Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Perturbed Information Processing Complexity in Experimental Epilepsy.

Comorbidities, such as cognitive deficits, which often accompany epilepsies, constitute a basal state, while seizures are rare and transient events. This suggests that neural dynamics, in particular those supporting cognitive function, are altered in a permanent manner in epilepsy. Here, we test the hypothesis that primitive processes of information processing at the core of cognitive function (i.e., storage and sharing of information) are altered in the hippocampus and the entorhinal cortex in experimental epilepsy in adult, male Wistar rats. We find that information storage and sharing are organized into substates across the stereotypic states of slow and theta oscillations in both epilepsy and control conditions. However, their internal composition and organization through time are disrupted in epilepsy, partially losing brain state selectivity compared with controls, and shifting toward a regimen of disorder. We propose that the alteration of information processing at this algorithmic level of computation, the theoretical intermediate level between structure and function, may be a mechanism behind the emergent and widespread comorbidities associated with epilepsy, and perhaps other disorders.SIGNIFICANCE STATEMENT Comorbidities, such as cognitive deficits, which often accompany epilepsies, constitute a basal state, while seizures are rare and transient events. This suggests that neural dynamics, in particular those supporting cognitive function, are altered in a permanent manner in epilepsy. Here, we show that basic processes of information processing at the core of cognitive function (i.e., storage and sharing of information) are altered in the hippocampus and the entorhinal cortex (two regions involved in memory processes) in experimental epilepsy. Such disruption of information processing at the algorithmic level itself could underlie the general performance impairments in epilepsy.

Long-term near-continuous recording with Neuropixels probes in healthy and epileptic rats.

Neuropixels probes have become a crucial tool for high-density electrophysiological recordings. Although most research involving these probes is in acute preparations, some scientific inquiries require long-term recordings in freely moving animals. Recent reports have presented prosthesis designs for chronic recordings, but some of them do not allow for probe recovery, which is desirable given their cost. Others appear to be fragile, as these articles describe numerous broken implants.Objective.This fragility presents a challenge for recordings in rats, particularly in epilepsy models where strong mechanical stress impinges upon the prosthesis. To overcome these limitations, we sought to develop a new prosthesis for long-term electrophysiological recordings in healthy and epileptic rats.Approach.We present a new prosthesis specifically designed to protect the probes from strong shocks and enable the safe retrieval of probes after experiments.Main results.This prosthesis was successfully used to record from healthy and epileptic rats for up to three weeks almost continuously. Overall, 10 out of 11 probes could be successfully retrieved with a retrieval and reuse success rate of 91%.Significance.Our design and protocol significantly improved previously described probe recycling performances and prove usage on epileptic rats.

The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABAA Receptors, Boosts Functional Recovery after Stroke.

Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAARs). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

The nucleus reuniens, a thalamic relay for cortico-hippocampal interaction in recent and remote memory consolidation.

The consolidation of declarative memories is believed to occur mostly during sleep and involves a dialogue between two brain regions, the hippocampus and the medial prefrontal cortex. The information encoded during experience by neuronal assemblies is replayed during sleep leading to the progressive strengthening and integration of the memory trace in the prefrontal cortex. The gradual transfer of information from the hippocampus to the medial prefrontal cortex for long-term storage requires the synchronization of cortico-hippocampal networks by different oscillations, like ripples, spindles, and slow oscillations. Recent studies suggest the involvement of a third partner, the nucleus reuniens, in memory consolidation. Its bidirectional connections with the hippocampus and medial prefrontal cortex place the reuniens in a key position to relay information between the two structures. Indeed, many topical works reveal the original role that the nucleus reuniens occupies in different recent and remote memories consolidation. This review aimed to examine these contributions, as well as its functional embedment in this complex memory network, and provide some insights on the possible mechanisms.

Cell Assemblies in the Cortico-Hippocampal-Reuniens Network during Slow Oscillations.

