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July 2012 - present
Publications
Publications (545)
An organism’s survival depends on its ability to anticipate forthcoming events and detect discrepancies between the expected and actual sensory inputs. We analyzed data from mice performing a visual go/no-go change-detection task where the sequence of stimulus presentations was intermittently interrupted by omission of a stimulus. The omission of a...
Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism’s responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting su...
Implantable active dense CMOS neural probes unlock the possibility of spatiotemporally resolving the activity of hundreds of single neurons in multiple brain circuits to investigate brain dynamics. Mapping neural dynamics in brain circuits with anatomical structures spanning several millimeters, however, remains challenging. Here, a CMOS neural pro...
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 l...
Neurons in the hippocampus are correlated with different variables, including space, time, sensory cues, rewards and actions, in which the extent of tuning depends on ongoing task demands1, 2, 3, 4, 5, 6, 7–8. However, it remains uncertain whether such diverse tuning corresponds to distinct functions within the hippocampal network or whether a more...
I am lucky to be part of the hippocampus story, if not from the beginning but at least in its formative decades. Being part of this community is a true privilege. As I try to illustrate below, science is made by scientists. My fierce competitors over the years have become my close friends. I hope the field of hippocampus research will stay that way...
Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism’s responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting su...
Physiological changes during awake immobility–related brain states remain one of the great unexplored behavioral states. Controlling periods of awake immobility is challenging because restraining the animal is stressful and is accompanied by altered physiological states. Here, we describe the ThermoMaze, a behavioral paradigm that allows for the co...
Implantable active dense CMOS neural probes unlock the possibility of spatiotemporally resolving the activity of hundreds of single neurons in multiple brain circuits to investigate brain dynamics. Mapping neural dynamics in brain circuits with anatomical structures spanning several millimeters, however, remains challenging. Here, we demonstrate th...
The mammillary bodies (MBOs), a group of hypothalamic nuclei, play a pivotal role in memory formation and spatial navigation. They receive extensive inputs from the hippocampus through the fornix, but the physiological significance of these connections remains poorly understood. Damage to the MBOs is associated with various forms of anterograde amn...
While visual responses to familiar and novel stimuli have been extensively studied, it is unknown how neuronal representations of familiar stimuli are affected when they are interleaved with novel images. We examined a large-scale dataset from mice performing a visual go/no-go change detection task. After training with eight images, six novel image...
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 p...
Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting popul...
A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different
neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various
brain states. Although these neuromod...
Hippocampal principal neurons display both spatial tuning properties and memory features. Whether this distinction corresponds to separate neuron types or a context-dependent continuum has been debated. We report here that the task-context (‘‘splitter’’) feature is highly variable along both trial and spatial position axes. Neurons acquire or lose...
Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism’s responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting su...
Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism’s responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting su...
The ability to store information about the past to dynamically predict and prepare for the future is among the most fundamental tasks the brain performs. To date, the problems of understanding how the brain stores and organizes information about the past (memory) and how the brain represents and processes temporal information for adaptive behavior...
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...
Over the past few decades, daily exposure to radiofrequency (RF) fields has been increasing due to the rapid development of wireless and medical imaging technologies. Under extreme circumstances, exposure to very strong RF energy can lead to heating of body tissue, even resulting in tissue injury. The presence of implanted devices, moreover, can am...
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,...
Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in ep...
Hippocampal sharp-wave ripples (SPW-Rs) are critical for memory consolidation and retrieval. The neuronal content of spiking during SPW-Rs is believed to be under the influence of neocortical inputs via the entorhinal cortex (EC). Optogenetic silencing of the medial EC (mEC) reduced the incidence of SPW-Rs with minor impacts on their magnitude or d...
Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no...
Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory b...
Neuronal oscillations offer access to neuronal operations, bringing microscopic and macroscopic mechanisms, experimental methods, and explanations to a common platform. The field of brain rhythms has become the agora of discussions from temporal coordination of neuronal populations within and across brain regions to cognitive phenomena, including l...
Flexible implantable neurointerfaces show great promise in addressing one of the major challenges of implantable neurotechnology, namely the loss of signal connected to unfavorable probe tissue interaction. The authors here show how multilayer polyimide probes allow high-density intracortical recordings to be combined with a reliable long-term stab...
