Abstract
The past decade of progress in neurobiology has uncovered important organizational principles for network preconfiguration and neuronal selection that suggest a generative grammar exists in the brain. In this Perspective, I discuss the competence of the hippocampal neural network to generically express temporally compressed sequences of neuronal firing that represent novel experiences, which is envisioned as a form of generative neural syntax supporting a neurobiological perspective on brain function. I compare this neural competence with the hippocampal network performance that represents specific experiences with higher fidelity after new learning during replay, which is envisioned as a form of neural semantic that supports a complementary neuropsychological perspective. I also demonstrate how the syntax of network competence emerges a priori during early postnatal life and is followed by the later development of network performance that enables rapid encoding and memory consolidation. Thus, I propose that this generative grammar of the brain is essential for internally generated representations, which are crucial for the cognitive processes underlying learning and memory, prospection, and inference, which ultimately underlie our reason and representation of the world.
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References
Locke, J. An Essay Concerning Human Understanding (Thomas Basset, 1690).
Hume, D. An Enquiry Concerning Human Understanding (A. Millar, 1748).
Leibniz, G. New Essays on Human Understanding (Cambridge Univ. Press, 1765).
Kant, I. Critique of Pure Reason (Cambridge Univ. Press, 1781).
Pauling, L. A theory of the structure and process of formation of antibodies. J. Am. Chem. Soc. 62, 2643–2657 (1940).
Deichmann, U. Template theories, the rule of parsimony, and disregard for irreproducibility — the example of Linus Pauling’s research on antibody formation. Hist. Stud. Nat. Sci. 51, 427–467 (2021).
Erlich, P. Croonian lecture: on immunity with special reference to cell life. Proc. R. Soc. Lond. 66, 424–448 (1900).
Jerne, N. K. The natural-selection theory of antibody formation. Proc. Natl Acad. Sci. USA 41, 849–857 (1955).
Talmage, D. W. Diversity of antibodies. J. Cell Physiol. Suppl. 50, 229–246 (1957).
Burnet, F. M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J. Clin. 26, 119–221 (1957).
Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).
Landsteiner, K. The Specificity of Serological Reactions (Howard Univ. Press, 1947).
Jerne, N. K. The generative grammar of the immune system. Science 229, 1057–1059 (1985).
Darwin, C. On the Origin of Species (John Murray, 1859).
Edelman, G. M., Benacerraf, B., Ovary, Z. & Poulik, M. D. Structural differences among antibodies of different specificities. Proc. Natl Acad. Sci. USA 47, 1751–1758 (1961).
Edelman, G. Neural Darwinism: The Theory Of Neuronal Group Selection (Basic Books, 1987).
Barlow, H. B. Neuroscience: a new era? Nature 331, 571 (1988).
Crick, F. Neural edelmanism. Trends Neurosci. 12, 240–248 (1989).
Dragoi, G. & Tonegawa, S. Preplay of future place cell sequences by hippocampal cellular assemblies. Nature 469, 397–401 (2011).
Dragoi, G. & Tonegawa, S. Distinct preplay of multiple novel spatial experiences in the rat. Proc. Natl Acad. Sci. USA 110, 9100–9105 (2013).
Dragoi, G. & Tonegawa, S. Selection of preconfigured cell assemblies for representation of novel spatial experiences. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20120522 (2014).
Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).
Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).
Tulving, E. Episodic memory: from mind to brain. Annu. Rev. Psychol. 53, 1–25 (2002).
O’Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Oxford Univ. Press, 1978).
Tolman, E. C. Cognitive maps in rats and men. Psychol. Rev. 55, 189–208 (1948).
Muller, R. U. & Kubie, J. L. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J. Neurosci. 7, 1951–1968 (1987).
Hafting, T., Fyhn, M., Molden, S., Moser, M. B. & Moser, E. I. Microstructure of a spatial map in the entorhinal cortex.Nature 436, 801–806 (2005).
Wills, T. J., Lever, C., Cacucci, F., Burgess, N. & O’Keefe, J. Attractor dynamics in the hippocampal representation of the local environment. Science 308, 873–876 (2005).
