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Summary: 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 find that CA1 population vectors decorrelate gradually within a session. In contrast, individual neurons exhibit predominantly step-like emergence and disappearance of place fields or sustained changes in within-field firing. The changes are not restricted to particular parts of the maze or trials and do not require apparent behavioral changes. The same place fields emerge, disappear, and reappear 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.

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 collection of large amounts of physiological data while the animal rests at distinct experimenter-determined locations. We found that the paradigm generated long periods of immobility and did not alter the brain temperature. We combined the ThermoMaze with electrophysiology recordings in the CA1 region of the hippocampus and found a location-specific distribution of sharp-wave ripple events. We describe the construction of the ThermoMaze with the intention that it helps enable large-scale data recordings on immobility-related brain states.

Summary: 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 amnesia. However, information about the physiological characteristics of the MBO is limited, primarily due to the limited number of studies that have directly monitored MBO activity along with population patterns of its upstream partners. Employing large-scale silicon probe recording in mice, we characterize MBO activity and its interaction with the subiculum across various brain states. We find that MBO cells are highly diverse in their relationship to theta, ripple, and slow oscillations. Several of the physiological features are inherited by the topographically organized inputs to MBO cells. Our study provides insights into the functional organization of the MBOs.

Summary: Homeostatic regulation of synapses is vital for nervous system function and key to understanding a range of neurological conditions. Synaptic homeostasis is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Surprisingly, we find that the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic, and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses can efficiently safeguard future capacity for synaptic plasticity. This mechanism of synaptic adaptation supports a broader set of homeostatic changes, including action potential autoregulation, and invites further inquiry into how such a mechanism varies in health and disease.

Summary: 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 splitter features across trials even when place field features remain unaltered. Multiple place fields of the same neuron can individually encode both past or future run trajectories, implying that splitter fields are under the control of assembly activity. Place fields can be differentiated into subfields by the behavioral choice of the animal, and splitting within subfields evolves across trials. Interneurons also differentiate choices by integrating inputs from pyramidal cells. Finally, bilateral optogenetic inactivation of the medial entorhinal cortex reversibly decreases the fraction of splitter fields. Our findings suggest that place or splitter features are different manifestations of the same hippocampal computation.

Abstract 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 approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

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 been less well characterized 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 underappreciated group of INs.

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 tissue is the keystone of environmental health considerations for this type of ever-growing non-ionizing radiation energy. In this study, we introduce a technique for direct in-vivo measurement of electric fields in living tissue. Proof of principle in-vivo electric field measurements were conducted in rodent brains using Bismuth Silicon Oxide (BSO) crystals exposed to varying levels of RF energy. Electric field measurements were calibrated and verified using in-vivo temperature measurements using optical temperature fibers alongside electromagnetic field simulations of a transverse electromagnetic (TEM) cell.

While the contribution of sharp wave ripples in memory consolidation and decision-making is established in rodent models, our understanding of their role in human memory is incomplete. Here, the authors discuss common methodological challenges in detecting, analyzing, and reporting sharp wave ripples, then they suggest practical solutions to distinguish them from other high-frequency events

The sequences of neuronal spikes during hippocampal sharp-wave ripples are important for memory storage. Here the authors show that inhibitory neurons activated before sharp-wave ripples regulate the orders of spikes during sharp-wave ripples.

Abstract 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 advances have enabled such large‐scale recording capabilities, the development of the high‐spatiotemporal‐resolution and large‐scale modulation techniques to accompany those recordings has lagged. A novel neural probe is presented in this work that enables simultaneous electrical monitoring and optogenetic manipulation of deep neuronal circuits at large scales with a high spatiotemporal resolution. The “hectoSTAR” micro‐light‐emitting‐diode (μLED) optoelectrode features 256 recording electrodes and 128 stimulation μLEDs monolithically integrated on the surface of its four 30‐µm thick silicon micro‐needle shanks, covering a large volume with 1.3‐mm × 0.9‐mm cross‐sectional area located as deep as 6 mm inside the brain. The use of this device in behaving mice for dissecting long‐distance network interactions across cortical layers and hippocampal regions is demonstrated. The recording‐and‐stimulation capabilities hectoSTAR μLED optoelectrodes enables will open up new possibilities for the cellular and circuit‐based investigation of brain functions in behaving animals.

Artifact-free opto-electrophysiology is key for precise modulation and monitoring of individual neurons at high spatio-temporal resolution. The authors present a method for eliminating stimulation artifacts in high-density micro-LED optoelectrodes for accurate functional mapping of local circuits.

Communication between the hippocampus and neocortex is organized through high frequency sharp wave ripple activity. Here, the authors report ripple activity coupling between the hippocampus and granular retrosplenial cortex suggesting an involvement in communicating with the neocortex.

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 mice have not advanced substantially for a decade. The surgery is complex, takes time to master, and involves handling expensive devices and valuable animal subjects. In addition, chronic silicon neural probes are practically single implant devices due to the current low success rate of probe recovery. To successfully recover silicon probes, improve upon the quality of electrophysiological recording, and make silicon probe recordings more accessible, we have designed a miniature, low cost, and recoverable microdrive system. The addition of a novel 3D-printed skull baseplate makes the surgery less invasive, faster, and simpler for both rats and mice. We provide detailed procedural instructions and print designs, allowing researchers to adapt and flexibly customize our designs to their experimental usage.

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 synaptic and cellular activity patterns across development using high spatiotemporal resolution in vivo electrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition is characterized by relative neural quiescence, after which spatially distributed, temporally precise, and internally organized activity occurs. We demonstrate a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism that could facilitate a transition in network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.

NREM sleep in rodents is characterized by internal dynamics in the form of UP/DOWN states in the neocortex and SWRs in the hippocampus. Here, the authors report that a mean field model with excitable dynamics captures the transition probabilities between these states from rodent sleep data.

