This review outlines the development of thalamic atlases from early post-mortem 2D histological maps to modern 3D multimodal atlases used in neuroscience and clinical practice. Given the central role of the thalamus in sensory processing, movement, and cognition, accurate anatomical mapping has been essential for both research and neurosurgical targeting. By synthesizing historical and modern approaches, we highlight the methodological advances, such as the development of thalamus-specific MRI sequences, that have improved the precision of thalamic nuclei delineation. We focus on open-source atlases that support reproducible research and clinical applications. Future developments will likely focus on integrating multi-scale data; combining cytoarchitectonic, with quantitative MRI and computational models to improve thalamic parcellation and accurate localization in vivo.
When thinking about the beginning of modern anatomical drawings that reflect topography in detail, our thoughts often turn to the more than 200 woodcuts included in Andreas Vesalius’s “De humani corporis fabrica libri septem.” However, Leonardo da Vinci also produced detailed anatomical sketches before the publication of the Fabrica, including drawings that addressed the cerebral ventricular system. The goal of this narrative historical review is to examine how medical knowledge of the ventricular system evolved from antiquity, represented by Galen of Pergamon and Hippocrates of Kos, toward post-Galenic anatomy. This analysis is based on four sketches created between approximately 1487 and 1509, held in the collections of the Royal Library at Windsor, England, and the Schlossmuseum in Weimar, Germany. Although medical literature frequently references Leonardo’s anatomical work, relatively few studies have focused specifically on the morphology of the ventricular system while also considering the physiology and philosophy of the turn of the 15th and 16th centuries. This study therefore analyzes Leonardo’s ventricular drawings as an important transitional episode in the visual history of neuroanatomy. At the same time, it acknowledges that Leonardo’s anatomical studies were largely unpublished during his lifetime, that their influence on later anatomists remains uncertain, and that retrospective interpretation of historical drawings requires caution.
IntroductionTo avoid image blurring, the vestibulo-ocular (VOR) and the optokinetic (OKR) reflexes stabilize gaze. In all vertebrates, the VOR is mediated via direct projections from the vestibular nuclei to the motor nuclei that control the extraocular muscles. Lampreys show three vestibular nuclei that are well characterized in terms of their projections and sensory inputs, but much less is known about their inputs from other brain regions and the connectivity between them.MethodsWe used tracer injections and extracellular electrophysiological recordings, to analyze the inputs to each vestibular nucleus.ResultsThe lamprey vestibular nuclei are largely interconnected, while their inputs from other brain regions are scarce. The main rostral areas projecting to the vestibular nuclei are the pretectum and the ventral tier of the thalamus, which send ipsilateral inputs to the three vestibular nuclei.DiscussionThese findings show that the interconnectivity of the vestibular nuclei was already stablished at the beginning of vertebrate evolution, and that the pretectal input provides visual information to all the vestibular nuclei, indicating that visuovestibular integration for gaze and body stabilization was already important at the base of vertebrate evolution.
Donald O. Hebb was born in Chester Nova Scotia on 22 July 1904, attended the Chester school and the Halifax County Academy, and obtained a BA in English and Philosophy from Dalhousie University in 1925. After obtaining a teacher’s certificate he taught in his old school in Chester for a year and then in Montreal while attending McGill University to obtain his MA in Psychology as a part-time student. He moved to Chicago to work with Karl Lashley and then completed his PhD with Lashley at Harvard in 1936. He was an instructor for a year at Harvard (1936–37) and then received a Fellowship to work at the Montreal Neurological Institute (1937–39), conducting neuropsychological tests on the patients of Dr. Wilder Penfield. From 1939 to 1942 he was a professor at Queen’s University in Kingston, Ontario and then a Research Associate of Professor Lashley, studying emotionality in chimpanzees at the Yerkes Primate Center in Florida (1942–1947). It was there that he began to write his influential book, The Organization of Behavior. This book introduced the concepts of synaptic change, cell assemblies, and phase sequences to account for the neural events underlying behavior. Hebb’s work revolutionized the study of brain and behavior by establishing a biological basis for psychological phenomena. Hebb became a professor of Psychology at McGill University in 1947 and head of this department in 1948, completing his book at McGill in 1949. The crucial element in Hebb’s theory was the concept of reverberatory circuits of Lorente de Nó, based on Cajal’s concept of closed circuits. This paper examines the unpublished notes and papers written by Hebb between 1932 and 1947 as he developed his theory of neuropsychological function based on the concept of closed or reverberatory circuits and how this theory was used in psychology, neuroscience and the computer modeling of brain functions.