Lee, A. K. & Wilson, M. A. Memory of sequential experience in the hippocampus during slow wave sleep. Neuron 36, 1183–1194 (2002).
Kudrimoti, H. S., Barnes, C. A. & McNaughton, B. L. Reactivation of hippocampal cell assemblies: effects of behavioral state, experience, and EEG dynamics. J. Neurosci. 19, 4090–4101 (1999).
Hirase, H., Leinekugel, X., Czurko, A., Csicsvari, J. & Buzsaki, G. Firing rates of hippocampal neurons are preserved during subsequent sleep episodes and modified by novel awake experience. Proc. Natl Acad. Sci. USA 98, 9386–9390 (2001).
Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).
Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
Moser, E. I., Krobert, K. A., Moser, M. B. & Morris, R. G. Impaired spatial learning after saturation of long-term potentiation. Science 281, 2038–2042 (1998).
Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).
Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).
Dragoi, G., Harris, K. D. & Buzsaki, G. Place representation within hippocampal networks is modified by long-term potentiation. Neuron 39, 843–853 (2003).
Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).
Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nat. Neurosci. 2, 597–604 (1999).
Magee, J. C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).
Pavlides, C. & Winson, J. Influences of hippocampal place cell firing in the awake state on the activity of these cells during subsequent sleep episodes. J. Neurosci. 9, 2907–2918 (1989).
Buzsaki, G. Two-stage model of memory trace formation: a role for “noisy” brain states. Neuroscience 31, 551–570 (1989).
Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).
Davidson, T. J., Kloosterman, F. & Wilson, M. A. Hippocampal replay of extended experience. Neuron 63, 497–507 (2009).
Frankland, P. W. & Bontempi, B. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130 (2005).
Kitamura, T. et al. Engrams and circuits crucial for systems consolidation of a memory. Science 356, 73–78 (2017).
Logothetis, N. K. et al. Hippocampal-cortical interaction during periods of subcortical silence. Nature 491, 547–553 (2012).
Tse, D. et al. Schema-dependent gene activation and memory encoding in neocortex. Science 333, 891–895 (2011).
Ji, D. & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat. Neurosci. 10, 100–107 (2007).
Dragoi, G. Cell assemblies, sequences and temporal coding in the hippocampus. Curr. Opin. Neurobiol. 64, 111–118 (2020).
Silva, D., Feng, T. & Foster, D. J. Trajectory events across hippocampal place cells require previous experience. Nat. Neurosci. 18, 1772–1779 (2015).
Foster, D. J. Replay comes of age. Annu. Rev. Neurosci. 40, 581–602 (2017).
Girardeau, G., Benchenane, K., Wiener, S. I., Buzsaki, G. & Zugaro, M. B. Selective suppression of hippocampal ripples impairs spatial memory. Nat. Neurosci. 12, 1222–1223 (2009).
Fernandez-Ruiz, A. et al. Long-duration hippocampal sharp wave ripples improve memory. Science 364, 1082–1086 (2019).
Luczak, A., Bartho, P. & Harris, K. D. Spontaneous events outline the realm of possible sensory responses in neocortical populations. Neuron 62, 413–425 (2009).
Kenet, T., Bibitchkov, D., Tsodyks, M., Grinvald, A. & Arieli, A. Spontaneously emerging cortical representations of visual attributes. Nature 425, 954–956 (2003).
Arieli, A., Sterkin, A., Grinvald, A. & Aertsen, A. Dynamics of ongoing activity: explanation of the large variability in evoked cortical responses. Science 273, 1868–1871 (1996).
Penn, A. A. & Shatz, C. J. Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development. Pediatr. Res. 45, 447–458 (1999).
McClelland, J. L., McNaughton, B. L. & O’Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995).
Nadasdy, Z., Hirase, H., Czurko, A., Csicsvari, J. & Buzsaki, G. Replay and time compression of recurring spike sequences in the hippocampus. J. Neurosci. 19, 9497–9507 (1999).
Hassabis, D., Kumaran, D., Vann, S. D. & Maguire, E. A. Patients with hippocampal amnesia cannot imagine new experiences. Proc. Natl Acad. Sci. USA 104, 1726–1731 (2007).
