Brain Rhythms and Neural Coding of Memory

Principal Investigator: Michaël ZUGARO, DR2 Cnrs

The hippocampus is a limbic structure that plays a critical role in the formation, consolidation and recall of various forms of memory, including episodic and spatial memory. How do such complex cognitive functions emerge from the activity of hippocampal neurons? One key property of the hippocampal network that has gained tremendous interest in recent years is its ability to encode and reactivate sequential activity patterns: specific subgroups of neurons become successively active, either in response to the ongoing behavioral and cognitive context, or spontaneously during recall, decision making and sleep. In the spatial domain, fast sequential activation of hippocampal ‘place cells’ anticipates future trajectories, associates traveled paths with rewarding or aversive stimuli, and appears to underlie certain forms of spatial learning. During subsequent sleep, reactivation of the same sequences plays a critical role in memory consolidation via a hippocampo-cortical dialogue. This versatile capacity to manipulate and memorize abstract information in the form of neural sequences may provide a unifying conceptual framework to reconcile the numerous functions of the hippocampus.

The goal of our research is to decipher the various roles of hippocampal dynamics, including their interactions with cortical and subcortical activity (in e.g. prefrontal cortex, medial and lateral entorhinal cortices, ventral and dorsal striatum, locus cœruleus, ventral tegmental area, etc.), and dissect their network mechanisms in freely moving rodents. We combine several cutting-edge technologies, including massively parallel electrophysiology across multiple brain areas, an innovative optical imaging approach, and optogenetics. We perform state-of-the-art electrophysiological recordings and are developing optical imaging and targeting approaches for real-time optical excitation or inhibition of single, identified neurons, as well as long-term monitoring of vast neural populations — all in freely moving rodents performing complex behavioral tasks in large scale mazes and sleeping. Advanced analytical and statistical methods allow us to unravel the mechanisms and roles of hippocampal sequences in the formation, consolidation and recall of memory.

Our team includes researchers with backgrounds in neurophysiology, animal behavior, physics and engineering.

Sid - Fig1 - rat
The 8 arm radial maze tests how well the rat learns the locations of chocolate treats.

Formation and Consolidation of Episodic-Like Memory Traces

The 'two-stage' theory of memory posits that memory consolidation involves a dialogue during sleep between the hippocampus, where memory traces are initially formed, and the neocortex, where they are stored for long term retention. A prominent target is the medial prefrontal cortex, which over days becomes progressively involved in memory recall, concomitantly with a gradual hippocampal disengagement. During sleep, task-related neural activity patterns are replayed in both structures, orchestrated by various brain oscillations related to memory consolidation, that are often observed in temporal proximity.

We have shown that fast sequential activation of hippocampal assemblies at the theta time scale ('theta sequences') are crucial to encode new memories, which are later replayed during sleep for memory consolidation ('sleep replay'). We further demonstrated that the formation of these sequences requires fine timescale coordination between hippocampal cell assemblies. We have also shown that subsequent replay during sleep ripples is instrumental for memory consolidation, a long-standing hypothesis that had never received experimental confirmation. Our subsequent work established that hippocampal replay underlies a hippocampo-cortical dialogue, involving enhanced coupling between ripples, cortical delta waves and spindles. More recently, we have shown that, contrary to a generally accepted tenet in systems neuroscience, an ever-changing minority of cortical neurons remain active during delta waves, forming assemblies between neurons involved in coding memories. Delta waves thus shut most of the cortical network off to isolate critical computations involved in memory consolidation.

Navigation and Spatial Memory

Our focus is on cognitive functions such as spatial navigation learning, memory and decision-making and how they are linked with neuro-electrical activity, ensembles of neurons and neural networks. With chronically implanted multiple electrodes, we record from rats as they perform tasks requiring specific types of cognitive processing. Much of the work is centered on a popular experimental model for abstract representations in the brain – the place and head direction cells in the hippocampal system and related areas. We have studied how self-movement cues are engaged for this activity and also how brain areas downstream from the hippocampus (ventral striatum, prefrontal cortex) exploit this for navigation, orienting behavior and spatial memory. The role of sleep and associated brain oscillations in off-line memory consolidation is another focus. Furthermore coherence between oscillatory local field potentials in multiple structures is studied as a potential mechanism of selection of active pathways within the massively interconnected brain. This work is carried out in collaboration with roboticians and computational modelers to facilitate creation of bio-inspired automatons.

Neuromodulation and Cognitive Processes

The neurobiological basis of memory formation and retrieval has been the major focus of my research over the past four decades. Combining in vivo electrophysiology and pharmacology with astute behavioral analysis, my thesis and subsequent publications provided early challenges the consolidation hypothesis. We published the first paper demonstrating 'reconsolidation after reactivation of memory' and showed the importance of the noradrenergic system in this reconsolidation processs. We study the role of the noradrenergic locus coeruleus (LC) in cognitive processes by recording the activity of neurons in this nucleus in behaving rats, engaged in various cognitive tasks. In this way we have elucidated the functional role of this tiny nucleus in modulating encoding and off-line memory consolidation, in concert with activity in frontal cortex and hippocampus. More recently, we have been investigating the role of sleep oscillations and associated LC activity in modulation of memory processes. Currently we are using optogenetic methods to stimulate or inhibit activity of LC neurons at critical periods during learning or during off-line memory consolidation.

Wiener Fig2a




Selected Publications 2005-2020

- Banquet, J.-P., Gaussier, P., Cuperlier, N., Hok, V., Save, E., Poucet, B., Quoy, M., and Wiener, S.I. (2020). Time as the fourth dimension in the hippocampus. Prog Neurobiol 101920.

