Biology subjects

Buzsaki, G.

Publications and source records attributed to Buzsaki, G..

At least 19 recordsLinked to original sources

bioRxiv2026

A disinhibition-based model of CA1 place field sequences

Because of the paucity of pattern-generating recurrent excitation in the CA1 hippocampal region, place field sequences are assumed to be inherited from upstream regions. Alternatively, disinhibition may play a role in shaping pyramidal cell activity. We propose a model of CA1 activity using one layer of excitatory cells and one layer of inhibitory cells, with local excitatory-to-inhibitory connectivity, broad inhibitory-to-excitatory connectivity without recurrent excitatory connections, and broad inhibitory-inhibitory connections. The layers need not follow a topographic organization; instead they can represent sequences of place cells structured by local inhibition. Our mathematical model of CA1 neurons with data-inspired connectivity demonstrates place fields sharpened by disinhibition, mimicking a recently discovered decrease in inhibitory input within place fields and matching in vivo patterns of disinhibition. Mathematical analysis of our model suggests the importance of inhibitory-to-excitatory connections in control of place cell firing rate and sparsity. We also demonstrate that a disinhibition-based mechanism of pattern generation is more flexible without recurrent excitation than the recurrent excitation-rich CA3-like model. Finally, we demonstrate disinhibition as an efficient mechanism for internally-generated sequential activity, where the speed of sequential change depends on both input strength and inhibitory-to-excitatory connection strength. Overall, our model suggests that theta time-scale disinhibition is a foundational mechanism of self-organized sequential activity in the CA1 region, and, possibly, in other networks.

neuroscience↗

bioRxiv2026

Hippocampal and prefrontal contributions to memory-guided navigation depend on task epoch

The hippocampus and medial prefrontal cortex (mPFC) are required for delayed working-memory tasks, but when in the task their engagement becomes necessary remains an open question. We trained mice on a delayed cue-guided T-maze navigation task and used transient optogenetic silencing to test the contribution of the mPFC and hippocampus during distinct task epochs. Surprisingly, silencing during the delay period did not impair performance. In contrast, perturbation during the early phase of the central arm traversal produced robust deficits. Mice made more perseverative choices, slowed their speed and ran farther down the track before turning towards the selected arm. Control experiments showed that these effects could not be explained by the manipulation targeting elapsed time and were rather specific to task phase. These results indicate that hippocampal and prefrontal contributions to memory-guided behavior are not uniform across the trial, but instead depend on task epoch. More broadly, they suggest that the functional engagement of these circuits is gated by behavioral state or context.

neuroscience↗

bioRxiv2026

Sharp wave-ripple clusters enhance hippocampal-neocortical engagement for memory consolidation

Hippocampal sharp wave-ripples (SPW-Rs), neocortical slow oscillations, and thalamocortical sleep spindles are hypothesized to provide a temporal framework for coordinated information transfer during memory consolidation. Hippocampal replay supports this process, yet replayed sequences often unfold across multiple SPW-Rs, suggesting that individual ripples may not constitute the fundamental unit of hippocampal output. Here, using large-scale electrophysiological recordings from the hippocampus and retrosplenial cortex, we show that hippocampal output is organized into clusters of SPW-Rs (cSPW-Rs) during UP states, which are often phase-locked to spindle troughs. Extending this approach with wide-field imaging and unsupervised latent-variable modeling, we found that cSPW-Rs enhanced segregation between the default mode and somatomotor networks and preferentially replayed spatially extended maze trajectories following learning. We propose that SPW-R clusters enable reverberating hippocampal-cortical spike exchange and the concatenation of sequential experiences, establishing ripple clusters as a previously unrecognized syntactic unit of hippocampal-neocortical dialogue.

