Abstract
The bulk of brain energy expenditure is allocated for maintenance of perpetual intrinsic activity of neurons and neural circuits. Long-term electrophysiological and neuroimaging studies in anesthetized and behaving animals show, however, that the great majority of nerve cells in the intact brain do not fire action potentials, i.e., are permanently silent. Herein, I review emerging data suggesting massive redundancy of nerve cells in mammalian nervous system, maintained in inhibited state at high energetic costs. Acquired in the course of evolution, these collections of dormant neurons and circuits evade routine functional undertakings, and hence, keep out of the reach of natural selection. Under penetrating stress and disease, however, they occasionally switch in active state and drive a variety of neuro-psychiatric symptoms and behavioral abnormalities. The increasing evidence for widespread occurrence of silent neurons warrants careful revision of functional models of the brain and entails unforeseen reserves for rehabilitation and plasticity.
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References
Ahrens MB, Orger MB, Robson DN, Li JM, Keller PJ (2013) Whole-brain functional imaging at cellular resolution using light-sheet microscopy. Nat Methods 10(5):413–420
Alexander-Bloch AF, Gogtay N, Meunier D, Birn R, Clasen L, Lalonde F, Lenroot R, Giedd J, Bullmore ET (2010) Disrupted modularity and local connectivity of brain functional networks in childhood-onset schizophrenia. Front Syst Neurosci 4:147
Andersen P, Eccles JC, Voorhoeve PE (1964) Postsynaptic inhibition of cerebellar purkinje cells. J Neurophysiol 27:1138–1153
Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21(10):1133–1145
Ayers J, Carpenter GA, Currie S, Kinch J (1983) Which behavior does the lamprey central motor program mediate? Science 221(4617):1312–1314
Barth AL, Poulet JF (2012) Experimental evidence for sparse firing in the neocortex. Trends Neurosci 35(6):345–355
Beloozerova IN, Sirota MG, Swadlow HA, Orlovsky GN, Popova LB, Deliagina TG (2003) Activity of different classes of neurons of the motor cortex during postural corrections. J Neurosci 23(21):7844–7853
Berger H (1940) Über das Elektrenkephalogramm des Menschen. Archiv für Psychiatrie und Nervenkrankheiten. Jena, Gustav Fischer
Blanche TJ, Spacek MA, Hetke JF, Swindale NV (2005) Polytrodes: high-density silicon electrode arrays for large-scale multiunit recording. J Neurophysiol 93(5):2987–3000
Borgstein J, Grootendorst C (2002) Clinical picture: half a brain. Lancet 359(9305):473
Brecht M, Roth A, Sakmann B (2003) Dynamic receptive fields of reconstructed pyramidal cells in layers 3 and 2 of rat somatosensory barrel cortex. J Physiol 553(Pt 1):243–265
Buckley PA (1969) Disruption of species-specific behavior patterns in F a hybrid Agapornis parents. Z Tieq sycho 26:737–743
Buzsaki G, Kaila K, Raichle M (2007) Inhibition brain work. Neuron 56(5):771–783
Carey N (2015) Junk DNA—a journey through the dark matter of the genome. Columbia University Press, New York
Chadderton P, Margrie TW, Hausser M (2004) Integration of quanta in cerebellar granule cells during sensory processing. Nature 428(6985):856–860
Chen X, Gabitto M, Peng Y, Ryba NJ, Zuker CS (2011) A gustotopic map of taste qualities in the mammalian brain. Science 333(6047):1262–1266
Corkin S, Amaral DG, Gonzalez RG, Johnson KA, Hyman BT (1997) H. M.’s medial temporal lobe lesion: findings from magnetic resonance imaging. J Neurosci 17(10):3964–3979
Corning PA (2014) Evolution “on purpose’: how behaviour has shaped the evolutionary process. Biol J Linn Soc 112(2):242–260
