About

Stefan Leutgeb is a researcher focused on understanding neuronal mechanisms of long-term memory storage at the systems level. His laboratory investigates how coordinated neuronal activity and synaptic plasticity in distributed cell assemblies contribute to the formation and retention of memories. His work involves recording from many single neurons in the brain simultaneously, complemented by computational, analytical, and molecular techniques to manipulate neuronal network activity and test mechanisms necessary for memory formation. Leutgeb's research has contributed to discovering neuronal network mechanisms that combine spatial and nonspatial information in the mammalian hippocampus, demonstrating how orthogonal encoding of these information types generates distinct neuronal firing patterns for similar sensory inputs. His studies explore how multiple memories are encoded in the hippocampus and cortical networks, as well as how memory processing is affected in the aged brain and neurodegenerative disorders. His work aims to understand how cell assemblies degrade before memory retrieval fails, providing insights into neurodegenerative processes such as dementia.

Research topics

• Neuroscience
• Cell biology
• Biology
• Computer Science
• Psychology
• Biochemistry
• Physics

Selected publications

• Identification of conserved frontal neurophysiological markers of cognitive flexibility in humans and rats

  OSF Preprints (OSF Preprints) · 2026-03-13

  otherOpen access

  This project used versions of a probabilistic reversal learning task aligned between humans and rats to conduct a a systematic cross-species comparison of behavioral, neurophysiological, and computational markers of cognitive flexibility.

  Publisher

• NPAS4 refines spatial and temporal firing in CA1 pyramidal neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-22

  articleOpen access

  ABSTRACT NPAS4 is an activity-dependent transcription factor that, in CA1 of the hippocampus, regulates inhibitory synapses made onto the active pyramidal neuron. In principle, NPAS4 thereby allows the past activity of a neuron to influence how it encodes information, although this has not yet been demonstrated. Here, we generated a sparse, CA1-specific knockout (KO) of NPAS4 in the mouse hippocampus and used optogenetic tagging to identify KO neurons in vivo . Recordings from intermingled wild-type (WT) and KO neurons in awake behaving animals revealed that NPAS4 deletion degrades spatial representations and temporal precision of spiking: KO neurons exhibited larger place fields with reduced in-field firing and increased out-of-field firing, less stable place fields, reduced coupling to local field potential theta oscillations, and diminished phase precession. These findings demonstrate that NPAS4 plays a crucial role in refining the spatial and temporal properties of CA1 pyramidal neuron spikes, which themselves are thought to be fundamental building blocks of more complex processes such as learning and memory.

  PublisherDOI

• Mental exploration of future choices during immobility theta oscillations

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-03 · 2 citations

  preprintOpen accessCorresponding

  Mental exploration enables flexible evaluation of potential future choices, guiding decision-making without requiring direct real-world iterations. Although the hippocampus is known to be active while imagining the future, the precise mechanisms that support mental exploration of future choices remain unclear. In the hippocampus, the theta rhythm (4-12 Hz) is prevalent during movement and supports memory coding during real-world exploration by organizing neuronal activity patterns into short virtual path segments (theta sequences) around the rat's location. We observed these theta-related neural activity patterns during movement in a hippocampus-dependent working memory task and also, unexpectedly, theta oscillations and theta-related neural activity during immobility. Compared to standard theta sequences during movement, theta sequences during immobility differed in that they occurred at a shifted theta phase and preferentially represented remote locations, in particular the next choice in the working memory task. Coding for future locations was also observed during awake sharp wave ripple, but these short-lasting events occurred rarely and were biased toward frequently visited locations. Therefore, our findings suggest that recurring bouts of theta oscillations during immobility, which are also observed in primates and humans, support the cognitive demands of mental exploration in the hippocampal network and facilitate ongoing predictions of future choices.

  PublisherOA PDFDOI

• Oscillations in the prefrontal-hippocampal circuit couple to respiration-related oscillations during all phases of a working memory task

  Frontiers in Behavioral Neuroscience · 2025-10-30

  articleOpen accessSenior authorCorresponding

  Oscillatory activity is thought to coordinate neural computations across brain regions, and theta oscillations are critical for learning and memory. Because respiration-related oscillations (RROs) in rodents can be identified in the prefrontal cortex (PFC) and the hippocampus in addition to canonical theta oscillations, we asked whether odor-cued working memory may be supported by both of these two oscillations. We first confirmed that RROs were propagated to the hippocampus and PFC and that RRO frequency spans a broad range that partially overlaps with canonical theta frequency. During all task phases, we found coherence between PFC and hippocampus at the RRO frequency, irrespective of whether RROs and canonical theta oscillations overlapped or differed in frequency. In parallel, there was also high coherence across PFC and hippocampus at theta frequency, except that the coupling at theta was weakest during odor sampling. Therefore, long-range coordination between brain regions occurs at more than one oscillation frequency in a working memory task, but the two types of oscillations did not show evidence of conjunctively supporting working memory.