IntroductionGlucagon-like peptide-1 (GLP-1) is an incretin hormone involved in glucose homeostasis, appetite regulation, and energy balance. Beyond its peripheral metabolic actions, growing evidence indicates that GLP-1 signalling within the central nervous system modulates reward-related processes. The nucleus accumbens (NAc), a key component of the mesolimbic reward pathway, represents a critical site where metabolic and motivational signals converge. However, the role of GLP-1 signalling within the human NAc remains incompletely understood. This systematic review aimed to synthesize current human evidence on GLP-1 expression and receptor signalling in the NAc and their role in reward and metabolic regulation.MethodsA systematic search of PubMed, Scopus, and Web of Science was conducted in December 2025. Human studies assessing GLP-1 or GLP-1 receptor (GLP-1R) in relation to NAc structure, function, or connectivity were included. Study selection and data extraction were performed independently by two reviewers.ResultsFrom 276 screened records, five studies were included, totalling 284 participants. No consistent evidence emerged for direct GLP-1-related alterations in isolated NAc activation or GLP-1R expression. Instead, GLP-1 modulation of mesolimbic connectivity, particularly between the NAc and orbitofrontal cortex (OFC), was observed.DiscussionCurrent human evidence suggests that GLP-1 modulates reward processing primarily through cortico-striatal connectivity rather than localized changes within the NAc, with potential translational implications for obesity and addiction. Further harmonized neuroimaging studies incorporating direct pharmacological manipulation are needed to clarify NAc-specific GLP-1 mechanisms.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251250453.
IntroductionThe superior clinical utility of 7T magnetic resonance imaging (MRI) is constrained by high acquisition costs and limited scanner availability. While deep learning-based 3T-to-7T synthesis offers a potential solution, prevailing models typically rely on heavy parameterization, which increases computational redundancy and risk of overfitting on restricted medical datasets. In this paper, we focus on model efficiency and propose LiteMamba-Synth, an architecturally streamlined state space framework designed for high-fidelity MRI translation with minimal resource requirements.MethodsOur core contribution is the integration of the ConvMamba block, which utilizes the linear-time complexity of State Space Models (SSMs) to capture expansive spatial dependencies without the prohibitive computational overhead of traditional attention mechanisms. To preserve essential anatomical details during the compression of the feature space, we introduce the Wavelet-Enhanced Skip connection (WES), a module that facilitates multi-scale frequency-domain feature fusion to safeguard high-frequency textures and edge information. Additionally, a lightweight Convolutional Block Attention Module (CBAM) is incorporated to adaptively recalibrate feature responses toward salient neuroanatomical regions.ResultsExperimental results on the UNC T1w dataset demonstrate that LiteMamba-Synth achieves a competitive PSNR of 20.82 dB and an SSIM of 0.711. Crucially, our model maintains a compact footprint of merely 2.15 million parameters, representing a substantial reduction in complexity compared to contemporary deep learning baselines.DiscussionBy delivering high-quality synthesis results with minimal parameter overhead, LiteMamba-Synth provides a practical and scalable solution for deploying advanced MRI synthesis in resource-constrained clinical environments.
Combining diffusion tract descriptors with structural connectome descriptors may help characterize athlete-related brain imaging patterns; however, this approach is challenging in small-sample studies, where flexible learned models can easily overfit. In such settings, simple linear classifiers often serve as strong baselines, although they do not explicitly encode the anatomical correspondence between tract-level microstructural descriptors and connectome-level organization. To address this gap, we introduce Tensor Connectome Consistency Residual (TC2-Res), a lightweight structured fusion framework that combines pair-aware tract representations, global modality branches, family-level encoders, and a tract-connectome consistency regularizer that encourages matched anatomical families to align in a shared latent space. In a small cohort of collegiate athletes, TC2-Res achieved a slightly higher mean balanced accuracy compared to a matched naive learned fusion baseline on the primary football-vs.-others task, whereas a classical linear support vector machine (SVM) remained the strongest overall classifier. The observed performance gain was modest and inconsistent across folds, and evidence of improvement specifically attributable to the consistency term was limited. These results suggest that anatomically structured fusion represents a plausible lightweight design direction for learned multimodal classification in limited-data settings while also highlighting the continued strength of classical linear baselines in this regime.