Addis, D. R., Wong, A. T. & Schacter, D. L. Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration. Neuropsychologia 45, 1363–1377 (2007).
Tse, D. et al. Schemas and memory consolidation. Science 316, 76–82 (2007).
Schacter, D. L., Addis, D. R. & Buckner, R. L. Episodic simulation of future events: concepts, data, and applications. Ann. N. Y. Acad. Sci. 1124, 39–60 (2008).
Bar, M. The proactive brain: memory for predictions. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 1235–1243 (2009).
Pezzulo, G., Kemere, C. & van der Meer, M. A. A. Internally generated hippocampal sequences as a vantage point to probe future-oriented cognition. Ann. N. Y. Acad. Sci. 1396, 144–165 (2017).
Spano, G. et al. Dreaming with hippocampal damage. eLife 9, e56211 (2020).
Schobel, S. A. et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 78, 81–93 (2013).
Tamminga, C. A., Stan, A. D. & Wagner, A. D. The hippocampal formation in schizophrenia. Am. J. Psychiatry 167, 1178–1193 (2010).
Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).
Dragoi, G. & Tonegawa, S. Development of schemas revealed by prior experience and NMDA receptor knock-out. eLife 2, e01326 (2013).
Farooq, U., Sibille, J., Liu, K. & Dragoi, G. Strengthened temporal coordination within pre-existing sequential cell assemblies supports trajectory replay. Neuron 103, 719–733.e7 (2019).
Liu, K., Sibille, J. & Dragoi, G. Generative predictive codes by multiplexed hippocampal neuronal tuplets. Neuron 99, 1329–1341.e6 (2018).
Liu, K., Sibille, J. & Dragoi, G. Preconfigured patterns are the primary driver of offline multi-neuronal sequence replay. Hippocampus 29, 275–283 (2019).
Grosmark, A. D. & Buzsaki, G. Diversity in neural firing dynamics supports both rigid and learned hippocampal sequences. Science 351, 1440–1443 (2016).
Olafsdottir, H. F., Barry, C., Saleem, A. B., Hassabis, D. & Spiers, H. J. Hippocampal place cells construct reward related sequences through unexplored space. eLife 4, e06063 (2015).
Liu, Y., Dolan, R. J., Kurth-Nelson, Z. & Behrens, T. E. J. Human replay spontaneously reorganizes experience. Cell 178, 640–652.e14 (2019).
Liu, K., Sibille, J. & Dragoi, G. Orientation selectivity enhances context generalization and generative predictive coding in the hippocampus. Neuron 109, 3688–3698.e6 (2021).
Crick, F. H., Barnett, L., Brenner, S. & Watts-Tobin, R. J. General nature of the genetic code for proteins. Nature 192, 1227–1232 (1961).
Dragoi, G. & Buzsaki, G. Temporal encoding of place sequences by hippocampal cell assemblies. Neuron 50, 145–157 (2006).
Diba, K. & Buzsaki, G. Forward and reverse hippocampal place-cell sequences during ripples. Nat. Neurosci. 10, 1241–1242 (2007).
Pfeiffer, B. E. & Foster, D. J. Hippocampal place-cell sequences depict future paths to remembered goals. Nature 497, 74–79 (2013).
Dragoi, G. Internal operations in the hippocampus: single cell and ensemble temporal coding. Front. Syst. Neurosci. 7, 46 (2013).
van de Ven, G. M., Trouche, S., McNamara, C. G., Allen, K. & Dupret, D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples. Neuron 92, 968–974 (2016).
van der Meer, M. A. A., Kemere, C. & Diba, K. Progress and issues in second-order analysis of hippocampal replay. Philos. Trans. R. Soc. Lond. B Biol. Sci. 375, 20190238 (2020).
Epsztein, J., Brecht, M. & Lee, A. K. Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment. Neuron 70, 109–120 (2011).
Monaco, J. D., Rao, G., Roth, E. D. & Knierim, J. J. Attentive scanning behavior drives one-trial potentiation of hippocampal place fields. Nat. Neurosci. 17, 725–731 (2014).