  PublisherOA PDFDOI

• Time cell sequences during delay intervals are not dependent on brain state and do not support hippocampus-dependent working memory

  Nature Communications · 2025-08-12 · 3 citations

  articleOpen accessSenior author

  Working memory (WM) is essential for performing cognitive tasks, and sequentially active hippocampal cells over many seconds ('time cells') have been observed during WM retention. Time cells predominantly occur when neural activity oscillates at theta frequency. To examine whether time cells during WM maintenance depend on ongoing theta oscillations, we controlled the persistence of theta during 10 s and 30 s delay intervals by either having rats run or rest, which resulted in conditions with and without persistent theta oscillations. In either condition, reliable time cells were limited to only the first few seconds of the delay interval while a second population of constitutively active cells emerged during the remainder of the delay period, neither of which were memory-related. Our results show that hippocampal sequential activity patterns are short-lasting and uninformative for WM, and that WM retention over more than ~5 s needs to include mechanisms other than hippocampal time cells.

  PublisherOA PDFDOI

• Identification of conserved frontal neurophysiological markers of cognitive flexibility in humans and rats

  Communications Biology · 2025-08-23 · 1 citations

  articleOpen access

  Cognitive flexibility broadly describes behavioral alterations made in response to environmental changes and is fundamental for survival. While human and non-human animal assessments of cognitive flexibility are available, a systematic cross-species comparison of behavioral, neurophysiological, and computational markers of cognitive flexibility has not been reported. Using versions of a probabilistic reversal learning task aligned between humans and rats, electroencephalogram recordings reveal a frontal reward positivity (RewP) associated with unexpected reward outcomes. Reinforcement Q-learning models of both species' task behavior reveal that prediction error (PE) magnitude was significantly related to RewP amplitude. The stimulant drug modafinil alters PEs in rats without affecting the RewP in either species. These findings reveal analogous neurophysiological markers associated with PEs in humans and rats using equivalent tasks and identical computational analyses. This translational approach may improve the predictive validity of tests for novel pharmacotherapies and accelerate neuropsychiatric treatment by assessing neural mechanisms conserved across species.

  PublisherOA PDFDOI

• Distinct roles of dentate gyrus and medial entorhinal cortex inputs for phase precession and temporal correlations in the hippocampal CA3 area

  Nature Communications · 2025-01-02 · 6 citations

  articleOpen accessCorresponding

  The hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta-modulated external excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs sharpen the temporal precision throughout the theta cycle. A computational model that accounts for empirical findings suggests that the unique contribution of DG inputs to theta-related spike timing is supported by targeting precisely timed inhibitory oscillations. Our results thus identify a novel and unique functional role of the DG for sequence coding in the CA3 circuit.

  PublisherOA PDFDOI

• Low rate hippocampal delay period activity encodes behavioral experience

  Hippocampus · 2024-06-05 · 2 citations

  articleOpen access

  Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

  PublisherOA PDFDOI

• Localized APP expression results in progressive network dysfunction by disorganizing spike timing

  Neuron · 2023 · 11 citations

  Senior authorCorresponding
  • Computer Science
  • Neuroscience
  • Cell biology

  Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.

  PublisherOA PDFDOI

• Low Rate Hippocampal Delay Period Activity Encodes Behavioral Experience

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-01-09

  preprintOpen access

  Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

  PublisherDOI

Recent grants

• NIH Grant R21MH100354

  NIH · $404k · 2017

• CRCNS: US-German Collaboration: Auditory and Spatial Sequence Encoding in the Hippocampus

  NSF · $350k · 2010–2014

• Mechanisms of abeta induced dysfunction in hippocampal neuronal circuitry

  NIH · $2.7M · 2014–2020

• Connectivity and function of microcircuits in the superficial layers of the entorhinal cortex

  NIH · $2.0M · 2017–2023

• Dependence of memory on precisely coordinated oscillations

  NIH · $3.1M · 2017–2028

Frequent coauthors

• Jill K. Leutgeb

  University of California, San Diego

  50 shared

• Edvard I Moser

  Norwegian University of Science and Technology

  18 shared

• May‐Britt Moser

  Norwegian Environment Agency

  17 shared

• Christian Leibold

  University of Freiburg

  14 shared

• Sheri J. Y. Mizumori

  University of Washington

  12 shared

• Carol A. Barnes

  University of Arizona

  11 shared

• Bruce L. McNaughton

  McGill University

  8 shared

• Robert E. Clark

  University of California, San Diego

  7 shared