Hyperpolarization-activated currents drive neuronal activation sequences in sleep.

Sequential neuronal patterns are believed to support information processing in the cortex, yet their origin is still a matter of debate. We report that neuronal activity in the mouse postsubiculum (PoSub), where a majority of neurons are modulated by the animal's head direction, was sequentially activated along the dorsoventral axis during sleep at the transition from hyperpolarized "DOWN" to activated "UP" states, while representing a stable direction. Computational modeling suggested that these dynamics could be attributed to a spatial gradient of hyperpolarization-activated currents (Ih), which we confirmed in ex vivo slice experiments and corroborated in other cortical structures. These findings open up the possibility that varying amounts of Ih across cortical neurons could result in sequential neuronal patterns and that traveling activity upstream of the entorhinal-hippocampal circuit organizes large-scale neuronal activity supporting learning and memory during sleep.

Local origin of excitatory-inhibitory tuning equivalence in a cortical network.

The interplay between excitation and inhibition determines the fidelity of cortical representations. The receptive fields of excitatory neurons are often finely tuned to encoded features, but the principles governing the tuning of inhibitory neurons remain elusive. In this study, we recorded populations of neurons in the mouse postsubiculum (PoSub), where the majority of excitatory neurons are head-direction (HD) cells. We show that the tuning of fast-spiking (FS) cells, the largest class of cortical inhibitory neurons, was broad and frequently radially symmetrical. By decomposing tuning curves using the Fourier transform, we identified an equivalence in tuning between PoSub-FS and PoSub-HD cell populations. Furthermore, recordings, optogenetic manipulations of upstream thalamic populations and computational modeling provide evidence that the tuning of PoSub-FS cells has a local origin. These findings support the notion that the equivalence of neuronal tuning between excitatory and inhibitory cell populations is an intrinsic property of local cortical networks.

Pynapple, a toolbox for data analysis in neuroscience.

Datasets collected in neuroscientific studies are of ever-growing complexity, often combining high-dimensional time series data from multiple data acquisition modalities. Handling and manipulating these various data streams in an adequate programming environment is crucial to ensure reliable analysis, and to facilitate sharing of reproducible analysis pipelines. Here, we present Pynapple, the PYthon Neural Analysis Package, a lightweight python package designed to process a broad range of time-resolved data in systems neuroscience. The core feature of this package is a small number of versatile objects that support the manipulation of any data streams and task parameters. The package includes a set of methods to read common data formats and allows users to easily write their own. The resulting code is easy to read and write, avoids low-level data processing and other error-prone steps, and is open source. Libraries for higher-level analyses are developed within the Pynapple framework but are contained within a collaborative repository of specialized and continuously updated analysis routines. This provides flexibility while ensuring long-term stability of the core package. In conclusion, Pynapple provides a common framework for data analysis in neuroscience.

Local neuronal excitation and global inhibition during epileptic fast ripples in humans.

Understanding the neuronal basis of epileptic activity is a major challenge in neurology. Cellular integration into larger scale networks is all the more challenging. In the local field potential, interictal epileptic discharges can be associated with fast ripples (200-600 Hz), which are a promising marker of the epileptogenic zone. Yet, how neuronal populations in the epileptogenic zone and in healthy tissue are affected by fast ripples remain unclear. Here, we used a novel 'hybrid' macro-micro depth electrode in nine drug-resistant epileptic patients, combining classic depth recording of local field potentials (macro-contacts) and two or three tetrodes (four micro-wires bundled together) enabling up to 15 neurons in local circuits to be simultaneously recorded. We characterized neuronal responses (190 single units) with the timing of fast ripples (2233 fast ripples) on the same hybrid and other electrodes that target other brain regions. Micro-wire recordings reveal signals that are not visible on macro-contacts. While fast ripples detected on the closest macro-contact to the tetrodes were always associated with fast ripples on the tetrodes, 82% of fast ripples detected on tetrodes were associated with detectable fast ripples on the nearest macro-contact. Moreover, neuronal recordings were taken in and outside the epileptogenic zone of implanted epileptic subjects and they revealed an interlay of excitation and inhibition across anatomical scales. While fast ripples were associated with increased neuronal activity in very local circuits only, they were followed by inhibition in large-scale networks (beyond the epileptogenic zone, even in healthy cortex). Neuronal responses to fast ripples were homogeneous in local networks but differed across brain areas. Similarly, post-fast ripple inhibition varied across recording locations and subjects and was shorter than typical inter-fast ripple intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that fast ripples engage local and global networks, including healthy tissue, and point to network features that pave the way for new diagnostic and therapeutic strategies. They also reveal how even localized pathological brain dynamics can affect a broad range of cognitive functions.