The nucleus reuniens (NR) is an important anatomic and functional relay between the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Whether the NR controls neuronal assemblies, a hallmark of information exchange between the HPC and mPFC for memory transfer/consolidation, is not known. Using simultaneous local field potential and unit recordings in NR, HPC, and mPFC in male rats during slow oscillations under anesthesia, we identified a reliable sequential activation of NR neurons at the beginning of UP states, which preceded mPFC ones. NR sequences were spatially organized, from dorsal to ventral NR. Chemical inactivation of the NR disrupted mPFC sequences at the onset of UP states as well as HPC sequences present during sharp-wave ripples. We conclude that the NR contributes to the coordination and stabilization of mPFC and HPC neuronal sequences during slow oscillations, possibly via the early activation of its own sequences.SIGNIFICANCE STATEMENT Neuronal assemblies are believed to be instrumental to code/encode/store information. They can be recorded in different brain regions, suggesting that widely distributed networks of networks are involved in such information processing. The medial prefrontal cortex, the hippocampus, and the thalamic nucleus reuniens constitute a typical example of a complex network involved in memory consolidation. In this study, we show that spatially organized cells assemblies are recruited in the nucleus reuniens at the UP state onset during slow oscillations. Nucleus reuniens activity appears to be necessary to the stability of medial prefrontal cortex and hippocampal cell assembly formation during slow oscillations. This result further highlights the role of the nucleus reuniens as a functional hub for exchanging and processing memories.

In Vivo Characterization of Neurophysiological Diversity in the Lateral Supramammillary Nucleus during Hippocampal Sharp-wave Ripples of Adult Rats.

The extent of the networks that control the genesis and modulation of hippocampal sharp-wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R-unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior to SPW-Rs peak power and prior to hippocampal excitatory cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged neurons. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation.

Computing hubs in the hippocampus and cortex.

Neural computation occurs within large neuron networks in the dynamic context of varying brain states. Whether functions are performed by specific subsets of neurons and whether they occur in specific dynamical regimes remain poorly understood. Using high-density recordings in the hippocampus, medial entorhinal, and medial prefrontal cortex of the rat, we identify computing substates where specific computing hub neurons perform well-defined storage and sharing operations in a brain state-dependent manner. We retrieve distinct computing substates within each global brain state, such as REM and nonREM sleep. Half of recorded neurons act as computing hubs in at least one substate, suggesting that functional roles are not hardwired but reassigned at the second time scale. We identify sequences of substates whose temporal organization is dynamic and stands between order and disorder. We propose that global brain states constrain the language of neuronal computations by regulating the syntactic complexity of substate sequences.

A bilayered PVA/PLGA-bioresorbable shuttle to improve the implantation of flexible neural probes.

OBJECTIVE: Neural electrophysiology is often conducted with traditional, rigid depth probes. The mechanical mismatch between these probes and soft brain tissue is unfavorable for tissue interfacing. Making probes compliant can improve biocompatibility, but as a consequence, they become more difficult to insert into the brain. Therefore, new methods for inserting compliant neural probes must be developed. APPROACH: Here, we present a new bioresorbable shuttle based on the hydrolytically degradable poly(vinyl alcohol) (PVA) and poly(lactic-co-glycolic acid) (PLGA). We show how to fabricate the PVA/PLGA shuttles on flexible and thin parylene probes. The method consists of PDMS molding used to fabricate a PVA shuttle aligned with the probe and to also impart a sharp tip necessary for piercing brain tissue. The PVA shuttle is then dip-coated with PLGA to create a bi-layered shuttle. MAIN RESULTS: While single layered PVA shuttles are able to penetrate agarose brain models, only limited depths were achieved and repositioning was not possible due to the fast degradation. We demonstrate that a bilayered approach incorporating a slower dissolving PLGA layer prolongs degradation and enables facile insertion for at least several millimeters depth. Impedances of electrodes before and after shuttle preparation were characterized and showed that careful deposition of PLGA is required to maintain low impedance. Facilitated by the shuttles, compliant parylene probes were also successfully implanted into anaesthetized mice and enabled the recording of high quality local field potentials. SIGNIFICANCE: This work thereby presents a solution towards addressing a key challenge of implanting compliant neural probes using a two polymer system. PVA and PLGA are polymers with properties ideal for translation: commercially available, biocompatible with FDA-approved uses and bioresorbable. By presenting new ways to implant compliant neural probes, we can begin to fully evaluate their chronic biocompatibility and performance compared to traditional, rigid electronics.

