Description

Adaptive decision-making depends on learning action-outcome contingencies. This, in turn, requires two tightly coupled processes: the encoding of experience during active behavior and the consolidation of those representations during offline states. Across hippocampal–prefrontal networks, coordinated ensemble activity and emergent population dynamics, including replay, sharp-wave ripples, UP/DOWN states, and gamma oscillations, are thought to mediate information transfer during memory formation, stabilization, and retrieval.
These processes rely on the plastic re-organization of hippocampal and cortical circuits through synapse formation and modification. Neuromodulators, such as dopamine, norepinephrine, and acetylcholine, play a pivotal role in regulating these processes by modulating neuronal excitability and synaptic plasticity, while providing brain-wide signaling of valence and saliency information. In this way, they can bias which representations are encoded, stabilized, or suppressed.
Despite extensive work on network dynamics and on neuromodulation separately, their interaction during memory processing remains poorly understood. Specifically, how neuromodulators shape the selection, coordination, and long-term stabilization of hippocampal-cortical ensembles across behavioral and sleep states remains unresolved.
This project tests the hypothesis that neuromodulators provide temporally precise instructive signals that gate ensemble formation during behavior and bias replay and consolidation during sleep. To address this, we combine large-scale electrophysiology with real-time monitoring and manipulation of neuromodulator release in freely behaving mice.
To study the various stages of memory, we have developed a novel task in which mice engage in voluntarily exploration of a large complex space while foraging for rewards. This design promotes repeated formation of novel spatial associations, enabling systematic examination of encoding, consolidation, and retrieval within hippocampal-cortical circuits.
To characterize the release of neuromodulators in target regions during behavior and sleep, we use novel genetically encoded neuromodulator sensors, coupled with fiber photometry. By combining these recordings with simultaneous multi-region recordings using high-density silicon probes (Neuropixels 2.0), we can jointly analyze how neuromodulator release during behavior correlates with neuronal activity and the emergence of neuronal ensembles and dynamics.
Beyond the observation and correlation of these phenomena, we aim to address the causal influence of hippocampal neuromodulation for memory processes. Towards this goal, we will employ closed-loop optogenetic manipulations to specifically silence (or stimulate) the neuromodulator release to the hippocampus using high-efficiency axon terminal inhibition or excitation during intrinsic neuronal (e.g., ripples) or behavioral (e.g., reward consumption) events.
In summary, this work will help uncover the dynamic interplay between neuromodulatory systems and neuronal circuit dynamics. This understanding is crucial for deciphering the underpinnings of complex behaviors and elucidating the mechanisms underlying the pathological re-configuration of circuits in mental and mood disorders.

Compétences requises

Expérience avec l'analyse de données d'expériences d'électrophysiologie in vivo De préférence, expérience avec les neuromodulateurs et l'hippocampe/le cortex préfrontal

Bibliographie

Girardeau G, Lopes-Dos-Santos V . Brain neural patterns and the memory function of sleep. Science 6567:560-564 (2021).

Atherton, L. A., Dupret, D. & Mellor, J. R. Memory trace replay: the shaping of memory consolidation by neuromodulation. Trends in
Neurosciences 38, 560–570 (2015).

Wu, Z., Lin, D. & Li, Y . Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators. Nat Rev Neurosci 23, 257–
274 (2022)

Likhtik, E. & Johansen, J. P . Neuromodulation in circuits of aversive emotional learning. Nat Neurosci 22, 1586–1597 (2019).

Karalis, N. & Sirota, A. Breathing coordinates cortico-hippocampal dynamics in mice during offline states. Nat Commun 13, 467 (2022).

Mots clés

mémoire, neuromodulation, hippocampe, cortex préfrontal, électrophysiologie in vivo, fiber photometry