Querying hippocampal replay with subcortical inputs.

During sleep, the hippocampus recapitulates neuronal patterns corresponding to behavioral trajectories during previous experiences. This hippocampal replay supports the formation of long-term memories. Yet, whether replay originates within the hippocampal circuitry or is initiated by extrahippocampal inputs is unknown. Here, I review recent findings regarding the organization of neuronal activity upstream to the hippocampus, in the head-direction (HD) and grid cell networks, and its relationship to replay. I argue that hippocampal activity at the onset of replay is under the influence of signals from primary spatial areas. In turn, hippocampal replay resets the HD network activity to select a new direction for the next replay event. This reciprocal interaction between the HD network and the hippocampus may be essential in grounding meaning to hippocampal activity, specifically by training decoders of hippocampal sequences. Neuronal dynamics in thalamo-hippocampal loops may thus be instrumental for memory processes during sleep.

Flexible cue anchoring strategies enable stable head direction coding in both sighted and blind animals.

Vision plays a crucial role in instructing the brain's spatial navigation systems. However, little is known about how vision loss affects the neuronal encoding of spatial information. Here, recording from head direction (HD) cells in the anterior dorsal nucleus of the thalamus in mice, we find stable and robust HD tuning in rd1 mice, a model of photoreceptor degeneration, that go blind by approximately one month of age. In contrast, placing sighted animals in darkness significantly impairs HD cell tuning. We find that blind mice use olfactory cues to maintain stable HD tuning and that prior visual experience leads to refined HD cell tuning in blind rd1 adult mice compared to congenitally blind animals. Finally, in the absence of both visual and olfactory cues, the HD attractor network remains intact but the preferred firing direction of HD cells drifts over time. These findings demonstrate flexibility in how the brain uses diverse sensory information to generate a stable directional representation of space.

Precise coupling of the thalamic head-direction system to hippocampal ripples.

The anterior thalamus is a key relay of neuronal signals within the limbic system. During sleep, the occurrence of hippocampal sharp wave-ripples (SWRs), believed to mediate consolidation of explicit memories, is modulated by thalamocortical network activity, yet how information is routed around SWRs and how this communication depends on neuronal dynamics remains unclear. Here, by simultaneously recording ensembles of neurons in the anterior thalamus and local field potentials in the CA1 area of the hippocampus, we show that the head-direction (HD) cells of the anterodorsal nucleus are set in stable directions immediately before SWRs. This response contrasts with other thalamic cells that exhibit diverse couplings to the hippocampus related to their intrinsic dynamics but independent of their anatomical location. Thus, our data suggest a specific and homogeneous contribution of the HD signal to hippocampal activity and a diverse and cell-specific coupling of non-HD neurons.

On the methods for reactivation and replay analysis.

A major task in the history of neurophysiology has been to relate patterns of neural activity to ongoing external stimuli. More recently, this approach has branched out to relating current neural activity patterns to external stimuli or experiences that occurred in the past or future. Here, we aim to review the large body of methodological approaches used towards this goal, and to assess the assumptions each makes with reference to the statistics of neural data that are commonly observed. These methods primarily fall into two categories, those that quantify zero-lag relationships without examining temporal evolution, termed reactivation, and those that quantify the temporal structure of changing activity patterns, termed replay. However, no two studies use the exact same approach, which prevents an unbiased comparison between findings. These observations should instead be validated by multiple and, if possible, previously established tests. This will help the community to speak a common language and will eventually provide tools to study, more generally, the organization of neuronal patterns in the brain. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

A mechanism for learning with sleep spindles.