Examination of cognition has historically been approached from language and introspection. However, human language–dependent definitions ignore the evolutionary roots of brain mechanisms and constrain their study in experimental animals. We promote an alternative view, namely that cognition, including memory, can be explained by exaptation and expa...
There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer’s disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found th...
With the development of novel technologies, radio frequency (RF) energy exposure is expanding at various wavelengths and power levels. These developments necessitate updated approaches of RF measurements in complex environments, particularly in live biological tissue. Accurate dosimetry of the absorbed RF electric fields (E-Fields) by the live tiss...
Neurons perform input-output operations that integrate synaptic inputs with intrinsic electrical properties; these operations are generally constrained by the brevity of synaptic events. Here, we report that sustained firing of CA1 hippocampal fast-spiking parvalbumin-expressing interneurons (PV-INs) can be persistently interrupted for several hund...
Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), a...
Philosophers, psychologists, and biologists have long pondered how experiences mark the mind. It is clear that there is no one seat of memory. Within each memory system there are multiple biological mechanisms for information storage. This chapter focuses on how memory could be supported by coincidence of neural activity, changes in synaptic streng...
Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodol...
The incorporation of new information into the hippocampal network is likely to be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization and consequences of such patterns remain poorly understood. In the present study we show that hippocampal network dynamics are affected by sequential n...
Neurons perform input-output operations that integrate synaptic inputs with intrinsic electrical properties, operations generally constrained by the brevity of synaptic events. Here we report that sustained firing of CA1 hippocampal fast-spiking parvalbumin-expressing interneurons (PV-INs) can be persistently interrupted for up to several hundred m...
Hippocampal place cells receive a disparate collection of excitatory and inhibitory currents that endow them with spatially selective discharges and rhythmic activity. Using a combination of in vivo intracellular and extracellular recordings with opto/chemogenetic manipulations and computational modeling, we investigate the influence of inhibitory...
Maladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments...
As the use of Radio Frequency (RF) technologies increases, the impact of RF radiation on neurological function continues to receive attention. Whether RF radiation can modulate ongoing neuronal activity by non-thermal mechanisms has been debated for decades. However, the interactions between radiated energy and metal-based neural probes during expe...
The current dominant view of the hippocampus is that it is a navigation “device” guided by environmental inputs. Yet, a critical aspect of navigation is a sequence of planned, coordinated actions. We examined the role of action in the neuronal organization of the hippocampus by training rats to jump a gap on a linear track. Recording local field po...
HectoSTAR µLED Optoelectrodes
The cover shows an illustrative image of multi‐region neural recording and optogenetic manipulation with high spatio‐temporal resolution in the brain. In article number 2105414, György Buzsáki, Antonio Fernández‐Ruiz, Euisik Yoon, and co‐workers design HectoSTAR µLED optoelectrodes with 256 recording sites and 128 micr...
Neurons use various forms of negative feedback to maintain their synaptic strengths within an operationally useful range. While this homeostatic plasticity is thought to distinctly counteract the destabilizing positive feedback of Hebbian plasticity, there is considerable overlap in the molecular components mediating both forms of plasticity. The v...
How do neurons and networks of neurons interact spatially? Here, we overview recent discoveries revealing how spatial dynamics of spiking and postsynaptic activity efficiently expose and explain fundamental brain and brainstem mechanisms behind detection, perception, learning, and behavior.
Significance
Bidirectional communication between the hippocampus and other brain areas via sharp wave ripples (SPW-Rs) has been hypothesized to play an important role in cognitive functions. However, brain-wide coupling to SPW-Rs has been difficult to study at high temporal and spatial resolution. Here, we show that SPW-Rs coincide with transient b...
The incorporation of novel information into the hippocampal network is likely be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization, and consequences of such patterns remain poorly understood. Here, we show that hippocampal network dynamics are affected by sequential neurogenesis. We...
Dynamic interactions within and across brain areas underlie behavioral and cognitive functions. To understand the basis of these processes, the activities of distributed local circuits inside the brain of a behaving animal must be synchronously recorded while the inputs to these circuits are precisely manipulated. Even though recent technological a...
Sets of spikes emitted sequentially across neurons constitute fundamental pulse packets in neural information processing, including offline memory replay during hippocampal sharp-wave ripples (SWRs). The relative timing of neuronal spikes is fine-tuned in each spike sequence but can vary between different sequences. However, the microcircuitry mech...