The Nucleus Reuniens Controls Long-Range Hippocampo-Prefrontal Gamma Synchronization during Slow Oscillations.

Gamma oscillations are involved in long-range coupling of distant regions that support various cognitive operations. Here we show in adult male rats that synchronized bursts of gamma oscillations bind the hippocampus (HPC) and prefrontal cortex (mPFC) during slow oscillations and slow-wave sleep, a brain state that is central for consolidation of memory traces. These gamma bursts entrained the firing of the local HPC and mPFC neuronal populations. Neurons of the nucleus reuniens (NR), which is a structural and functional hub between HPC and mPFC, demonstrated a specific increase in their firing before gamma burst onset, suggesting their involvement in HPC-mPFC binding. Chemical inactivation of NR disrupted the temporal pattern of gamma bursts and their synchronization, as well as mPFC neuronal firing. We propose that the NR drives long-range hippocampo-prefrontal coupling via gamma bursts providing temporal windows for information exchange between the HPC and mPFC during slow-wave sleep.SIGNIFICANCE STATEMENT Long-range coupling between hippocampus (HPC) and prefrontal cortex (mPFC) is believed to support numerous cognitive functions, including memory consolidation occurring during sleep. Gamma-band synchronization is a fundamental process in many neuronal operations and is instrumental in long-range coupling. Recent evidence highlights the role of nucleus reuniens (NR) in consolidation; however, how it influences hippocampo-prefrontal coupling is unknown. In this study, we show that HPC and mPFC are synchronized by gamma bursts during slow oscillations in anesthesia and natural sleep. By manipulating and recording the NR-HPC-mPFC network, we provide evidence that the NR actively promotes this long-range gamma coupling. This coupling provides the hippocampo-prefrontal circuit with a novel mechanism to exchange information during slow-wave sleep.

Autoclave Sterilization of PEDOT:PSS Electrophysiology Devices.

Autoclaving, the most widely available sterilization method, is applied to poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) electrophysiology devices. The process does not harm morphology or electrical properties, while it effectively kills E. coli intentionally cultured on the devices. This finding paves the way to widespread introduction of PEDOT:PSS electrophysiology devices to the clinic.

Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges.

Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges.

A systematic framework for functional connectivity measures.

Various methods have been proposed to characterize the functional connectivity between nodes in a network measured with different modalities (electrophysiology, functional magnetic resonance imaging etc.). Since different measures of functional connectivity yield different results for the same dataset, it is important to assess when and how they can be used. In this work, we provide a systematic framework for evaluating the performance of a large range of functional connectivity measures-based upon a comprehensive portfolio of models generating measurable responses. Specifically, we benchmarked 42 methods using 10,000 simulated datasets from 5 different types of generative models with different connectivity structures. Since all functional connectivity methods require the setting of some parameters (window size and number, model order etc.), we first optimized these parameters using performance criteria based upon (threshold free) ROC analysis. We then evaluated the performance of the methods on data simulated with different types of models. Finally, we assessed the performance of the methods against different levels of signal-to-noise ratios and network configurations. A MATLAB toolbox is provided to perform such analyses using other methods and simulated datasets.

On the nature of seizure dynamics.

Seizures can occur spontaneously and in a recurrent manner, which defines epilepsy; or they can be induced in a normal brain under a variety of conditions in most neuronal networks and species from flies to humans. Such universality raises the possibility that invariant properties exist that characterize seizures under different physiological and pathological conditions. Here, we analysed seizure dynamics mathematically and established a taxonomy of seizures based on first principles. For the predominant seizure class we developed a generic model called Epileptor. As an experimental model system, we used ictal-like discharges induced in vitro in mouse hippocampi. We show that only five state variables linked by integral-differential equations are sufficient to describe the onset, time course and offset of ictal-like discharges as well as their recurrence. Two state variables are responsible for generating rapid discharges (fast time scale), two for spike and wave events (intermediate time scale) and one for the control of time course, including the alternation between 'normal' and ictal periods (slow time scale). We propose that normal and ictal activities coexist: a separatrix acts as a barrier (or seizure threshold) between these states. Seizure onset is reached upon the collision of normal brain trajectories with the separatrix. We show theoretically and experimentally how a system can be pushed toward seizure under a wide variety of conditions. Within our experimental model, the onset and offset of ictal-like discharges are well-defined mathematical events: a saddle-node and homoclinic bifurcation, respectively. These bifurcations necessitate a baseline shift at onset and a logarithmic scaling of interspike intervals at offset. These predictions were not only confirmed in our in vitro experiments, but also for focal seizures recorded in different syndromes, brain regions and species (humans and zebrafish). Finally, we identified several possible biophysical parameters contributing to the five state variables in our model system. We show that these parameters apply to specific experimental conditions and propose that there exists a wide array of possible biophysical mechanisms for seizure genesis, while preserving central invariant properties. Epileptor and the seizure taxonomy will guide future modeling and translational research by identifying universal rules governing the initiation and termination of seizures and predicting the conditions necessary for those transitions.