neuroscience↗

bioRxiv2026

Subspace communication in the hippocampal-retrosplenial axis

The capacity and flexibility of hippocampal circuits for transforming inputs into downstream outputs is fundamental for navigation and memory, yet the circuit-level mechanisms that allow this operation to adapt across experiences remain unknown. We approach this problem by performing large-scale (up to 1024-channel) recordings across the hippocampal-retrosplenial cortex (RSC) circuit in behaving mice, enabling simultaneous access to spiking activity in dentate gyrus (DG), CA3, CA2, CA1, RSC. Based on a linear dimensionality reduction technique known as partial canonical correlation analysis, we identify low-dimensional communication subspaces1 between two regions while accounting for measured third-area influences. These subspaces captured distinct input-output transformations in CA1, linking upstream (DG, CA3, and CA2) hippocampal activity to downstream cortical targets (RSC). Iintrinsic firing properties and anatomical location constrained subspace memberships--members were mapped to deep sublayers of the CA3-CA1-RSC axis during both spatial and non-spatial tasks. These subspaces could recombine overlapping neuronal pools to support distinct interareal interactions across changing experiences and brain states. Reactivation patterns of CA1-CA3 subspaces, but not those of CA1-RSC, during post-experience sleep correlated with replay, reflecting a plasticity-stability balance of the input-output transformation in the hippocampal-retrosplenial axis. Our data suggest a model in which hippocampal-neocortical communication reconfigures predetermined circuit motifs to flexibly encode experiences.

neuroscience↗

bioRxiv2025

From labels to latents: revealing state-dependent hippocampal computations with Jump Latent Variable Model

Neural activity is usually interpreted by imposing external labels (e.g., stimuli or position during locomotion) and decoding within that space (e.g. replay). While powerful, such supervision can mask structure in the data that do not correspond to the label. Unsupervised methods, in turn, often assume smooth latent dynamics and miss genuine discontinuities. We introduce a conceptually simple, computationally efficient latent variable model that infers both (i) the latent variables organizing population activity and (ii) whether their dynamics are continuous or fragmented in time. Fitting reduces to an expectation-maximization (EM) procedure that alternates two operations familiar to systems neuroscience--tuning-curve estimation and label decoding--without requiring external labels. Applied to rodent hippocampal spike recordings, the model reveals distinct population patterns at the same physical position that supervised spatial decoding fails to detect. While learned latents exhibit place-field-like tuning, their reactivation patterns are better distinguished by behavioral states. The model further identifies a continuity-fragmentation axis that characterizes population activities across sleep-wake brain states that is modulated by cholinergic inputs. By not relying on externally imposed spatial labels, our approach exposes structure that supervised approaches obscure and provides a powerful tool for datasets lacking behavioral tracking.

neuroscience↗

bioRxiv2025

Non-invasive modulation of brain activity and behavior by transcranial radio frequency stimulation

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSAchieving non-invasive, targeted modulation of deep brain tissue remains a major challenge in neurotechnology. Current non-invasive brain stimulation methods--such as transcranial electrical (TES), magnetic (TMS), and focused ultrasound (TFUS) stimulation--suffer from limitations in spatial focality, penetration depth, or skull-related distortions. Radio frequency (RF) energy, which penetrates biological tissue effectively, offers an alternative avenue for neural modulation. This study introduces Transcranial Radio Frequency Stimulation (TRFS) as a novel, contactless neuromodulation technique that leverages RF-induced thermal effects to modulate neural activity in vivo. MethodsWe developed a custom RF stimulation system using 945 MHz stub antennas optimized for localized brain heating in mice. Using our unique experimental setup, we developed and tested two operational modes of TRFS: Pristine mode: RF stimulation applied to intact brain tissue. RF-genetics mode: RF stimulation applied to brain regions virally transduced to overexpress the thermosensitive TRPV1 ion channel. Neural activity was recorded using metal-free one-photon fiber photometry with GCaMP calcium indicators. Behavioral effects were assessed through a rotational test in freely moving mice after MK-801-induced hyperlocomotion. Local temperature changes were monitored by optical thermometry. ResultsIn pristine mode, RF exposure induced temperature rises leading to dose-dependent suppression of cortical parvalbumin (PV) interneuron activity. This neural suppression translated behaviorally into a unilateral rotational bias ipsilateral to the stimulated hemisphere in hyperlocomotive freely moving mice. In RF-genetics mode, RF stimulation of TRPV1-overexpressing regions produced temperature-dependent excitation of neural activity once local change in temperatures exceeded {Delta}T {approx} 1.5 {degrees}C. Behaviorally, this excitation reversed the direction of rotation in hyperlocomotive freely moving mice, yielding a contralateral bias. ConclusionsTRFS represents a conceptual advance in neuromodulation, uniting the inherent capability of RF energy to target deep brain tissue with the biophysical reliability of thermal modulation. TRFS applications are bimodal, capable of influencing the pristine brain by suppressing the activity of specific neuronal populations in targeted regions, or of exciting selectively transfected neural ensembles expressing thermosensitive TRPV1 ion channels. The latter modality, first introduced here, represents a novel concept termed "RF-genetics." TRFS represents a promising platform for next-generation non-invasive brain stimulation with potential translational applications in treating various neurological and psychiatric disorders.