Understanding how excitatory (E) and inhibitory (I) inputs are integrated by neurons requires monitoring their subthreshold behavior. We probed the subthreshold dynamics using optogenetic depolarizing pulses in hippocampal neuronal assemblies in freely moving mice. Excitability decreased during sharp-wave ripples coupled with increased I. In contra...
Biochemical mechanisms are temperature-dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here we report on the coupling of various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate, and duration are correlate...
By linking the past with the future, our memories define our sense of identity. Because human memory engages the conscious realm, its examination has historically been approached from language and introspection and proceeded largely along separate parallel paths in humans and other animals. Here, we first highlight the achievements and limitations...
In understanding circuit operations, a key problem is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. We addressed this issue in the hippocampus by performing combined optogenetic and pharmacogenetic local and upstream inactivation. Silencing the medial entorhinal cortex (mEC) largely abolished extra...
The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the “chandelier” or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics...
Neuronal firing patterns have significant spatiotemporal variety with no agreed upon theoretical framework. Using a combined experimental and modeling approach, we found that spike interval statistics can be described by discrete modes of activity. A "ground state" (GS) mode of low-rate spiking is universal among forebrain excitatory neurons and ch...
The hippocampus has previously been implicated in both cognitive and endocrine functions1–15. We simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats to identify an activity pattern that may link these disparate functions of the hippocampus. Here we re...
The large diversity of neuron types provides the means by which cortical circuits perform complex operations. Neuron can be described by biophysical and molecular characteristics, afferent inputs, and neuron targets. To quantify, visualize, and standardize those features, we developed the open-source, MATLAB-based framework CellExplorer. It consist...
Extracellular recordings in freely moving animals allow the monitoring of brain activity from populations of neurons at single-spike temporal resolution. While state-of-the-art electrophysiological recording devices have been developed in recent years (e.g., µLED and Neuropixels silicon probes), implantation methods for silicon probes in rats and m...
Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synap...
High-yield electrophysiological extracellular recording in freely moving rodents provides a unique window into the temporal dynamics of neural circuits. Recording from unrestrained animals is critical to investigate brain activity during natural behaviors. The use and implantation of high-channel-count silicon probes represent the largest cost and...
We describe the spatiotemporal course of cortical high-gamma activity, hippocampal ripple activity and interictal epileptiform discharges during an associative memory task in 15 epilepsy patients undergoing invasive EEG. Successful encoding trials manifested significantly greater high-gamma activity in hippocampus and frontal regions. Successful cu...
Brain region coordination in learning
Gamma-frequency oscillations have been hypothesized as a physiological mechanism of interregional communication in the brain. However, until now, all supporting data have been correlational and thus indirect. Fernández-Ruiz et al. examined gamma-frequency activity and spike coupling between the entorhinal corte...
Pyramidal cells and GABAergic interneurons fire together in balanced cortical networks. In contrast to this general rule, we describe a distinct neuron type in mice and rats whose spiking activity is anti-correlated with all principal cells and interneurons in all brain states but, most prevalently, during the down state of non-REM (NREM) sleep. We...
Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synap...
Memory models often emphasize the need to encode novel patterns of neural activity imposed by sensory drive. Prior learning and innate architecture likely restrict neural plasticity, however. Here, we test how the incorporation of synthetic hippocampal signals is constrained by preexisting circuit dynamics. We optogenetically stimulated small group...
High-yield electrophysiological extracellular recording in freely moving rodents provides a unique window into the temporal dynamics of neural circuits. Recording from unrestrained animals is critical to investigate brain activity during natural behaviors. The use and implantation of high-channel-count silicon probes represent the largest cost and...
The hippocampus is thought to guide navigation by forming a cognitive map of space. Different environments differ in geometry and the availability of cues that can be used for navigation. Although several spatial coding mechanisms are known to coexist in the hippocampus, how they are influenced by various environmental features is not well understo...
We present a device that can be utilized for a large-scale in vivo extracellular recording, from more than 250 electrodes, with the capability to optically modulate activities of neurons located at more than a hundred individual stimulation targets at the anatomical resolution.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Hippocampal theta oscillations coordinate neuronal firing to support memory and spatial navigation. The medial septum (MS) is critical in theta generation by two possible mechanisms: either a unitary “pacemaker” timing signal is imposed on the hippocampal system, or it may assist in organizing target subcircuits within the phase space of theta osci...
The large diversity of neuron types of the brain, with numerous unique electrophysiological characteristics, provides the means by which cortical circuits perform complex operations. To quantify, compare and visualize the functional features of single neurons, we have developed a MATLAB-based framework, CellExplorer, consisting of three components:...