Brain state-dependent neuronal computation.

Neuronal firing pattern, which includes both the frequency and the timing of action potentials, is a key component of information processing in the brain. Although the relationship between neuronal output (the firing pattern) and function (during a task/behavior) is not fully understood, there is now considerable evidence that a given neuron can show very different firing patterns according to brain state. Thus, such neurons assembled into neuronal networks generate different rhythms (e.g., theta, gamma and sharp wave ripples), which sign specific brain states (e.g., learning, sleep). This implies that a given neuronal network, defined by its hard-wired physical connectivity, can support different brain state-dependent activities through the modulation of its functional connectivity. Here, we review data demonstrating that not only the firing pattern, but also the functional connections between neurons, can change dynamically. We then explore the possible mechanisms of such versatility, focusing on the intrinsic properties of neurons and the properties of the synapses they establish, and how they can be modified by neuromodulators, i.e., the different ways that neurons can use to switch from one mode of communication to the other.

Brain state dependent postinhibitory rebound in entorhinal cortex interneurons.

Postinhibitory rebound (PIR) is believed to play an important role in the genesis and maintenance of biological rhythms. While it has been demonstrated during several in vitro studies, in vivo evidence for PIR remains scarce. Here, we report that PIR can be observed in the dorsomedial entorhinal cortex of anesthetized rats, mostly between putatively connected GABAergic interneurons, and that it is more prevalent during the theta (4-6 Hz) oscillation state than the slow (0.5-2 Hz) oscillation state. Functional inhibition was also found to be brain state and postsynaptic cell type dependent but that alone could not explain this brain state dependence of PIR. A theoretical analysis, using two Fitzhugh-Nagumo neurons coupled to an external periodic drive, predicted that the modulation of a faster spiking rate by the slower periodic drive could account for the brain state dependence of PIR. Model predictions were verified experimentally. We conclude that PIR is cell type and brain state dependent and propose that this could impact network synchrony and rhythmogenesis.

Hub GABA neurons mediate gamma-frequency oscillations at ictal-like event onset in the immature hippocampus.

Gamma-frequency oscillations (GFOs, >40 Hz) are a general network signature at seizure onset at all stages of development, with possible deleterious consequences in the immature brain. At early developmental stages, the simultaneous occurrence of GFOs in different brain regions suggests the existence of a long-ranging synchronizing mechanism at seizure onset. Here, we show that hippocamposeptal (HS) neurons, which are GABA long-range projection neurons, are mandatory to drive the firing of hippocampal interneurons in a high-frequency regime at the onset of epileptiform discharges in the intact, immature septohippocampal formation. The synchronized firing of interneurons in turn produces GFOs, which are abolished after the elimination of a small number of HS neurons. Because they provide the necessary fast conduit for pacing large neuronal populations and display intra- and extrahippocampal long-range projections, HS neurons appear to belong to the class of hub cells that play a crucial role in the synchronization of developing networks.

Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels.

PURPOSE: Stiripentol (STP) is currently an efficient drug for add-on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown. METHODS: We examined the interactions of STP with gamma-aminobutyric acid (GABA) transmission by using patch-clamp methods in CA3 pyramidal neurons in the neonatal rat. RESULTS: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay-time constant in a concentration-dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT-1 inhibitors (SKF-89976A and NO-711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP-mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside-out patches, because STP increased the duration and not the frequency of opening of GABAA channels. CONCLUSIONS: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate-like effect, suggesting that STP should possess an antiepileptic effect by itself.