neuroscience↗

bioRxiv2025

Inhibitory and disinhibitory VIP IN-mediated circuits in neocortex

Cortical GABAergic interneurons (INs) expressing the neuropeptide vasoactive-intestinal peptide (VIP) predominantly function by inhibiting dendritic-targeting somatostatin (SST) expressing INs, thereby disinhibiting pyramidal cells (PCs) and facilitating cortical circuit plasticity. VIP INs are a molecularly heterogeneous group, but the physiological significance of this diversity is unclear at present. Here, we have characterized the functional diversity of VIP INs in the primary somatosensory cortex (vS1) using intersectional genetic approaches. We found that VIP INs are comprised of four primary populations that exhibit different laminar distributions, axonal and dendritic arbors, intrinsic electrophysiological properties, and efferent connectivity. Furthermore, we observe that these populations are differentially activated by long-range inputs, and display distinct responses to neuromodulation by endocannabinoids, acetylcholine and noradrenaline. Stimulation of VIP IN subpopulations in vivo results in differential effects on the cortical network, thus providing evidence for specialized modes of VIP IN-mediated regulation of PC activity during cortical information processing.

neuroscience↗

bioRxiv2025

Spatiotemporal Patterns Differentiate Hippocampal Sharp-Wave Ripples from Interictal Epileptiform Discharges in Mice and Humans

Hippocampal sharp-wave ripples (SPW-Rs) are high-frequency oscillations critical for memory consolidation in mammals. Despite extensive characterization in rodents, their application as biomarkers to track and treat memory dysfunction in humans is limited by coarse spatial sampling, interference from interictal epileptiform discharges (IEDs), and lack of consensus on human SPW-R localization and morphology. We demonstrate that mouse and human hippocampal ripples share spatial, spectral and temporal features, which are clearly distinct from IEDs. In 1024-channel hippocampal recordings from APP/PS1 mice, SPW-Rs were distinguishable from IEDs by their narrow localization to the CA1 pyramidal layer, narrowband frequency peaks, and multiple ripple cycles on the unfiltered local field potential. In epilepsy patients, ripples showed similar narrowband frequency peaks and visible ripple cycles in CA1 and the subiculum but were absent in the dentate gyrus. Conversely, IEDs showed a broad spatial extent and wide-band frequency power. We introduce a semi-automated, human ripple detection toolbox ("ripmap") selecting optimal detection channels and separating event waveforms by low-dimensional embedding. Our approach improves ripple detection accuracy, providing a firm foundation for future human memory research.