Markus, E. J. et al. Interactions between location and task affect the spatial and directional firing of hippocampal neurons. J. Neurosci. 15, 7079–7094 (1995).
Buzsaki, G. The Brain from Inside Out (Oxford Univ. Press, 2019).
Vaz, A. P., Wittig, J. H. Jr., Inati, S. K. & Zaghloul, K. A. Backbone spiking sequence as a basis for preplay, replay, and default states in human cortex. Nat. Commun. 14, 4723 (2023).
Hall, A. F. & Wang, D. V. The two tales of hippocampal sharp-wave ripple content: the rigid and the plastic. Prog. Neurobiol. 221, 102396 (2023).
Harvey, R. E., Robinson, H. L., Liu, C., Oliva, A. & Fernandez-Ruiz, A. Hippocampo-cortical circuits for selective memory encoding, routing, and replay. Neuron 111, 2076–2090.e9 (2023).
Geiller, T., Fattahi, M., Choi, J. S. & Royer, S. Place cells are more strongly tied to landmarks in deep than in superficial CA1. Nat. Commun. 8, 14531 (2017).
Chomsky, N. Aspects of the Theory of Syntax (MIT Press, 1965).
Mueller-Vollmer, K. & Messling, M. in The Stanford Encyclopedia of Philosophy (Summer 2022 Edition) (Ed. Zalta, E. N.) (2022).
Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).
Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S. I. & Battaglia, F. P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nat. Neurosci. 12, 919–926 (2009).
Churchland, P. S. & Sejnowski, T. The Computational Brain (MIT Press, 1992).
Bullock, T. H. et al. Neuroscience. The neuron doctrine, redux. Science 310, 791–793 (2005).
Dragoi, G., Carpi, D., Recce, M., Csicsvari, J. & Buzsaki, G. Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat. J. Neurosci. 19, 6191–6199 (1999).
Tingley, D. & Buzsaki, G. Routing of hippocampal ripples to subcortical structures via the lateral septum. Neuron 105, 138–149.e5 (2020).
Siapas, A. G. & Wilson, M. A. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron 21, 1123–1128 (1998).
O’Neill, J., Boccara, C. N., Stella, F., Schoenenberger, P. & Csicsvari, J. Superficial layers of the medial entorhinal cortex replay independently of the hippocampus. Science 355, 184–188 (2017).
Shin, J. D., Tang, W. & Jadhav, S. P. Dynamics of awake hippocampal-prefrontal replay for spatial learning and memory-guided decision making. Neuron 104, 1110–1125.e7 (2019).
Buzsaki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).
Euston, D. R., Tatsuno, M. & McNaughton, B. L. Fast-forward playback of recent memory sequences in prefrontal cortex during sleep. Science 318, 1147–1150 (2007).
Olafsdottir, H. F., Carpenter, F. & Barry, C. Coordinated grid and place cell replay during rest. Nat. Neurosci. 19, 792–794 (2016).
Markowitz, J. E. et al. Spontaneous behaviour is structured by reinforcement without explicit reward. Nature 614, 108–117 (2023).
van der Meer, M. A., Johnson, A., Schmitzer-Torbert, N. C. & Redish, A. D. Triple dissociation of information processing in dorsal striatum, ventral striatum, and hippocampus on a learned spatial decision task. Neuron 67, 25–32 (2010).
Amador, A., Perl, Y. S., Mindlin, G. B. & Margoliash, D. Elemental gesture dynamics are encoded by song premotor cortical neurons. Nature 495, 59–64 (2013).
Hahnloser, R. H., Kozhevnikov, A. A. & Fee, M. S. An ultra-sparse code underlies the generation of neural sequences in a songbird. Nature 419, 65–70 (2002).
Chambers, B. & MacLean, J. N. Higher-order synaptic interactions coordinate dynamics in recurrent networks. PLoS Comput. Biol. 12, e1005078 (2016).
Carrillo-Reid, L., Yang, W., Bando, Y., Peterka, D. S. & Yuste, R. Imprinting and recalling cortical ensembles. Science 353, 691–694 (2016).
van der Meer, M. A. A., Carey, A. A. & Tanaka, Y. Optimizing for generalization in the decoding of internally generated activity in the hippocampus. Hippocampus 27, 580–595 (2017).