Spindles are ubiquitous oscillations during non-rapid eye movement (NREM) sleep. A growing body of evidence points to a possible link with learning and memory, and the underlying mechanisms are now starting to be unveiled. Specifically, spindles are associated with increased dendritic activity and high intracellular calcium levels, a situation favourable to plasticity, as well as with control of spiking output by feed-forward inhibition. During spindles, thalamocortical networks become unresponsive to inputs, thus potentially preventing interference between memory-related internal information processing and extrinsic signals. At the system level, spindles are co-modulated with other major NREM oscillations, including hippocampal sharp wave-ripples (SWRs) and neocortical slow waves, both previously shown to be associated with learning and memory. The sequential occurrence of reactivation at the time of SWRs followed by neuronal plasticity-promoting spindles is a possible mechanism to explain NREM sleep-dependent consolidation of memories. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Integrated open-source software for multiscale electrophysiology.

The methods for electrophysiology in neuroscience have evolved tremendously over the recent years with a growing emphasis on dense-array signal recordings. Such increased complexity and augmented wealth in the volume of data recorded, have not been accompanied by efforts to streamline and facilitate access to processing methods, which too are susceptible to grow in sophistication. Moreover, unsuccessful attempts to reproduce peer-reviewed publications indicate a problem of transparency in science. This growing problem could be tackled by unrestricted access to methods that promote research transparency and data sharing, ensuring the reproducibility of published results. Here, we provide a free, extensive, open-source software that provides data-analysis, data-management and multi-modality integration solutions for invasive neurophysiology. Users can perform their entire analysis through a user-friendly environment without the need of programming skills, in a tractable (logged) way. This work contributes to open-science, analysis standardization, transparency and reproducibility in invasive neurophysiology.

Thalamocortical processing of the head-direction sense.

Our thoughts and sensations are examples of cognitive processes that emerge from the collective activity of billions of neurons in the brain. Thalamocortical circuits form the canonical building-blocks of the brain networks supporting the most complex cognitive functions. How these neurons communicate and interact has been the focus of extensive research in "classical" sensory systems. Similar to visual, auditory or somatosensory thalamic pathways, one primary nucleus in the anterior (limbic) thalamus - the antero-dorsal nucleus - conveys a low-level input, the head-direction (HD) signal, to the cortex. Its activity is controlled in large part by the vestibular system and is relayed by a serially connected group of subcortical nuclei to the thalamus. HD cells serve as the brain's internal 'compass' and each of them is tuned to the specific direction the animal is facing. Recently, recordings of HD neuronal populations in the antero-dorsal nucleus and its main cortical target, the post-subiculum, have revealed that neuronal activity in the thalamocortical HD network are largely invariant to brain states at three levels: static (preserved functional organization), temporal (same drifting speed during exploration and Rapid Eye Movement sleep) and inter-area interaction (from thalamus to cortex). These observations suggest that HD neurons are certainly more driven by intrinsic wiring and dynamics than by sensory inputs and that the information flows bottom-up, even during sleep. Altogether, thalamic HD cells convey a highly reliable, near-noiseless signal that broadly influences the emergence of spatial maps in the cortex and may play a key role in sleep-dependent memory processes.

The intrinsic attractor manifold and population dynamics of a canonical cognitive circuit across waking and sleep.

Neural circuits construct distributed representations of key variables-external stimuli or internal constructs of quantities relevant for survival, such as an estimate of one's location in the world-as vectors of population activity. Although population activity vectors may have thousands of entries (dimensions), we consider that they trace out a low-dimensional manifold whose dimension and topology match the represented variable. This manifold perspective enables blind discovery and decoding of the represented variable using only neural population activity (without knowledge of the input, output, behavior or topography). We characterize and directly visualize manifold structure in the mammalian head direction circuit, revealing that the states form a topologically nontrivial one-dimensional ring. The ring exhibits isometry and is invariant across waking and rapid eye movement sleep. This result directly demonstrates that there are continuous attractor dynamics and enables powerful inference about mechanism. Finally, external rather than internal noise limits memory fidelity, and the manifold approach reveals new dynamical trajectories during sleep.