de Oliveira MF, Pinto FC, Nishikuni K, Botelho RV, Lima AM, Rotta JM (2011) Revisiting hydrocephalus as a model to study brain resilience. Front Hum Neurosci 5:181
DeWeese MR, Wehr M, Zador AM (2003) Binary spiking in auditory cortex. J Neurosci 23(21):7940–7949
Dobzhansky T (1977) Evolution. W. H. Freeman, San Francisco
Eagleman D (2017) The Brain: the story of you. Vintage, Delhi (reprint edition)
Feuillet L, Dufour H, Pelletier J (2007) Brain of a white-collar worker. Lancet 370(9583):262
Fino E, Yuste R (2011) Dense inhibitory connectivity in neocortex. Neuron 69(6):1188–1203
Fornito A, Zalesky A, Pantelis C, Bullmore ET (2012) Schizophrenia neuroimaging connectomics. Neuroimage 62(4):2296–2314
Forsdyke DR (2014) Long-term memory: scaling of information to brain size. Front Hum Neurosci 8:397
Galilei G (1610) Sidereus nuncius: magna longeque admirabilia spectacula pandens, suspiciendaque proponens vnicuique, praesertim verò philosophis atq[ue] astronomis, quae à Galileo Galileo, patritio Florentino, Patauini Gymnasij publico mathematico, perspicilli : nuper à se reperiti beneficio sunt obseruata in lunae facie, fixis innumeris, Lacteo Circulo, stellis nebulosis, apprime verò in quatuor planetis circa Iouis stellam disparibus interuallis, atque periodis, celeritate mirabili circumuolutis … atque Medicea sidera nuncupandos decreuit. Venetijs, Apud Thomam Baglionum
Getting PA, Dekin MS (1985) Mechanisms of pattern generation underlying swimming in Tritonia. IV. Gating of central pattern generator. J Neurophysiol 53(2):466–480
Greenberg DS, Houweling AR, Kerr JN (2008) Population imaging of ongoing neuronal activity in the visual cortex of awake rats. Nat Neurosci 11(7):749–751
Hahnloser RH, Kozhevnikov AA, Fee MS (2002) An ultra-sparse code underlies the generation of neural sequences in a songbird. Nature 419(6902):65–70
Henze DA, Borhegyi Z, Csicsvari J, Mamiya A, Harris KD, Buzsaki G (2000) Intracellular features predicted by extracellular recordings in the hippocampus in vivo. J Neurophysiol 84(1):390–400
Hromadka T, Deweese MR, Zador AM (2008) Sparse representation of sounds in the unanesthetized auditory cortex. PLoS Biol 6(1):e16
Jackson JH (1887) Remarks on evolution and dissolution of the nervous system. Br J Psychiatry 33(141):25–48
James W (1907) The energies of men. Science 25(635):321–332
Jarrett C (2015) Great myths of the brain. Wiley, West Sussex
Jueptner M, Weiller C (1995) Review: does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage 2(2):148–156
Kavanau JL (1987) Lovebirds, cockatiels, budgerigars. Science Software Systems, Los Angeles
Kavanau JL (1990) Conservative behavioural evolution, the neural substrate. Anim Behav 39(4):758–767
Kehrer HE (1992) Savant capabilities of autistic persons. Acta Paedopsychiatr 55:151–155
Kelvin WT (1904) Baltimore lectures on molecular dynamics and the wave theory of light. C.J. Clay and Sons, London
Kerr JN, de Kock CP, Greenberg DS, Bruno RM, Sakmann B, Helmchen F (2007) Spatial organization of neuronal population responses in layer 2/3 of rat barrel cortex. J Neurosci 27(48):13316–13328
Krishnan GP, Hetrick WP, Brenner CA, Shekhar A, Steffen AN, O’Donnell BF (2009) Steady state and induced auditory gamma deficits in schizophrenia. Neuroimage 47(4):1711–1719
Laughlin SB, Sejnowski TJ (2003) Communication in neuronal networks. Science 301(5641):1870–1874
Leckman JF, Bloch MH, Smith ME, Larabi D, Hampson M (2010) Neurobiological substrates of Tourette’s disorder. J Child Adolesc Psychopharmacol 20(4):237–247
Lennie P (2003) The cost of cortical computation. Curr Biol 13(6):493–497
