motion discrimination task. Nat. Neurosci. 9, 682–689 (2006).
Cannon, S.C., Robinson, D.A. & Shamma, S. A proposed neural network for the integrator of the oculomotor system. Biol. Cybern. 49, 127–136 (1983).
Galiana, H.L. & Outerbridge, J.S. A bilateral model for central neural pathways in vestibuloocular reflex. J. Neurophysiol. 51, 210–241 (1984).
Arnold, D.B. & Robinson, D.A. The oculomotor integrator: testing of a neural network model. Exp. Brain Res. 113, 57–74 (1997).
Usher, M. & McClelland, J.L. The time course of perceptual choice: the leaky, competing accumulator model. Psychol. Rev. 108, 550–592 (2001).
Sklavos, S.G. & Moschovakis, A.K. Neural network simulations of the primate oculomotor system IV. A distributed bilateral stochastic model of the neural integrator of the vertical saccadic system. Biol. Cybern. 86, 97–109 (2002).
Brown, E. et al. Simple neural networks that optimize decisions. Int. J. Bifurc. Chaos 15, 803–826 (2005).
Aksay, E., Gamkrelidze, G., Seung, H.S., Baker, R. & Tank, D.W. In vivo intracellular recording and perturbation of persistent activity in a neural integrator. Nat. Neurosci. 4, 184–193 (2001).
Goldman-Rakic, P.S. Cellular basis of working memory. Neuron 14, 477–485 (1995).
Pesaran, B., Pezaris, J.S., Sahani, M., Mitra, P.P. & Andersen, R.A. Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat. Neurosci. 5, 805–811 (2002).
Seung, H.S., Lee, D.D., Reis, B.Y. & Tank, D.W. Stability of the memory of eye position in a recurrent network of conductance-based model neurons. Neuron 26, 259–271 (2000).
Egorov, A.V., Hamam, B.N., Fransen, E., Hasselmo, M.E. & Alonso, A.A. Graded persistent activity in entorhinal cortex neurons. Nature 420, 173–178 (2002).
Navarro-Lopez Jde, D. et al. A cholinergic synaptically triggered event participates in the generation of persistent activity necessary for eye fixation. J. Neurosci. 24, 5109–5118 (2004).
Kiehn, O. & Eken, T. Functional role of plateau potentials in vertebrate motor neurons. Curr. Opin. Neurobiol. 8, 746–752 (1998).
Idoux, E. et al. Oscillatory and intrinsic membrane properties of guinea pig nucleus prepositus hypoglossi neurons in vitro. J. Neurophysiol. 96, 175–196 (2006).
Camperi, M. & Wang, X.J. A model of visuospatial working memory in prefrontal cortex: recurrent network and cellular bistability. J. Comput. Neurosci. 5, 383–405 (1998).
Koulakov, A.A., Raghavachari, S., Kepecs, A. & Lisman, J.E. Model for a robust neural integrator. Nat. Neurosci. 5, 775–782 (2002).
Goldman, M.S., Levine, J.H., Major, G., Tank, D.W. & Seung, H.S. Dendritic hysteresis adds robustness to persistent neural activity in a model neural integrator. Cereb. Cortex 13, 1185–1195 (2003).
Loewenstein, Y. & Sompolinsky, H. Temporal integration by calcium dynamics in a model neuron. Nat. Neurosci. 6, 961–967 (2003).
Fransen, E., Tahvildari, B., Egorov, A.V., Hasselmo, M.E. & Alonso, A.A. Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons. Neuron 49, 735–746 (2006).
Fall, C.P. & Rinzel, J. An intracellular Ca2+ subsystem as a biologically plausible source of intrinsic conditional bistability in a network model of working memory. J. Comput. Neurosci. 20, 97–107 (2006).
Pastor, A.M., de La Cruz, R.R. & Baker, R. Eye position and eye velocity integrators reside in separate brainstem nuclei. Proc. Natl. Acad. Sci. USA 91, 807–811 (1994).