Genzel, L. et al. A consensus statement: defining terms for reactivation analysis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 375, 20200001 (2020).
Diba, K., Maboudi, K., Giri, B., Miyawaki, H. & Kemere, C. Retuning of hippocampal representations during sleep. Preprint at Res. Square https://doi.org/10.21203/rs.3.rs-2191626/v1 (2022).
MacDonald, C. J., Lepage, K. Q., Eden, U. T. & Eichenbaum, H. Hippocampal “time cells” bridge the gap in memory for discontiguous events. Neuron 71, 737–749 (2011).
Aronov, D., Nevers, R. & Tank, D. W. Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit. Nature 543, 719–722 (2017).
Friston, K. The free-energy principle: a unified brain theory? Nat. Rev. Neurosci. 11, 127–138 (2010).
Heeger, D. J. Theory of cortical function. Proc. Natl Acad. Sci. USA 114, 1773–1782 (2017).
Stachenfeld, K. L., Botvinick, M. M. & Gershman, S. J. The hippocampus as a predictive map. Nat. Neurosci. 20, 1643–1653 (2017).
Teufel, C. & Fletcher, P. C. Forms of prediction in the nervous system. Nat. Rev. Neurosci. 21, 231–242 (2020).
Eichenbaum, H. & Cohen, N. J. Can we reconcile the declarative memory and spatial navigation views on hippocampal function? Neuron 83, 764–770 (2014).
Muller, R. U., Stead, M. & Pach, J. The hippocampus as a cognitive graph. J. Gen. Physiol. 107, 663–694 (1996).
Gupta, A. S., van der Meer, M. A., Touretzky, D. S. & Redish, A. D. Segmentation of spatial experience by hippocampal theta sequences. Nat. Neurosci. 15, 1032–1039 (2012).
Skaggs, W. E., McNaughton, B. L., Wilson, M. A. & Barnes, C. A. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6, 149–172 (1996).
Drieu, C., Todorova, R. & Zugaro, M. Nested sequences of hippocampal assemblies during behavior support subsequent sleep replay. Science 362, 675–679 (2018).
Wang, Y., Romani, S., Lustig, B., Leonardo, A. & Pastalkova, E. Theta sequences are essential for internally generated hippocampal firing fields. Nat. Neurosci. 18, 282–288 (2015).
Ego-Stengel, V. & Wilson, M. A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20, 1–10 (2010).
Farooq, U. & Dragoi, G. Emergence of preconfigured and plastic time-compressed sequences in early postnatal development. Science 363, 168–173 (2019).
Muessig, L., Lasek, M., Varsavsky, I., Cacucci, F. & Wills, T. J. Coordinated emergence of hippocampal replay and theta sequences during post-natal development. Curr. Biol. 29, 834–840.e4 (2019).
Travaglia, A., Bisaz, R., Sweet, E. S., Blitzer, R. D. & Alberini, C. M. Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat. Neurosci. 19, 1225–1233 (2016).
Bessieres, B., Travaglia, A., Mowery, T. M., Zhang, X. & Alberini, C. M. Early life experiences selectively mature learning and memory abilities. Nat. Commun. 11, 628 (2020).
Donato, F. et al. The ontogeny of hippocampus-dependent memories. J. Neurosci. 41, 920–926 (2021).
Stark, E., Roux, L., Eichler, R. & Buzsaki, G. Local generation of multineuronal spike sequences in the hippocampal CA1 region. Proc. Natl Acad. Sci. USA 112, 10521–10526 (2015).
Oliva, A., Fernandez-Ruiz, A., Leroy, F. & Siegelbaum, S. A. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature 587, 264–269 (2020).
Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, 1949).
Huszar, R., Zhang, Y., Blockus, H. & Buzsaki, G. Preconfigured dynamics in the hippocampus are guided by embryonic birthdate and rate of neurogenesis. Nat. Neurosci. 25, 1201–1212 (2022).
Cavalieri, D. et al. CA1 pyramidal cell diversity is rooted in the time of neurogenesis. eLife 10, e69270 (2021).