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bioRxiv2024

Topography of putative bidirectional interaction between hippocampal sharp wave ripples and neocortical slow oscillations

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability was correlated with UP/DOWN states in mouse default mode network, with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN[->]UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

neuroscience↗

bioRxiv2024

Hippocampal neuronal activity is aligned with action plans

Neurons in the hippocampus are correlated with different variables, including space, time, sensory cues, rewards, and actions, where the extent of tuning depends on ongoing task demands. However, it remains uncertain whether such diverse tuning corresponds to distinct functions within the hippocampal network or if a more generic computation can account for these observations. To disentangle the contribution of externally driven cues versus internal computation, we developed a task in mice where space, auditory tones, rewards, and context were juxtaposed with changing relevance. High-density electrophysiological recordings revealed that neurons were tuned to each of these modalities. By comparing movement paths and action sequences, we observed that external variables had limited direct influence on hippocampal firing. Instead, spiking was influenced by online action plans modulated by goal uncertainty. Our results suggest that internally generated cell assembly sequences are selected and updated by action plans toward deliberate goals. The apparent tuning of hippocampal neuronal spiking to different sensory modalities might emerge due to alignment to the afforded action progression within a task rather than representation of external cues.

neuroscience↗

bioRxiv2024

Imaging high-frequency voltage dynamics in multiple neuron classes of behaving mammals

Fluorescent genetically encoded voltage indicators report transmembrane potentials of targeted cell-types. However, voltage-imaging instrumentation has lacked the sensitivity to track spontaneous or evoked high-frequency voltage oscillations in neural populations. Here we describe two complementary TEMPO voltage-sensing technologies that capture neural oscillations up to [~]100 Hz. Fiber-optic TEMPO achieves [~]10-fold greater sensitivity than prior photometry systems, allows hour-long recordings, and monitors two neuron-classes per fiber-optic probe in freely moving mice. With it, we uncovered cross-frequency-coupled theta- and gamma-range oscillations and characterized excitatory-inhibitory neural dynamics during hippocampal ripples and visual cortical processing. The TEMPO mesoscope images voltage activity in two cell-classes across a [~]8-mm-wide field-of-view in head-fixed animals. In awake mice, it revealed sensory-evoked excitatory-inhibitory neural interactions and traveling gamma and 3-7 Hz waves in the visual cortex, and previously unreported propagation directions for hippocampal theta and beta waves. These technologies have widespread applications probing diverse oscillations and neuron-type interactions in healthy and diseased brains.

neuroscience↗

bioRxiv2024

Dual-color micro-LEDs integrated neural interface for multi-control optogenetic electrophysiology

Over recent decades, optogenetics has become a pivotal technique for elucidating the functionality of neuronal circuits in living organisms. By genetically modifying specific cells within targeted tissues to respond to particular optical stimuli, researchers can achieve precise activation or inhibition of these cells. This capability enables detailed investigations of neural circuitry with unprecedented accuracy. However, there is a rising need for hardware that supports bidirectional control in conjunction with electrophysiological recording. A significant challenge in this domain is the compact integration of dual light sources and a recording system. This study addresses this challenge through the development of a novel microfabrication and assembly technique for embedding dual-color micro-LEDs and recording electrodes into a Michigan-type neural probe structure, designated as DuoLite (Dual-color micro-LEDs Integrated Neural-Interface Optoelectrode for Multi-Control Optogenetic Electrophysiology). We present two device variants: (a) a small-group and (b) a large-group cell-targeted design, each incorporating micro-LEDs with a minimal area of <100 m2 for both red and blue light. The design and assembly techniques for integrating all three components within a shank width of <100 m are thoroughly detailed, and the functionality of the devices is validated through in vivo experiments.

bioengineering↗

bioRxiv2024

Self-Assembled Origami Neural Probes for Scalable, Multifunctional, Three-Dimensional Neural Interface