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 experimental complexity associated with such recordings making a recoverable and reusable system desirable. To address this, we have designed and tested a novel 3D printed head-gear system for freely moving mice and rats. The system consists of a recoverable microdrive printed in stainless steel and a plastic head cap system, allowing researchers to reuse the silicon probes with ease, decreasing the effective cost, and the experimental effort and complexity. The cap designs are modular and provide structural protection and electrical shielding to the implanted hardware and electronics. We provide detailed procedural instructions allowing researchers to adapt and flexibly modify the head-gear system.

Transcranial electrical stimulation techniques, such as tDCS and tACS, are popular tools for neuroscience and clinical therapy, but how low-intensity current might modulate brain activity remains unclear. In this review, the authors review the evidence on mechanisms of transcranial electrical stimulation.

Though transcranial electric stimulation has been used to influence brain activity, it is debated whether neuronal spiking activity is directly affected by commonly-used protocols. Here, the authors quantify the voltage gradients necessary to instantaneously affect neuronal spiking and show that they are higher than commonly-used protocols.

Transcranial alternating current stimulation (tACS) has been proposed to enhance neural rhythms supporting memory. Here, the authors leverage human intracranial recordings to show that low-frequency tACS does not entrain key rhythms in non-REM sleep or resting wakefulness.

Summary: 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 run behavior or sleep. In comparison with an optimized quad-core central processing unit (CPU) implementation, our approach achieves an ∼20- to 50-fold increase in speed in eight tested rat hippocampal, cortical, and thalamic ensemble recordings, with real-time decoding speed (approximately fraction of a millisecond per spike) and scalability up to thousands of channels. By accommodating parallel shuffling in real time (computation time

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Summary: 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 slow “gamma” oscillation (20–40 Hz). Using laminar hippocampal recordings and optogenetic manipulations, we dissected the origin of these spectral components. We show that increased power in the 20–40 Hz band does not reflect an entrainment of CA1 and CA3 neurons at gamma frequency but the power envelope of overlapping ripples. Spike-local field potential coupling between unit firing in CA1 and CA3 regions during SPW-Rs is lowest in the gamma band. Longer SPW-Rs are preceded by increased firing in the entorhinal cortex. Thus, fusion of SPW-Rs leads to lengthening of their duration associated with increased power in the slow gamma band without the presence of true oscillation. : SWRs are thought to support memory consolidation and planning. They are characterized by several spectral components: a slow-frequency wave (sharp-wave), a high-frequency oscillation (ripple), and a slow “gamma” band. Here, we report a mechanism, involving the concatenation of several SWRs, which explains the generation of the “gamma” frequency band. Keywords: hippocampus, oscillations, memory consolidation, sharp-wave ripples, gamma, entorhinal cortex, optogenetics

It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Figure 11. The corrected figures are now properly calibrated to 1 mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section ‘Intensity ranged from 0.5 to 2.5 mA (current density 0.125–0.625 mA mA/cm2), which is stronger than in previous reports’, should have read ‘Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625–0.3125 mA/cm2), which is stronger than in previous reports.’ These errors do not affect any of the Article’s conclusions.

Despite the importance of the discharge frequency in neuronal communication, little is known about the firing-rate patterns of cortical populations. Using large-scale recordings from multiple layers of the entorhinal-hippocampal loop, we found that the firing rates of principal neurons showed a lognormal-like distribution in all brain states. Mean and peak rates within place fields of hippocampal neurons were also strongly skewed. Importantly, firing rates of the same neurons showed reliable correlations in different brain states and testing situations, as well as across familiar and novel environments. The fraction of neurons that participated in population oscillations displayed a lognormal pattern. Such skewed firing rates of individual neurons may be due to a skewed distribution of synaptic weights, which is supported by our observation of a lognormal distribution of the efficacy of spike transfer from principal neurons to interneurons. The persistent skewed distribution of firing rates implies that a preconfigured, highly active minority dominates information transmission in cortical networks.

Using silicon-based recording electrodes, we recorded neuronal activity of the dorsal hippocampus and dorsomedial entorhinal cortex from behaving rats. The entorhinal neurons were classified as principal neurons and interneurons based on monosynaptic interactions and wave-shapes. The hippocampal neurons were classified as principal neurons and interneurons based on monosynaptic interactions, wave-shapes and burstiness. The data set contains recordings from 7,736 neurons (6,100 classified as principal neurons, 1,132 as interneurons, and 504 cells that did not clearly fit into either category) obtained during 442 recording sessions from 11 rats (a total of 204.5 hours) while they were engaged in one of eight different behaviours/tasks. Both original and processed data (time stamp of spikes, spike waveforms, result of spike sorting and local field potential) are included, along with metadata of behavioural markers. Community-driven data sharing may offer cross-validation of findings, refinement of interpretations and facilitate discoveries.

Large and long-lasting cytosolic calcium surges in astrocytes have been described in cultured cells and acute slice preparations. The mechanisms that give rise to these calcium events have been extensively studied in vitro. However, their existence and functions in the intact brain are unknown. We have topically applied Fluo-4 AM on the cerebral cortex of anesthetized rats, and imaged cytosolic calcium fluctuation in astrocyte populations of superficial cortical layers in vivo, using two-photon laser scanning microscopy. Spontaneous [Ca(2+)](i) events in individual astrocytes were similar to those observed in vitro. Coordination of [Ca(2+)](i) events among astrocytes was indicated by the broad cross-correlograms. Increased neuronal discharge was associated with increased astrocytic [Ca(2+)](i) activity in individual cells and a robust coordination of [Ca(2+)](i) signals in neighboring astrocytes. These findings indicate potential neuron-glia communication in the intact brain.