The combination of in vivo extracellular recording and genetic-engineering-assisted optical stimulation is a powerful tool for the study of neuronal circuits. Precise analysis of complex neural circuits requires high-density integration of multiple cellular-size light sources and recording electrodes. However, high-density integration inevitably in...
Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-corti...
Hippocampal sharp wave-ripples (SWR) are thought to mediate brain-wide reactivation of memory traces in service of memory consolidation. However, rather than the faithful replay of neural activity observed during a specific experience, reactivation in both the hippocampus and downstream regions is more variable. We suggest that variable reactivatio...
Spiking activity of place cells in the hippocampus encodes the animal’s position as it moves through an environment. Within a cell’s place field, both the firing rate and the phase of spiking in the local theta oscillation contain spatial information. We propose a position–theta-phase (PTP) model that captures the simultaneous expression of the fir...
The mnemonic functions of hippocampal sharp wave ripples (SPW-Rs) have been studied extensively. Because hippocampal outputs affect not only cortical but also subcortical targets, we examined the impact of SPW-Rs on the firing patterns of lateral septal (LS) neurons in behaving rats. A large fraction of SPW-Rs were temporally locked to high-frequen...
Using clever experimental design and exploiting the high temporal resolution power of magnetoencephalography, Liu et al. show in humans how “offline” reactivation of brain patterns allows the abstraction of new knowledge from previous experience. The key mechanism may involve hippocampal sharp-wave ripples.
The Brain from Inside Out takes a critical look at contemporary brain research and reminds us that theoretical framework does matter. Current technology-driven neuroscience is still largely fueled by an empiricist philosophy assuming that the brain’s goal is to perceive, represent the world, and learn the truth. An inevitable consequence of this fr...
The science of space and time began with the invention of measuring instruments, which changed these dimensionless concepts into distance and duration with precise units. This process created a special problem for neuroscience. If space and time correspond to their measured variants, we may wonder what space and time mean without such instruments,...
Longer ripples make better memories
Sharp wave ripples in the hippocampus are thought to play a role in memory formation and action planning. Fernández-Ruiz et al. used multisite electrophysiological recordings combined with optogenetic activation of hippocampal pyramidal neurons in rats performing learning tasks. Learning and correct recall in spa...
During non-rapid eye movement (NREM) sleep, neuronal populations in the mammalian forebrain alternate between periods of spiking and inactivity. Termed the slow oscillation in the neocortex and sharp wave-ripples in the hippocampus, these alternations are often considered separately but are both crucial for NREM functions. By directly comparing exp...
In vivo extracellular electrophysiology and genetic-engineering-assisted optical stimulation combined (in vivo optoEphys) has proven its great potential to be one of the best tools for study of the intricate networks inside the brain. Micro-LED optoelectrode, the Michigan Probe with monolithically integrated cell-sized LEDs, enabled in vivo optoEph...
The relationship between mesoscopic local field potentials (LFPs) and single-neuron firing in the multi-layered neocortex is poorly understood. Simultaneous recordings from all layers in the primary visual cortex (V1) of the behaving mouse revealed functionally defined layers in V1. The depth of maximum spike power and sink-source distributions of...
Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intracellular and extracellular electrophysiological recordings. Genetically-identified classes of neurons are optically manipulated, though the versatility of optogenetics would be increased if independent control of distinct neural population...
Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its co...
Uncovering spatial representations from large-scale ensemble spike activity in specific brain circuits provides valuable feedback in closed-loop experiments. We develop a graphics processing unit (GPU)-powered population-decoding system for ultrafast reconstruction of spatial positions from rodents’ unsorted spatiotemporal spiking patterns, during...
Hippocampal sharp-wave ripples (SPW-Rs) support consolidation of recently acquired episodic memories and planning future actions by generating ordered neuronal sequences of previous or future experiences. SPW-Rs are characterized by several spectral components: a slow (5–15 Hz) sharp-wave, a high-frequency “ripple” oscillation (150–200 Hz), and a s...
Neural computations are often compared to instrument-measured distance or duration, and such relationships are interpreted by a human observer. However , neural circuits do not depend on human-made instruments but perform computations relative to an internally defined rate-of-change. While neuronal correlations with external measures, such as dista...
In the version of this article initially published, author Charan Ranganath's last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article.
