The vagus nerve constitutes a core bidirectional pathway linking the central nervous system with peripheral organs and plays a fundamental role in gut-brain communication. Beyond its classical autonomic functions, accumulating evidence positions vagal signaling as a candidate integrative mechanism through which visceral, immune, and microbial inputs may modulate stress regulation, affective processing, cognition, and neuroplasticity. This narrative review synthesizes current anatomical and physiological knowledge of vagal pathways, with emphasis on afferent projections to the nucleus tractus solitarius and downstream modulation of noradrenergic, serotonergic, and cholinergic circuits involving the locus coeruleus, hippocampus, and prefrontal cortex. We further examine vagus nerve stimulation, including invasive and noninvasive approaches, as a neuromodulatory strategy for neurological and psychiatric disorders. Evidence is reviewed for its effects in epilepsy, mood and anxiety disorders, cognitive impairment, and neurodegenerative conditions, highlighting mechanisms such as synaptic plasticity enhancement, neuroimmune modulation, and regulation of hypothalamic-pituitary-adrenal axis activity. While findings support the translational relevance of vagal modulation, variability in stimulation parameters and outcome measures limits cross-study comparison. Greater methodological standardization and integration of neurocognitive endpoints are required to clarify its clinical and neuroscientific significance.
Although spina bifida (SB) and tethered cord syndrome (TCS) are often discussed and studied as separate conditions, their co-occurrence is common, clinically consequential, and understudied, particularly with respect to neurogenic bladder and bowel dysfunction. SB arises from incomplete neural tube closure, whereas TCS involves abnormal fixation of the spinal cord, often leading to progressive neurologic deficits. SB affects approximately 3.63 per 10,000 live births in the United States, and TCS occurs in a significant proportion of affected individuals; however, the true incidence of their co-occurrence remains unknown. Current clinical strategies include surgical intervention and symptomatic management, but long-term outcomes are variable, and gaps persist in diagnosis, presentation, and optimal treatment. Bladder and bowel dysfunction are among the most prevalent and functionally impactful complications, yet these outcomes are inconsistently documented and rarely tracked longitudinally. Preclinical models in rodent, porcine, ovine, and feline species provide insight into spinal cord development, tethering mechanisms, and functional consequences, but few examine bladder or bowel function. This review synthesizes clinical and preclinical evidence to characterize overlapping SB and TCS presentations, identifies gaps in bladder and bowel outcome reporting, and highlights opportunities to improve translational animal models and long-term care.
This review examines how distributed neural circuits involving the hippocampus, entorhinal cortex, and neocortex collectively support learning and memory functions. The hippocampus and entorhinal cortex are densely and bidirectionally connected, forming a core circuit that supports the formation of episodic memories as well as spatial learning and navigation. Their interactions with neocortical regions underlie decision making and the transformation of episodic experience into abstract concepts. These functions are supported by precisely timed interactions between neuronal ensembles across distributed circuits, coordinated by neural oscillations. During learning and navigation, theta oscillations synchronize the firing of neuronal ensembles and mediate the flow of information across structures. During periods of rest and sleep, hippocampal sharp-wave ripples coordinate the reactivation of experience-related activity patterns. Sharp-wave ripples mediate the transfer of memory traces from the hippocampus to the neocortex and their long-term consolidation. Rather than a unidirectional transfer from hippocampus to neocortex, emerging evidence reveals continuous bidirectional interactions throughout memory encoding, consolidation, and retrieval. Critically, recurrent processing loops among the entorhinal cortex, hippocampus, and neocortex enable ongoing updating and integration of memory representations, challenging traditional sequential processing models and emphasizing the dynamic and interactive nature of these circuits.
Background: Chronic pain affects up to one-third of adults worldwide and remains refractory to conventional therapies in a substantial proportion of patients. Increasing evidence suggests that chronic pain arises from maladaptive interactions across distributed peripheral, spinal, and supraspinal networks rather than dysfunction confined to a single anatomic locus. Objective: To synthesise animal and human evidence relating to supraspinal pain networks and examine how cortical and subcortical neuromodulation may influence these systems in refractory chronic pain. Methods: This narrative review integrates findings from electrophysiology, neuroimaging, intracranial stimulation, connectomics, and clinical neuromodulation studies. Evidence is organised around interacting systems involved in chronic pain processing: sensory discriminative, salience and affective valuation, thalamocortical oscillatory, descending modulatory, and interoceptive-predictive. Results: Chronic pain is associated with abnormalities across distributed sensory, salience, oscillatory, and modulatory systems. Distinct neuromodulation targets engage overlapping but nonidentical network mechanisms: motor cortex stimulation has been associated with modulation of descending inhibitory and thalamocortical systems; somatosensory stimulation may influence sensory gain and oscillatory coupling; anterior cingulate and insular stimulation primarily engages the affective salience and interoceptive systems; and deep brain stimulation provides access to thalamic and brainstem modulatory circuits. Variability and waning efficacy across modalities likely reflect heterogeneous and dynamically evolving network pathology. Conclusions: A network-guided framework conceptualising chronic pain as a disorder of distributed brain systems supports increasingly personalised, connectivity-informed, multisite, and adaptive neuromodulation strategies. Future approaches may benefit from integrating electrophysiologic and connectomic biomarkers to improve patient selection, target engagement, and durability of analgesia.
Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviours, collectively affecting nearly 2% of the global population. ASD is strongly heritable, with genetic variants converging on molecular pathways that regulate synaptic connectivity. Protocadherins, particularly nonclustered protocadherins (ncPCDHs), have emerged as high-confidence ASD-associated genes. By mediating cell surface adhesion and downstream signalling, ncPCDHs regulate essential neurodevelopmental processes ranging from neuronal production and migration to synaptic maturation, while generating combinatorial surface codes that organize circuit wiring-all mechanisms highly relevant to ASD. Here, we review recent findings from human genetics and rodent models, highlighting activity-dependent signalling as a central hub through which ncPCDHs coordinate synaptic refinement and maintain excitatory/inhibitory balance. Finally, we discuss how dissecting ncPCDH molecular mechanisms may clarify ASD pathogenesis and inform targeted therapeutic strategies.
Brain-on-a-chip is a microphysiologic platform that comprises cultured brain cells to understand brain disease pathogenesis and treatment. The blood-brain barrier (BBB) of the neurovascular unit serves as a highly selective molecular transport interface for brain homeostasis. BBB dysfunction promotes neuroinflammation, exacerbates disease progression, and contributes to neurodegenerative diseases. However, the mechanisms of BBB disruption underlying brain disorders remain poorly understood; thus, developing neurotherapeutics that can effectively cross the BBB remains a major challenge. Recent advances in microfluidic brain-on-a-chip platforms now enable the creation of BBB-on-a-chip systems that replicate key structural and functional aspects of the human BBB under dynamic flow conditions. Integration of microelectrode arrays into these microfluidic systems enhances their utility by enabling high-throughput drug screening and targeted delivery, allowing real-time monitoring of neuronal activity and network behavior. Although current brain organoid, brain-on-a-chip, and BBB-on-a-chip platforms remain in developmental stages, significant progress has been made using induced pluripotent stem cell-derived neurons, astrocytes, endothelial cells, pericytes, and microglia from healthy individuals and patients with neurodegenerative diseases. This review highlights recent advances in brain- and BBB-on-a-chip technologies and their potential applications in studying disease pathogenesis and preclinical drug screening for neurodegenerative disorders.
The left ventral premotor cortex (PMv) has not been fully acknowledged as a key component of the brain's network for reading. This region, corresponding to Brodmann area (BA) 6, is cytoarchitecturally distinct from adjacent Broca's area (BA44/45) and primary motor cortex (BA4) and specifically involved in articulatory codes for speech production. The left PMv is known to receive direct white matter projections from posterior brain regions responsible for visual and phonological processing. Consequently, the region plays a significant role in reading when the expert visual word-form system in the left occipitotemporal cortex is underdeveloped or compromised in early literacy development in childhood or in neurologic disorders in adulthood. Recent functional neuroimaging and brain stimulation studies further suggest that those direct neural pathways connecting the left PMv with the occipital cortex are fully functioning in literate adults, rapidly generating speech motor codes at a very early stage of reading, and faster than thought previously. This region may therefore serve as an alternative and promising cortical target for future neuromodulation research aimed at boosting cognitive components involved in reading.
Learning and memory were long thought to be the domains of neurons and neural networks, but recent work across brain systems has established that astrocytes play a role in synaptic plasticity and information storage. However, it remains unclear what this role is. In Hebbian and spike timing-dependent plasticity, simultaneous activation of pre- and postsynaptic neurons on a millisecond timescale determines plasticity, yet emerging evidence suggests that slow astrocyte signaling over many seconds is directly linked to memory. Here we take an astrocyte-centric view on plasticity to explore the possible computational and coding roles of astrocytes. We propose that in a 3-body arrangement with pre- and postsynaptic compartments, astrocytes may participate in the synaptic credit assignment problem. This review thus offers a candidate conceptual framework for understanding the interplay between astrocytes and neurons in the context of neural network performance and plasticity.