Lewin R (1980) Is your brain really necessary? Science 210(4475):1232–1234
Lisman J (2012) Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr Opin Neurobiol 22(3):537–544
Llinas R, Urbano FJ, Leznik E, Ramirez RR, van Marle HJ (2005) Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends Neurosci 28(6):325–333
Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453(7197):869–878
Lorenz K (1970) Studies in animal and human behaviour. Harvard University Press., Cambridge
Lynall ME, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Muller U, Bullmore E (2010) Functional connectivity and brain networks in schizophrenia. J Neurosci 30(28):9477–9487
Margrie TW, Brecht M, Sakmann B (2002) In vivo, low-resistance, whole-cell recordings from neurons in the anaesthetized and awake mammalian brain. Pflugers Arch 444(4):491–498
Matthews WB (1982) Diseases of the nervous system. Blackwell Scientific Publications, Boston
Mayr E (1958) Behavior and systematics. Yale University Press, New Haven
McClellan AD (1982) Movements and motor patterns of the buccal mass of pleurobranchaea during feeding, regurgitation and rejection. J Exp Biol 98:195–211
Meyrand P, Simmers J, Moulins M (1991) Construction of a pattern-generating circuit with neurons of different networks. Nature 351(6321):60–63
Meyrand P, Simmers J, Moulins M (1994) Dynamic construction of a neural network from multiple pattern generators in the lobster stomatogastric nervous system. J Neurosci 14(2):630–644
Miller BL, Cummings J, Mishkin F, Boone K, Prince F, Ponton M, Cotman C (1998) Emergence of artistic talent in frontotemporal dementia. Neurology 51(4):978–982
Nejad AB, Ebdrup BH, Glenthoj BY, Siebner HR (2012) Brain connectivity studies in schizophrenia: unravelling the effects of antipsychotics. Curr Neuropharmacol 10(3):219–230
Nusbaum MP, Beenhakker MP (2002) A small-systems approach to motor pattern generation. Nature 417(6886):343–350
Ohki K, Chung S, Ch’ng YH, Kara P, Reid RC (2005) Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex. Nature 433(7026):597–603
Olshausen BA, Field DJ (2004) Sparse coding of sensory inputs. Curr Opin Neurobiol 14(4):481–487
Papadopoulou M, Cassenaer S, Nowotny T, Laurent G (2011) Normalization for sparse encoding of odors by a wide-field interneuron. Science 332(6030):721–725
Parrington J (2015) The deeper genome: why there is more to the human genome than meets the eye. Oxford University Press, Oxford
Penfield W (1977) No man alone: a neurosurgeon’s life. McGill University, Montreal Neurological Institute, Little, Brown and Company, Montreal
Perez-Orive J, Mazor O, Turner GC, Cassenaer S, Wilson RI, Laurent G (2002) Oscillations sparsening of odor representations in the mushroom body. Science 297(5580):359–365
Poo C, Isaacson JS (2009) Odor representations in olfactory cortex: “sparse” coding, global inhibition, and oscillations. Neuron 62(6):850–861
Poplawsky AJ, Fukuda M, Kim SG (2017) Foundations of layer-specific fMRI and investigations of neurophysiological activity in the laminarized neocortex and olfactory bulb of animal models. Neuroimage. https://doi.org/10.1016/j.neuroimage.2017.05.023
Raichle ME (2010) The brain’s dark energy. Sci Am 302(3):44–49
Raichle ME (2015) The restless brain: how intrinsic activity organizes brain function. Philos Trans R Soc Lond B Biol Sci 370(1668)
Robinson DA (1968) The electrical properties of metal microeletrodes. Proc IEEE 56:1065–1071
Romanes GJ (1887) Mental differences between men and women. Ninet Century 123:654–672
Roy CS, Sherrington CS (1890) On the regulation of the blood-supply of the brain. J Physiol 11(1–2):85–158 117