- Todorova, R., and Zugaro, M. (2019). Isolated cortical computations during delta waves support memory consolidation. Science 366, 377–381.

- Drieu, C., and Zugaro, M. (2019). Hippocampal Sequences During Exploration: Mechanisms and Functions. Front Cell Neurosci 13, 232. 

- Wiener-Vacher, S.R., Wiener, S.I., Ajrezo, L., Obeid, R., Mohamed, D., Boizeau, P., Alberti, C., and Bucci, M.P. (2019). Dizziness and Convergence Insufficiency in Children: Screening and Management. Front Integr Neurosci 13, 25.

- Drieu, C., Todorova, R., and Zugaro, M. (2018). Nested sequences of hippocampal assemblies during behavior support subsequent sleep replay. Science 362, 675–679.

- Todorova, R., and Zugaro, M. (2018). Hippocampal ripples as a mode of communication with cortical and subcortical areas. Hippocampus.

- Maingret, N., Girardeau, G., Todorova, R., Goutierre, M. & Zugaro, M. (2016), Hippocampo-cortical coupling mediates memory consolidation during sleep. Nat. Neurosci. May 16.

- Albertin, S. V., and Wiener, S. I. (2015). Neuronal Activity in the Nucleus Accumbens and Hippocampus in Rats during Formation of Seeking Behavior in a Radial Maze. Bull. Exp. Biol. Med. 158, 405–409.

- Catanese, J., Viggiano, A., Cerasti, E., Zugaro, M. B., and Wiener, S. I. (2014), Retrospectively and prospectively modulated hippocampal place responses are differentially distributed along a common path in a continuous T-maze. J. Neurosci. 34, 13163–13169.

- Girardeau G., Cei A. & Zugaro M. (2014), Learning-induced plasticity regulates hippocampal sharp wave-ripple drive. Journal of Neuroscience 34(15):5176-83.

- Cattan S., Bachatene L., Bharmauria V., Jeyabalaratnam J., Milleret C. & Molotchnikoff S. (2014), Comparative analysis of orientation maps in areas 17 and 18 of the cat primary visual cortex following adaptation. Eur. J. Neurosci. 40, 2554–2563.

- Cei A., Girardeau G., Drieu C., Kanbi KE & Zugaro M. (2014), Reversed theta sequences of hippocampal cell assemblies during backward travel. Nature Neuroscience 17(5):719-24

- Wiener-Vacher S. R., Hamilton D. A. & Wiener S. I. (2013), Vestibular activity and cognitive development in children: Perspectives. Frontiers in Integrative Neuroscience, vol.7, article 92, p. 1-13.

- Arleo A., Déjean C., Allegraud P., Khamassi M., Zugaro M. B. & Wiener S. I. (2013), Optic flow stimuli update anterodorsal thalamus head direction neuronal activity in rats. J Neurosci. 33(42):16790-5.

- Catanese J., Cerasti E., M. Zugaro M., Viggiano A. & Wiener S. I. (2012), Dynamics of decision-related activity in prospective, hippocampal place cells. Hippocampus 22 (9):1901-11.

- Sara S. J. & Bouret S. (2012), Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron, 76(1):130-41.

- Eschenko O., Magri C., Panzeri S. & Sara S. J. (2012), Noradrenergic neurons of the locus coeruleus are phase locked to cortical up-down states during sleep. Cereb Cortex, 22(2):426-35.

- Battaglia F. P., Benchenane K., Sirota A., Pennartz C. M. & Wiener S. I. (2011), The hippocampus: Hub of brain network communication for memory. Trends Cogn Sci 15:310-318.

- Girardeau G. & Zugaro M. B. (2011), Hippocampal ripples and memory consolidation. Current Opinion in Neurobiology. 21(3):452-9.

- Peyrache A., Benchenane K., Khamassi M., Wiener S. I. & Battaglia F. P. (2010), Sequential reinstatement of neocortical activity during slow oscillations depends on cells' global activity. Front Syst Neurosci, 3:18.

- Benchenane K., Peyrache A., Khamassi M., Tierney P., Gioanni Y., Battaglia F. P. & Wiener S. I. (2010), Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning. Neuron, 66;921-36.

- Sara S. J. (2009), The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci, 10(3):211-23.

- Ramadan W., Eschenko O. & Sara S. J. (2009), Hippocampal sharp wave/ripples during sleep for consolidation of associative memory. PLoS One, 4(8):e6697.

- Girardeau G., Benchenane K., Wiener S. I., Buzsaki G. & Zugaro M. B. (2009), Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci, 12:1222-1223.

- Peyrache A., Benchenane K., Khamassi M., Wiener S. I. & Battaglia F. P. (2009), Principal component analysis of ensemble recordings reveals cell assemblies at high temporal resolution. J Comput Neurosci, Jun 16.

- Peyrache A., Khamassi M., Benchenane K., Wiener S. I. & Battaglia F. P. (2009), Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nat Neurosci, 12:919-926.

- Khamassi M., Mulder A. B., Tabuchi E., Douchamps V. & Wiener S. I. (2008), Anticipatory reward signals in ventral striatal neurons of behaving rats. Eur J Neurosci, 28:1849-1866.


Group leader:
Zugaro Michaël, DR2 CNRS

Senior researchers:
Wiener Sidney, DR1 CNRS
Susan Sara, NYU (prof. invitée)
Alain Berthoz, Pr émérite CdF

Postdoctoral fellows, PhD Students & Master student:
Pompili Marco, Postdoctoral fellow
Hoa Ombeline, Postdoctoral fellow
Bochereau Ariane, PhD student
Brito Raphaël, PhD student
Mathevet Théo, PhD student

Technical staff:
Zaoui Mohamed, IEHC CNRS
Todorova Ralitsa, CDD IR