Astrocytes play key roles in shaping the synaptic environment, yet the cellular structures through which they interact with individual synapses remain incompletely understood. Perisynaptic astrocytic processes (PAPs) are ultrathin astrocytic leaflets that variably appose synapses and form a major structural interface between astrocytes and neuronal synapses. PAPs are best viewed as a perisynaptic configuration within a broader population of fine astrocytic protrusions, with coverage, geometry, and molecular composition varying across brain regions, developmental stages, and species. In this review, we synthesize current evidence that PAPs define local microdomains around synapses in which astrocytes sense neuronal activity and regulate the synaptic milieu. We discuss how PAP organization and plasticity influence neurotransmitter clearance, ion homeostasis, and structural remodeling at synapses. We also consider how regional differences in PAP organization may contribute to selective circuit vulnerability and how early PAP dysfunction may contribute to synaptic dysfunction in neurodegenerative disease. Finally, we highlight emerging approaches needed to resolve the structure and function of PAP at synapses in vivo and to establish causal mechanisms.
Schizophrenia is a severe mental disorder characterized by a range of symptoms and significant disability, with disrupted proteostasis identified as a critical pathophysiological factor. This comprehensive review evaluates the involvement of heat shock proteins (HSPs) in schizophrenia, highlighting immunologic, genetic, and expression-based evidence, while proposing a potential role for cold shock proteins (CSPs). HSPs, particularly HSP60, HSP70, and HSP90, function as molecular chaperones essential for maintaining proteostasis during stress. HSP autoantibodies are increased in individuals with schizophrenia, and levels correlate with symptom severity, blood-brain barrier dysfunction, and response to antipsychotics such as clozapine. Genetic research links HSP gene polymorphisms (e.g., HSPA1A, HSPA1B, and HSPB1) to disease risk, symptom severity, and treatment outcomes. Altered HSP levels in brain regions like the dorsolateral prefrontal cortex suggest roles in neuroprotection, oxidative stress, and synaptic dysfunction. Antipsychotics modulate HSP expression, indicating potential for precision medicine using HSP coinducers like BGP-15. While HSPs are well linked to schizophrenia, limited evidence suggests that CSPs could affect deficits in synaptic structure and pruning, known to play a role in schizophrenia, through actions involving BDNF-TrkB signaling. Despite recent advancements, challenges remain in achieving consistent immune responses, ensuring genetic relevance across populations, and fully understanding the importance of CSPs, which calls for longitudinal multiomics studies, diverse cohort analyses, and advanced preclinical models. This review positions HSPs as central to the molecular framework of schizophrenia and CSPs as a largely unexplored area, advocating for integrated research to enhance mechanistic understanding and therapeutic approaches for this complex disorder.
Reconstructing mental experience from brain activity is becoming increasingly feasible through advances in neuroimaging and deep learning. Neural signals have been translated into images, text, and speech and have been applied clinically to restore communication and movement in patients with motor paralysis. Extending reconstruction to patients with disorders of consciousness (DoCs) represents the next critical step. DoCs encompass conditions such as the vegetative and minimally conscious states, in which wakefulness is preserved but behavioral signs of awareness are absent, inconsistent, or difficult to interpret. These behavioral signs may not reflect patients' underlying cognitive capacities, as neuroimaging studies have shown that a subset retains cognitive function. Reconstruction could offer insight into these otherwise inaccessible experiences and potentially restore communication. However, if applied incorrectly, reconstruction risks mischaracterizing a patient's inner life and compromising their autonomy. To clarify the current landscape, this article reviews the development of reconstruction methods, their emerging clinical applications, and the distinct interpretive challenges associated with applying these approaches to DoCs. It then offers recommendations for evaluating reconstruction results, centered on identifying awareness, validating reconstruction models, and protecting patient autonomy. The aim is to support the responsible advancement of reconstruction and its potential to transform understanding of DoCs.