Gava, G. P. et al. Integrating new memories into the hippocampal network activity space. Nat. Neurosci. 24, 326–330 (2021).
Azizi, A. H., Wiskott, L. & Cheng, S. A computational model for preplay in the hippocampus. Front. Comput. Neurosci. 7, 161 (2013).
Leibold, C. A model for navigation in unknown environments based on a reservoir of hippocampal sequences. Neural Netw. 124, 328–342 (2020).
Haldane, J. The truth about death. J. Genet. 58, 463–464 (1963).
Berners-Lee, A. et al. Hippocampal replays appear after a single experience and incorporate greater detail with more experience. Neuron 110, 1829–1842.e5 (2022).
Abraham, W. C. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387 (2008).
Jedlicka, P., Tomko, M., Robins, A. & Abraham, W. C. Contributions by metaplasticity to solving the catastrophic forgetting problem. Trends Neurosci. 45, 656–666 (2022).
Morris, R. G. Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. Eur. J. Neurosci. 23, 2829–2846 (2006).
Cai, D. J. et al. A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534, 115–118 (2016).
Ramsaran, A. I. et al. A shift in the mechanisms controlling hippocampal engram formation during brain maturation. Science 380, 543–551 (2023).
Ramirez, S. et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013).
Poo, M. M. et al. What is memory? The present state of the engram. BMC Biol. 14, 40 (2016).
Han, J. H. et al. Neuronal competition and selection during memory formation. Science 316, 457–460 (2007).
McKenzie, S., Robinson, N. T., Herrera, L., Churchill, J. C. & Eichenbaum, H. Learning causes reorganization of neuronal firing patterns to represent related experiences within a hippocampal schema. J. Neurosci. 33, 10243–10256 (2013).
El-Gaby, M. et al. An emergent neural coactivity code for dynamic memory. Nat. Neurosci. 24, 694–704 (2021).
Jadhav, S. P., Kemere, C., German, P. W. & Frank, L. M. Awake hippocampal sharp-wave ripples support spatial memory. Science 336, 1454–1458 (2012).
Roux, L., Hu, B., Eichler, R., Stark, E. & Buzsaki, G. Sharp wave ripples during learning stabilize the hippocampal spatial map. Nat. Neurosci. 20, 845–853 (2017).
Rao, R. P. N. & Ballard, D. H. Predictive coding in the visual cortex: a functional interpretation of some extra-classical receptive-field effects. Nat. Neurosci. 2, 79–87 (1999).
Farooq, U. & Dragoi, G. Geometry of space sculpts hippocampal sequential place cell assemblies during development. Soc. Neurosci. Abstr. 324, 15 (2022).
Wood, E. R., Dudchenko, P. A. & Eichenbaum, H. The global record of memory in hippocampal neuronal activity. Nature 397, 613–616 (1999).
Eichenbaum, H., Dudchenko, P., Wood, E., Shapiro, M. & Tanila, H. The hippocampus, memory, and place cells: is it spatial memory or a memory space? Neuron 23, 209–226 (1999).
Wagner, U., Gais, S., Haider, H., Verleger, R. & Born, J. Sleep inspires insight. Nature 427, 352–355 (2004).
Dusek, J. A. & Eichenbaum, H. The hippocampus and memory for orderly stimulus relations. Proc. Natl Acad. Sci. USA 94, 7109–7114 (1997).
Wallenstein, G. V., Eichenbaum, H. & Hasselmo, M. E. The hippocampus as an associator of discontiguous events. Trends Neurosci. 21, 317–323 (1998).
Aru, J., Druke, M., Pikamae, J. & Larkum, M. E. Mental navigation and the neural mechanisms of insight. Trends Neurosci. 46, 100–109 (2023).
Thakral, P. P., Barberio, N. M., Devitt, A. L. & Schacter, D. L. Constructive episodic retrieval processes underlying memory distortion contribute to creative thinking and everyday problem solving. Mem. Cogn. 51, 1125–1144 (2022).
Raichle, M. E. et al. A default mode of brain function. Proc. Natl Acad. Sci. USA 98, 676–682 (2001).