The nuclear ubiquitin proteasome system (UPS) is fundamental to maintaining proteostasis and ensuring the quality control of nuclear proteins. Within the nucleus, proteasomes are distributed throughout the nucleoplasm and can aggregate into nuclear bodies. In 2002, our group provided the first description in mammalian cells of a specific subtype of nuclear body highly enriched in: (i) ubiquitin conjugates, (ii) the proteolytically active 20S and 19S regulatory complexes of the 26S proteasome, (iii) the molecular chaperone Hsp70, and (iv) proteasome substrates. We coined the term clastosome to define this nuclear proteolytic center of the UPS. Clastosomes exhibit dynamic behavior, and their formation is transiently and robustly induced in mammalian neurons during osmotic stress, coinciding with enhanced proteasomal activity. Subsequent studies have confirmed and mechanistically expanded our understanding of these nuclear proteolytic centers, which are now recognized as nuclear condensates formed via liquid–liquid phase separation mechanisms. Notably, PML nuclear bodies can establish interactions with clastosomes, thereby linking the PML protein and the SUMOylation pathway with UPS-mediated protein degradation. The association between PML nuclear bodies and clastosomes has been implicated in the clearance of toxic mutant proteins associated with certain neurodegenerative diseases. This review examines the structure, composition, and dynamic regulation of clastosomes, focusing on their modulation during stress responses and neurodegeneration. Given the essential role of nuclear proteolytic centers in proteostasis regulation, a better understanding of mechanisms that modulate their assembly may offer therapeutic strategies for neurodegenerative proteinopathies and other pathologies.
The evolutionary expansion of the primate prefrontal cortex (PFC) presents a profound biological enigma: how does this region achieve a highly ordered, modular architecture in the absence of direct dense sensory templates that govern primary sensory areas? In this review, we synthesize classical neuroanatomical frameworks with recent advances in spatial transcriptomics and connectomics to delineate a model of intrinsic elaboration. We propose that PFC modularity emerges from a developmental program facilitated by expansion of the outer subventricular zone (OSVZ) and the legacy of whole-genome duplication (2R-WGD). Central to this proposal is a “Dual-Control Model” of circuit assembly, inferred by integrating anatomical tracer data with spatial and spatiotemporal transcriptomic datasets. This framework suggests that long-range connectivity is established through pre-target axon bundling (fasciculation), governed by a high-dimensional navigation code (e.g., ephrin/Eph, PCDH11X, PCDH17, ROBO2), while these bundles are anchored onto vertical columnar scaffolds through synaptic docking mechanisms (e.g., CBLN2, cadherins). By contrasting the PFC with the map-driven visual system, point-driven olfactory system, and layer-driven hippocampus, we argue that PFC uniqueness lies not in novel genes but in a combinatorial logic of a shared molecular toolkit, which can be understood as intrinsic elaboration. This framework may facilitate the emergence of a cognitive scaffold under relatively weak external sensory constraints. These molecular systems are considered to operate in concert with activity-dependent developmental refinement rather than independently of neural activity.
The transcription factor 4 (TCF4) gene is essential for brain development, and its disruption causes Pitt-Hopkins syndrome. Common genetic variants in TCF4 also confer risk for schizophrenia and related psychiatric disorders. While the developmental roles of TCF4 are well established, its postnatal functions remain poorly defined, particularly during the prolonged maturation of the primate neocortex, when many neuropsychiatric symptoms first emerge. Here, we mapped cell-type-specific TCF4 expression across postnatal development in rhesus macaque neocortex using immunofluorescence, and in situ hybridization. We also re-analyzed public bulk-tissue and single-nucleus transcriptomic datasets spanning 16 brain regions in both humans and macaques. TCF4 was predominantly neuronal, with minimal expression in microglia, oligodendrocytes, and astrocytes. In late gestation, TCF4 was broadly expressed in excitatory and inhibitory neurons, but expression declined with maturation and became selectively enriched in inhibitory populations. By young adulthood, nuclear TCF4 levels were highest in somatostatin-positive and vasoactive intestinal peptide-positive interneurons, intermediate in parvalbumin interneurons (~6-fold above non-GABAergic cells), and lowest in cholecystokinin interneurons (~4-fold above non-GABAergic cells). This interneuron-subtype hierarchy was independently reproduced by single-nucleus RNA sequencing across all neocortical regions. Together, these findings position mature GABAergic interneurons as the principal site of TCF4 function in the primate neocortex, providing a cellular framework for linking TCF4 dysfunction to cortical circuit imbalance in Pitt-Hopkins syndrome and psychiatric disease.