Mitochondria are multifaceted organelles positioned at the intersection of multiple signaling pathways. Beyond serving as one of the main energy providers in the brain, they play crucial roles in shaping cytosolic calcium signals across both neuronal and glial cell populations, modulating synaptic transmission and plasticity, and regulating neuronal excitability and network activity. The involvement of mitochondrial calcium handling in brain cell physiology has been explored for many years. However, by enabling in vivo cell-specific manipulations, the molecular identification of mitochondrial calcium signaling protein complexes, over the past 2 decades, has tremendously improved our understanding of how mitochondria regulate brain function and behavior.This review synthesizes current knowledge of mitochondrial calcium handling mechanisms and protein complexes in the nervous system, as well as their involvement in brain function, from cellular physiology to behavioral consequences. We discuss pharmacological and genetic evidence for a role of mitochondrial calcium handling in synaptic transmission, neuronal excitability, astrocyte functions, and circuit activity. We underline experimental differences across approaches and models, as well as show how genetic tools have challenged or confirmed earlier pharmacological results. Finally, we examine how recent advances using transgenic models have revealed complex roles for mitochondrial calcium signaling in behavioral responses and opened new research avenues.
In recent years, a growing body of research has demonstrated that parents' and children's brains often exhibit neural similarity and synchrony during shared activities, emotional exchanges, and everyday interactions. This interbrain alignment offers a novel window into the mechanisms through which social connection, caregiving, and development unfold. In this review, we provide a comprehensive synthesis of studies investigating parent-child neural similarity and synchrony, drawing on diverse neuroimaging tools, including functional magnetic resonance imaging, functional near-infrared spectroscopy, and electroencephalography. To bring conceptual clarity to this rapidly growing field, we introduce a 2 × 2 framework that categorizes research contexts along two key dimensions: level of interaction (low vs. high) and emotional salience (low vs. high). Using this framework, we organize and interpret the empirical literature, highlighting consistent findings, methodological variations, and developmental implications across different types of parent-child engagement. This framework not only helps structure existing knowledge but also reveals context-specific understanding in the literature. Finally, we outline future directions that emphasize the importance of longitudinal designs, cultural diversity, multimodal imaging, and expanding beyond the dyadic unit. This review aims to deepen the understanding of how neural alignment within families supports learning, emotion regulation, and social development across the life span.
Learning shapes the human brain, yet structural changes underlying this process remain difficult to characterize in vivo. Recent advances in magnetic resonance imaging (MRI)-including relaxometry, magnetization transfer, proton density, and diffusion imaging-combined with improved hardware and biophysical models, now allow highly specific assessment of subtle microstructural changes during learning. Here, we review studies documenting learning-induced changes in brain microstructure. Short training intervals elicit rapid MRI-detectable changes, including increases in restricted diffusion and local tissue volume, particularly in the hippocampus, potentially reflecting early neurite and glial adaptations. Longer training periods reveal additional changes in task-relevant gray and white matter, suggestive of adaptations in myelin, neurites, and neuroglia. The link between MRI changes and behavioral improvements is inconsistent, likely due to heterogeneous temporal dynamics of plasticity and interindividual variability. Because MRI provides only indirect insight into tissue microstructure, initial studies combine complementary contrasts with multivariate statistics to reduce interpretational ambiguities. High-field imaging, cross-modal approaches such as transcranial magnetic stimulation, and cross-species studies further bridge animal models and human research. Together, these developments refine biologically grounded models of human plasticity and hold promise for translational applications in personalized learning and rehabilitation.
Memory is stored in distributed neuronal ensembles known as engrams, which are defined by their activation during encoding and their necessity for recall. Current research relies heavily on immediate-early gene (IEG) expression to map these traces; however, the temporal lag of transcription fails to account for the real-time processing of neural activity or the long-term structural remodeling required for memory persistence. In this review, we propose that the noncoding genome serves as the essential regulatory infrastructure of the engram, governing the transition from transient firing to stable physical change. We outline a 3-phase model of noncoding RNA (ncRNA) regulation: first, we discuss how synaptic microRNAs act as high-speed filters during encoding to gate excitability and potentially solve the IEG latency paradox. Second, we examine how long ncRNAs maintain epigenetic identity and valence during the interim state. Finally, we argue that consolidation involves a "pseudo-developmental" reactivation of neurogenic and synaptogenic programs driven by ncRNAs. This framework provides a unified perspective on how mature neurons multiplex diverse experiences, suggesting that ncRNAs are not merely accessory molecules but the central architects of memory maintenance, specificity, and stability.
Alzheimer's disease (AD) is increasingly understood as a disorder of network-state and plasticity-capacity, in which amyloid-β and tau pathologies disrupt the activity-dependent mechanisms that build and stabilize memory engrams. Here, I review how amyloid-β-driven neuronal hyperactivity contributes to plasticity and memory deficits in AD. I also discuss how various cellular pathologies reinforce one another, leading to a cellular environment that is impermissive to plasticity. I relate these cellular and circuit-level disturbances to failures in memory encoding, consolidation, and recall, emphasizing the role of interference arising from coexisting hyper- and hypoactive neuronal populations. Finally, I discuss the relevance and limitations of amyloid mouse models in understanding the cognitive decline in AD.
