Forming associations between temporally separated events depends on pathways linking the CA1, the subiculum (SUB), and the entorhinal cortex. The degree to which this process requires the CA2, which shares extensive connectivity with these regions, remains unknown. Using trace fear conditioning (TFC), in which mice learn to associate a tone and shock separated by a temporal gap, we found that chronic blockade of dorsal CA2 (dCA2) output reduced cue-associated freezing without comparable effects following delay fear conditioning or during contextual fear recall. In contrast, acute inhibition of dCA2→dCA1 projections during either conditioning or recall increased cue-test freezing, whereas inhibition of dCA2→dSUB projections produced no detectable behavioral effect. These manipulations were associated with distinct patterns of hippocampal cFos expression. Fiber photometry showed that dCA2→dCA1 calcium activity exhibited tone-onset modulation during conditioning and late-trace modulation near the time at which shock had occurred during conditioning. Moreover, acute CA2 inhibition during conditioning was associated with persistent tone-onset CA1 modulation during subsequent drug-free recall. Together, these findings identify dCA2 as a contributor to TFC and link dCA2→dCA1 signaling to fear expression and the temporal organization of CA1 activity across learning and recall.
BACKGROUND Different types of electrical stimulations (ES), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS) have emerged as neuromodulatory treatments to promote remyelination in multiple sclerosis (MS). Although preclinical evidence continues to accumulate, a systematic review assessing the effect of ES on remyelination across MS-relevant models has not been undertaken. METHODS PubMed-MEDLINE, Embase, and Scopus databases were systematically searched up to January 2026 for in vivo studies investigating ES in demyelinating animal models. Two reviewers independently extracted data on study design, stimulation parameters, and quantitative measures of myelin integrity, including visual evoked potential (VEP) latency, and histological myelin content outcomes. Risk of bias was assessed using SYRCLE's tool. RESULTS Six eligible studies met the inclusion criteria, comprising EAE, cuprizone, and lysolecithin lesion models. Across these studies, ES was associated with improvements in indices of remyelination, evidenced by reduced VEP latency, and increased myelin protein expression. Effects of tDCS depended on polarity and timing, with anodal stimulation supporting oligodendrocyte maturation during recovery and cathodal stimulation attenuating glial activation during inflammation. VNS promoted remyelination through anti-inflammatory and trophic signaling, and PNS supported spinal remyelination via peripheral to central neuroimmune modulation. CONCLUSION Limited but convergent preclinical evidence suggests ES may enhance remyelination by modulating neuronal and inflammatory pathways. However, standardized protocols of stimulation and multimodal imaging studies are needed for clinical translation in MS.
Sudden unexpected death in epilepsy (SUDEP) remains the primary cause of epilepsy-related mortality, yet the preictal brain dynamics that distinguish fatal from nonfatal seizures are not well understood. Identifying the network mechanisms determining these outcomes is critical for developing SUDEP risk biomarkers. Using a neuron-specific PTEN knockout mouse model of cortical dysplasia—which exhibits spontaneous seizures and SUDEP-like events—we employed long-term video-EEG monitoring to analyze cortical state transitions and network signatures. We found that nonfatal seizures are preceded by a progressive "ramp-up" of cortical up and down states, characterized by alternating neuronal depolarization and hyperpolarization, which appears to facilitate seizure initiation. In sharp contrast, sudden death is preceded by a marked suppression of these state transitions and the emergence of infraslow EEG activity, suggestive of spreading depolarizations. This pattern differed from the sustained spike-wave complexes and preserved state transitions observed during status epilepticus. These physiological differences are mirrored behaviorally: nonfatal events typically feature forelimb clonus and spike-wave discharges, whereas fatal seizures are characterized by kicking, tonic hindlimb extension, and diffuse EEG attenuation. Together, these findings suggest that cortical up and down states support seizure initiation, while their disruption and failure to recover postictally predisposes neocortical networks to spreading depression episodes that very likely propagate to brainstem circuits, ultimately triggering SUDEP. By delineating these divergent peri-ictal signatures, this study identifies candidate neurophysiological markers for SUDEP risk stratification.
Myelin sheaths are produced by myelinating glia and provide metabolic support to neuronal axons while accelerating electrical signal conduction. Myelinating glia, which include oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), have distinct developmental origins and biological characteristics that profoundly influence their capacity for myelin regeneration following demyelinating insults. In various demyelinating diseases, loss of myelin and myelinating glia resulting from autoimmune disorders, inflammation, or genetic defects causes neurological dysfunction. Beyond removing disease-causing factors, inducing and accelerating remyelination represents a critical therapeutic goal for demyelinating diseases. In this review, we first summarize and compare molecular mechanisms underlying CNS and PNS remyelination, including extracellular signaling pathways, transcriptional regulation, and intercellular communication. We then highlight current treatments and ongoing clinical trials for common demyelination disorders, including neonatal white matter injury, multiple sclerosis, and inherited peripheral neuropathies.