Seung, H.S. Amplification, Attenuation, and Integration. in The Handbook of Brain Theory and Neural Networks 2nd edn. (ed. Arbib, M. A.) 94–97 (MIT Press, Cambridge, 2003).
Cheron, G., Godaux, E., Laune, J.M. & Vanderkelen, B. Lesions in the cat prepositus complex: effects on the vestibulo-ocular reflex and saccades. J. Physiol. (Lond.) 372, 75–94 (1986).
Cannon, S.C. & Robinson, D.A. Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey. J. Neurophysiol. 57, 1383–1409 (1987).
Crawford, J.D. & Vilis, T. Modularity and parallel processing in the oculomotor integrator. Exp. Brain Res. 96, 443–456 (1993).
Mettens, P., Godaux, E., Cheron, G. & Galiana, H.L. Effect of muscimol microinjections into the prepositus hypoglossi and the medial vestibular nuclei on cat eye movements. J. Neurophysiol. 72, 785–802 (1994).
Kaneko, C.R.S. Eye movement deficits after ibotenic acid lesions of the nucleus prepositus hypoglossi in monkeys. I. Saccades and fixation. J. Neurophysiol. 78, 1753–1768 (1997).
Arnold, D.B., Robinson, D.A. & Leigh, R.J. Nystagmus induced by pharmacological inactivation of the brainstem ocular motor integrator in monkey. Vision Res. 39, 4286–4295 (1999).
Major, G., Baker, R., Aksay, E., Seung, H.S. & Tank, D.W. Plasticity and tuning of the time course of analog persistent firing in a neural integrator. Proc. Natl. Acad. Sci. USA 101, 7745–7750 (2004).
Aksay, E. et al. History dependence of rate covariation between neurons during persistent activity in an oculomotor integrator. Cereb. Cortex 13, 1173–1184 (2003).
Wilson, R.I. & Nicoll, R.A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).
Diana, M.A. & Marty, A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br. J. Pharmacol. 142, 9–19 (2004).
Nicoll, R.A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).
Grillner, S. The motor infrastructure: from ion channels to neuronal networks. Nat. Rev. Neurosci. 4, 573–586 (2003).
Kiehn, O. Locomotor circuits in the mammalian spinal cord. Annu. Rev. Neurosci. 29, 279–306 (2006).
Acknowledgements
We thank H.S. Seung, C. Brody and J. Raymond for helpful discussions and critique. The experimental phase of this work was supported by Bell Laboratories. E.A. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. M.S.G. holds a Brachmann–Hoffman Fellowship from Wellesley College. All authors received support from the US National Institutes of Health.
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D.W.T. supervised the experimental component of the project. E.A., R.B. and D.W.T. conceived the experiments. E.A. and D.W.T. developed the instrumentation. E.A. collected and analyzed the data with assistance by B.M. M.S.G. supervised the theoretical component of the project. E.A., I.O., R.B., M.S.G. and D.W.T. provide data interpretation and coordination between experiments and modeling. I.O. and M.S.G. developed the mathematical models and performed the simulations. E.A., M.S.G. and D.W.T. wrote the paper.
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Supplementary information
Supplementary Fig. 1
Model tuning curves defined by experimentally measured rate versus position relationships. (PDF 200 kb)
Supplementary Fig. 2
Method for functional dissection of a circuit. (PDF 1071 kb)
Supplementary Table 1
Change in position drift for each complete left inactivation. (PDF 123 kb)
Supplementary Table 2
Change in rate drift for each complete left inactivation. (PDF 92 kb)
Supplementary Table 3
Change in rate drift for each caudal right inactivation. (PDF 89 kb)
Supplementary Table 4
Values of η for the model simulations. (PDF 119 kb)
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Aksay, E., Olasagasti, I., Mensh, B. et al. Functional dissection of circuitry in a neural integrator. Nat Neurosci 10, 494–504 (2007). https://doi.org/10.1038/nn1877
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DOI: https://doi.org/10.1038/nn1877
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