Neuropathic pain (NP) is a chronic pain condition caused by nerve damage. Current NP treatments have limited efficacy and significant side effects. Emerging evidence demonstrates that N-methyl-d-aspartate receptors (NMDARs) play a key role in the development of NP, especially in their pre- and postsynaptic functions. This review provides an overview of the mechanistic roles of NMDARs in NP, focusing on their subunit structures and involvement in pain transmission. The interactions between NMDARs and other neurotransmitter receptors are further discussed, emphasizing NMDARs as a promising therapeutic target. Finally, we discuss the pharmacologic mechanisms of NMDARs relevant to pain management and nonpharmacologic interventions, which have not been covered in previous reviews. This review aims to advance future research on NMDAR-mediated mechanisms in NP and promote the development of targeted, low-side effect therapeutic strategies.
In September 1887, the 28-year-old neuropathologist Carlo Martinotti, an assistant to Camillo Golgi, presented his discovery of a new cell type in the mammalian cerebral cortex at the 12th congress of the Italian Medical Association, held in Pavia. The actual papers were published between 1888 and 1890. This neuron received the eponym "Martinotti cell" by Albert Kölliker and Santiago Ramón y Cajal, while its axon was designated the "Martinotti fiber" by Ramón y Cajal and other pioneer neuroanatomists, including Constantin von Economo and Georg N. Koskinas. Martinotti cells were later found to be inhibitory interneurons scattered throughout cortical layers II to VI, having an axon that ascends and extends rich collaterals into the molecular layer. Based on modern experiments, Martinotti cells have been implicated in a broad spectrum of functions, including regulation of cortical activity, speed of information processing, cortical plasticity, audition, motor learning, sensorimotor integration, and sleep.
The glymphatic system is a recently discovered brain clearance pathway that removes metabolic waste, including toxic proteins, via cerebrospinal fluid flow along perivascular spaces. It helps maintain neural homeostasis, and its dysfunction is linked to neurodegenerative diseases like Alzheimer's. Emerging evidence suggests that physical exercise can enhance glymphatic function and promote cerebral clearance, offering a potential nonpharmacological approach to support brain health. In rodent studies, voluntary wheel running has been shown to increase glymphatic flux, likely through improvements in cerebrospinal fluid circulation, vascular pulsatility, and the exchange of interstitial fluid along perivascular routes. Exercise also upregulates the expression and polarization of aquaporin 4 on astrocytic endfeet, which is essential for directing fluid movement and facilitating efficient glymphatic transport, potentially reducing the accumulation of neurotoxic proteins such as β-amyloid and tau. Beyond these direct effects, exercise-induced enhancements in cerebral blood flow, arterial compliance, and sleep quality may indirectly optimize the physiological environment for glymphatic clearance. Together, these mechanisms suggest that regular physical activity is an established, noninvasive intervention to maintain cerebral homeostasis, accelerate metabolic waste removal, and support long-term cognitive function. This review summarizes evidence linking exercise to glymphatic function and its role in brain waste clearance and cognitive function.
Emerging evidence highlights the potential role of auditory stimulation in enhancing sleep-dependent memory consolidation. Pink noise appears to be an effective auditory stimulus for enhancing memory consolidation, likely due to its wide-range influence on brain oscillations. However, the specific underlying mechanisms by which pink noise enhances memory consolidation remain unclear. This perspective article presents a novel hypothesis exploring how pink noise, delivered through closed-loop auditory stimulation, may facilitate memory consolidation. Specifically, we suggest that pink noise may reach the hippocampus via the rapid auditory pathway, potentially increasing the likelihood of sharp-wave ripple (SW-R) generation. By increasing hippocampal ripple activity, the overall likelihood of synchronization with spindles and slow oscillations is also increased, enhancing hippocampal-cortical coupling. This suggests that pink noise might indirectly support slow oscillation-ripple-spindle coordination to promote systems-level consolidation and interregional information transfer. This, in turn, could enable long-term memory storage and support abstraction and generalization. Our hypothesis emphasizes a bottom-up mechanism originating from the hippocampus. Although this hypothesis currently lacks direct support from subcortical recordings, it builds on existing knowledge of sleep rhythms, hippocampal auditory pathways, and the known effects of SW-R modulation on memory formation. This perspective offers a framework for future work investigating the mechanisms by which pink noise stimulation can lead to memory enhancement.