Sacks O (1995) An antropologist on Mars. Picador, London
Sacks O (2007) Musicophilia: tales of music and the brain. Kopf Publishing Group, New York
Segev R, Goodhouse J, Puchalla J, Berry MJ II (2004) Recording spikes from a large fraction of the ganglion cells in a retinal patch. Nat Neurosci 7(10):1154–1161
Sherrington C (1932) From nobel lectures, physiology or medicine 1922–1941. Elsevier Publishing Company, Amsterdam
Shoham S, O’Connor DH, Segev R (2006) How silent is the brain: is there a “dark matter” problem in neuroscience?. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 192(8):777–784
Silberberg G, Markram H (2007) Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 53(5):735–746
Sillar KT, Combes D, Ramanathan S, Molinari M, Simmers J (2008) Neuromodulation and developmental plasticity in the locomotor system of anuran amphibians during metamorphosis. Brain Res Rev 57(1):94–102
Snyder AW, Mulcahy E, Taylor JL, Mitchell D, Sachdev P, Gandevia SC (2003) Savant-like skills exposed in normal people by suppressing the left fronto-temporal lobe. J Integr Neurosci 2:149–158
Sofroniew NJ, Flickinger D, King J, Svoboda K (2016) A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging. Elife 5:e14472
Spencer KM, Salisbury DF, Shenton ME, McCarley RW (2008) Gamma-band auditory steady-state responses are impaired in first episode psychosis. Biol Psychiatry 64(5):369–375
Swadlow HA, Hicks TP (1996) Somatosensory cortical efferent neurons of the awake rabbit: latencies to activation via supra- and subthreshold receptive fields. J Neurophysiol 75(4):1753–1759
Swaiman KF, Wright FS (1975) The practice of pediatric neurology. C. V. Moseby, St Louis
Tan KR, Rudolph U, Luscher C (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 34(4):188–197
Thompson LT, Best PJ (1989) Place cells and silent cells in the hippocampus of freely-behaving rats. J Neurosci 9(7):2382–2390
Tierney AJ (1996) Evolutionary implications of neural circuit structure and function. Behav Process 35:173–182
Treffert DA (2006) Extraordinary people: understanding savant syndrom. Ballantine Books, New York
Treffert DA (2014) Savant syndrome: realities, myths and misconceptions. J Autism Dev Disord 44(3):564–571
Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11(2):100–113
Wolfe J, Houweling AR, Brecht M (2010) Sparse and powerful cortical spikes. Curr Opin Neurobiol 20(3):306–312
Young RL, Ridding MC, Morrell TL (2004) Switching skills by turning off part of the brain. Neurocase 10:215–222
Zalesky A, Fornito A, Egan GF, Pantelis C, Bullmore ET (2012) The relationship between regional and inter-regional functional connectivity deficits in schizophrenia. Hum Brain Mapp 33(11):2535–2549
Acknowledgements
This review is dedicated to the memory of Dr. Oliver Sacks. The author would like to thank Drs. R. Llinas, G. Buzsaki, M. Raichle, N. Logothetis and other leaders in the field of neuroscience and neuroimaging for their excellent research and inspiring articles and books. Special thanks go to Dr. V. O’Leary for insightful discussions and for proofreading the manuscript. The author would like to thank the National Sustainability Program 1 of the Czech Republic for supporting ongoing research projects (nr. LO1611) within the Department of Experimental Neurobiology at the National Institute of Mental Health, Czech Republic.
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Ovsepian, S.V. The dark matter of the brain. Brain Struct Funct 224, 973–983 (2019). https://doi.org/10.1007/s00429-019-01835-7
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DOI: https://doi.org/10.1007/s00429-019-01835-7