Schopenhauer, A. The World as Will and Representation (Dover, 1969).
Karlsson, M. P. & Frank, L. M. Awake replay of remote experiences in the hippocampus. Nat. Neurosci. 12, 913–918 (2009).
Acknowledgements
The author thanks all the members of the Dragoi lab for their contribution to the primary research work that led to some of the findings included in this opinion. G.D. discloses support for the research of this work from the NIH grants R01NS104917, R01MH121372 and R35NS132342. The funding sources had no involvement in the content of this manuscript.
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- Backbone
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Robust pre-existing organization of neuronal (sequential) activity, on the framework of which new information is encoded.
- Blank slate
-
An original state of neural networks (or the mind) believed to be devoid of any functional organization, which will be configured only because of direct experience. Also known as tabula rasa.
- Cell assemblies
-
Groups of interconnected neurons repeatedly co-activated within short timeframes (of a few tens of milliseconds) thought to underlie an associative representational code.
- Generative grammar
-
A set of organizational rules that can explain current patterns and predict the expression of future new patterns from (re)combination of existing elements.
- Morpheme
-
The smallest unit of semantic meaning within a word.
- Multi-neuronal primitive sequence
-
Overall probabilistic organization of neurons into one generic or backbone neuronal sequence characteristic to a network that is mostly preserved across experiences.
- Network preconfiguration
-
A state of neural network functional organization often related to, constraining or predictive of future patterns of network activation; in contrast to a blank slate.
- Neural code
-
Patterns of neuronal and neuronal ensemble activity believed to encode and represent specific stimuli or states, which could be decoded by a downstream entity.
- Neural grammar
-
A set of hierarchical organization rules for the generation of current and future novel neural patterns from (re)combination of pre-existing cellular and circuit neural motifs.
- Neural semantic
-
A representational feature gained by specific neural patterns for the depiction of specific objects or events from the external world, often interpreted as a neural code.
- Neural syntax
-
A set of rules for the combinatorial hierarchical organization of the neuronal activity of individual neurons into cell assemblies and short circuit motifs towards extended neural sequences.
- Neurobiological
-
A level of explanation of neuronal ensemble activity with a focus on the rules for the combinatorial organization of neural activity (neural syntax).
- Neuro-codons
-
Recurring short sequence motifs of 3 ± 1 neurons, also called neuronal tuplets, that are further multiplexed into extended neuronal sequences; part of neural syntax.
- Neuronal selection
-
A theory in neuroscience postulating that patterns of neural activity are selected from a larger pre-existing repertoire, rather than exclusively created de novo, during a novel experience.
- Neuropsychological
-
A level of explanation of neuronal ensemble activity with a focus on the representational value of neuronal activity as a form of neural semantic or code.
- Phoneme
-
The smallest perceptually distinct unit of sound that composes a word (and can separate it from another word), often represented by one letter or a small cluster of letters.
- Place cells
-
A neuron type functionally tuned primarily to the position of an animal in external space; most abundant in the hippocampus.
- Plasticity
-
The property of neural activity of being modified within normal ranges owing to a certain experience, lasting for a variable amount of time after the experience has ended.
- Plasticity in replay
-
Recent experience-related changes in sequence replay that increase its fidelity, incidence or extent in depicting the experience compared with preplay (plasticity in replay over preplay). Considered a form of gain in network performance, not a new competence.
- Preplay
-
Significant correlations between sequential patterns of neuronal ensemble activity during a novel (spatial) experience and those expressed during the preceding sleep or rest, prospective in nature. Demonstrates that preconfigured network patterns contribute to encoding of future novel experiences.
- Pre-representations
-
Decoded neuronal ensemble activities during sleep and rest that resemble virtual trajectories through subsequently explored novel spaces.
- Universal biological grammar
-
A set of rules for the hierarchical organization of elements into increasingly complex assemblies with added meaning, common across different aspects of biology.
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Dragoi, G. The generative grammar of the brain: a critique of internally generated representations. Nat. Rev. Neurosci. 25, 60–75 (2024). https://doi.org/10.1038/s41583-023-00763-0
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DOI: https://doi.org/10.1038/s41583-023-00763-0