Flexible intracortical neural probes have drawn attention for their enhanced longevity in high-resolution neural recordings due to reduced tissue reaction. However, the conventional monolithic fabrication approach has met significant challenges in: (i) scaling the number of recording sites for electrophysiology; (ii) integrating of other physiological sensing and modulation; and (iii) configuring into three-dimensional (3D) shapes for multi-sided electrode arrays. We report an innovative self-assembly technology that allows for implementing flexible origami neural probes as an effective alternative to overcome these challenges. By using magnetic-field-assisted hybrid self-assembly, multiple probes with various modalities can be stacked on top of each other with precise alignment. Using this approach, we demonstrated a multifunctional device with scalable high-density recording sites, dopamine sensors and a temperature sensor integrated on a single flexible probe. Simultaneous large-scale, high-spatial-resolution electrophysiology was demonstrated along with local temperature sensing and dopamine concentration monitoring. A high-density 3D origami probe was assembled by wrapping planar probes around a thin fiber in a diameter of 80[~]105 m using optimal foldable design and capillary force. Directional optogenetic modulation could be achieved with illumination from the neuron-sized micro-LEDs (LEDs) integrated on the surface of 3D origami probes. We could identify angular heterogeneous single-unit signals and neural connectivity 360{degrees} surrounding the probe. The probe longevity was validated by chronic recordings of 64-channel stacked probes in behaving mice for up to 140 days. With the modular, customizable assembly technologies presented, we demonstrated a novel and highly flexible solution to accommodate multifunctional integration, channel scaling, and 3D array configuration.

neuroscience↗

bioRxiv2024

Perpetual step-like restructuring of hippocampal circuit dynamics

Representation of the environment by hippocampal populations is known to drift even within a familiar environment, which could reflect gradual changes in single cell activity or result from averaging across discrete switches of single neurons. Disambiguating these possibilities is crucial, as they each imply distinct mechanisms. Leveraging change point detection and model comparison, we found that CA1 population vectors decorrelated gradually within a session. In contrast, individual neurons exhibited predominantly step-like emergence and disappearance of place fields or sustained change in within-field firing. The changes were not restricted to particular parts of the maze or trials and did not require apparent behavioral changes. The same place fields emerged, disappeared, and reappeared across days, suggesting that the hippocampus reuses pre-existing assemblies, rather than forming new fields de novo. Our results suggest an internally-driven perpetual step-like reorganization of the neuronal assemblies.

neuroscience↗

bioRxiv2023

Selection of experience for memory by hippocampal sharp wave ripples

A general wisdom is that experiences need to be tagged during learning for further consolidation. However, brain mechanisms that select experiences for lasting memory are not known. Combining large-scale neural recordings with a novel application of dimensionality reduction techniques, we observed that successive traversals in the maze were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered (trial number). When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials and their unique spike content most often decoded the trial in which they occurred. In turn, during post-experience sleep, SPW-Rs continued to replay those trials that were reactivated most frequently during awake SPW-Rs. These findings suggest that replay content of awake SPW-Rs provides a tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

neuroscience↗

bioRxiv2023

ThermoMaze: A behavioral paradigm for readout of immobility-related brain events

Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organisms responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting sufficient amounts of brain data. To achieve this goal, we developed the ThermoMaze, which exploits the animals natural warmth-seeking homeostatic behavior. By decreasing the floor temperature and selectively heating unmarked areas, mice avoid the aversive state by exploring the maze and finding the warm spot. In its design, the ThermoMaze is analogous to the widely used water maze but without the inconvenience of a wet environment and, therefore, allows the collection of physiological data in many trials. We combined the ThermoMaze with electrophysiology recording, and report that spiking activity of hippocampal CA1 neurons during sharp-wave ripple events encode the position of the animal. Thus, place-specific firing is not confined to locomotion and associated theta oscillations but persist during waking immobility and sleep at the same location. The ThermoMaze will allow for detailed studies of brain correlates of immobility, preparatory-consummatory transitions and open new options for studying behavior-mediated temperature homeostasis.

neuroscience↗

bioRxiv2023

Intricate epileptiform discharges affect memory in an Alzheimer's Disease mouse model

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimers Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory. Significant StatementPrevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Id2 GABAergic interneurons comprise a neglected fourth major group of cortical inhibitory cells

Cortical GABAergic interneurons (INs) represent a diverse population of mainly locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP). However, a fourth group that includes neurogliaform cells (NGFCs) has remained enigmatic due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 INs had more variable properties, with most cells corresponding to a diverse group of INs that strongly expresses the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several distinguishing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this neglected group of INs.

neuroscience↗