Electrophysiological monitoring of inhibition in mammalian species, from rodents to humans.

GABAergic interneurons constitute a highly diverse family of neurons that play a critical role in cortical functions. Due to their prominent role in cortical network dynamics, genetic, developmental, or other dysfunctions in GABAergic neurons have been linked to neurological disorders such as epilepsy. Thus, it is crucial to investigate the interaction of these various neurons and to develop methods to specifically and directly monitor inhibitory activity in vivo. While research in small mammals has benefited from a wealth of recent technological development, bridging the gap to large mammals and humans remains a challenge. This is of particular interest since single neuron monitoring with intracranial electrodes in epileptic patients is developing quickly, opening new avenues for understanding the role of different cell types in epilepsy. Here, we review currently available techniques that monitor inhibitory activity in the brain and the respective validations in rodents. Finally, we discuss the future developments of these techniques and how knowledge from animal research can be translated to the study of neuronal circuit dynamics in the human brain.

Medial Prefrontal Cortex Population Activity Is Plastic Irrespective of Learning.

The prefrontal cortex (PFC) is thought to learn the relationships between actions and their outcomes. But little is known about what changes to population activity in PFC are specific to learning these relationships. Here we characterize the plasticity of population activity in the medial PFC (mPFC) of male rats learning rules on a Y-maze. First, we show that the population always changes its patterns of joint activity between the periods of sleep either side of a training session on the maze, regardless of successful rule learning during training. Next, by comparing the structure of population activity in sleep and training, we show that this population plasticity differs between learning and nonlearning sessions. In learning sessions, the changes in population activity in post-training sleep incorporate the changes to the population activity during training on the maze. In nonlearning sessions, the changes in sleep and training are unrelated. Finally, we show evidence that the nonlearning and learning forms of population plasticity are driven by different neuron-level changes, with the nonlearning form entirely accounted for by independent changes to the excitability of individual neurons, and the learning form also including changes to firing rate couplings between neurons. Collectively, our results suggest two different forms of population plasticity in mPFC during the learning of action-outcome relationships: one a persistent change in population activity structure decoupled from overt rule-learning, and the other a directional change driven by feedback during behavior.SIGNIFICANCE STATEMENT The PFC is thought to represent our knowledge about what action is worth doing in which context. But we do not know how the activity of neurons in PFC collectively changes when learning which actions are relevant. Here we show, in a trial-and-error task, that population activity in PFC is persistently changing, regardless of learning. Only during episodes of clear learning of relevant actions are the accompanying changes to population activity carried forward into sleep, suggesting a long-lasting form of neural plasticity. Our results suggest that representations of relevant actions in PFC are acquired by reward imposing a direction onto ongoing population plasticity.

An ensemble code in medial prefrontal cortex links prior events to outcomes during learning.

The prefrontal cortex is implicated in learning the rules of an environment through trial and error. But it is unclear how such learning is related to the prefrontal cortex's role in short-term memory. Here we ask if the encoding of short-term memory in prefrontal cortex is used by rats learning decision rules in a Y-maze task. We find that a similar pattern of neural ensemble activity is selectively recalled after reinforcement for a correct decision. This reinforcement-selective recall only reliably occurs immediately before the abrupt behavioural transitions indicating successful learning of the current rule, and fades quickly thereafter. We could simultaneously decode multiple, retrospective task events from the ensemble activity, suggesting the recalled ensemble activity has multiplexed encoding of prior events. Our results suggest that successful trial-and-error learning is dependent on reinforcement tagging the relevant features of the environment to maintain in prefrontal cortex short-term memory.

Cocaine Place Conditioning Strengthens Location-Specific Hippocampal Coupling to the Nucleus Accumbens.

Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings provide in vivo evidence suggesting that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.