Defining neural connectivity between peripheral organs and the nervous system remains a fundamental challenge. While neural tract tracing techniques are well established and highly effective in the central nervous system, their application in peripheral tissues—particularly through retrograde approaches—continues to generate controversy. This article highlights an alternative approach based on the neuronal injury response. Specifically, I discuss the use of activating transcription factor 3 (ATF3), a molecular marker robustly upregulated in neurons following axonal injury, as an indirect means of identifying organ-specific innervation. By integrating classical and injury-induced approaches, this framework may help resolve longstanding debates regarding visceral innervation and improve the reliability of circuit-mapping strategies in the peripheral nervous system.
Introduction:This study examined how curcumin influences spinal cord morphological parameters in rats with STZ-induced diabetes using unbiased stereological methods. Methods:Fifty-six female Wistar albino rats were randomly divided into seven experimental groups (n = 8): Control, Sham, Curcumin, Diabetes Mellitus (DM), DM + Curcumin after 7 days (DC1), DM + Curcumin after 21 days (DC2), and DM + Curcumin simultaneously (DC3). Diabetes was induced via a single intraperitoneal dose of STZ (50 mg/kg). Curcumin was administered at a dose of 30 mg/kg via intragastric gavage for 14 consecutive days. C3-C5 spinal segments were collected at the end of the experiment, processed for histology, and stained with toluidine blue and cresyl violet for stereological analysis. Neuronal quantification in the anterior horn was performed using physical fractionator. The volume fractions of the spinal cord, including white matter (WM/total volume) and gray matter (GM/total volume), were estimated using the Cavalieri's principle. Results:The diabetic (DM) group showed a significant reduction in motor neuron number compared with the Control group (p = 0.019), demonstrating diabetes-induced neuronal loss. In contrast, the DC2 treatment group showed a significant increase in motor neuron counts compared with DM (p = 0.04), suggesting a possible neuroprotective effect of curcumin. Total spinal cord volume did not differ significantly among groups. WM/Total ratio decreased in the Sham group but increased with curcumin (DC3). GM/Total ratio was lower in DC3 than Sham, and curcumin produced a non-significant improvement compared with diabetic rats. Increased caspase-3 immunoreactivity in the diabetic group indicates activation of apoptotic pathways, consistent with the observed reduction in motor neuron number and soma size. Furthermore, the marked increase in GFAP immunoreactivity, particularly in the DC2 group, reflects astrocyte activation and a reactive gliosis, which are commonly associated with metabolic stress and neuroinflammation in diabetic conditions. Discussion:Curcumin administration partially mitigated spinal motor neuron loss induced by experimental diabetes. The timing of curcumin treatment influenced its efficacy. These findings suggest that curcumin may have therapeutic potential for preventing diabetes-induced spinal cord neurodegeneration.
Semilunar granule cells in the dentate gyrus represent a distinct type of granule cell, distinguished by their unique morphology and physiology. These cells are located within the inner molecular layer and the upper juxta-granule cell layer of the dentate gyrus. The presence of a smaller number of granule cells has also been observed in the outer molecular layer; however, the information regarding these cells is limited. In the present study, the perisomatic innervation that these two types of granule cells receive was characterized using confocal and electron microscopy. Our findings revealed that both semilunar granule cells and outer molecular layer granule cells receive substantial excitatory and inhibitory perisomatic contacts. The inhibitory contacts are derived from parvalbumin fast-spiking cells and cholecystokinin regular-spiking cells. The origin of excitatory contacts has been traced to hilar mossy cells and supramammillary afferents.
Accurate quantification of cellular composition is fundamental to understanding the structural and functional organization of the cerebral cortex. In the present study, we quantified the proportions of neurons, glia, and vascular cells (primarily endothelial cells) across the full cortical thickness (layers I-VI) of the mouse primary somatosensory cortex (S1HL) and the human temporal cortex (BA21) using immunocytochemical techniques and a direct 3D counting method. Over 25,000 cells in the mouse and 13,000 cells in the human cortex were individually identified and classified. For this purpose, we utilized EspINA software, which enables precise cell identification and volumetric analysis while preserving laminar and spatial context. Our results reveal marked species-specific differences in cellular proportions: neurons represent approximately 60% of all cells in the mouse S1HL but only 30% in the human BA21. These differences are reflected in the glia-to-neuron ratio (GNR) and non-neuron-to-neuron ratio (nNNR), which were consistently below 1.0 in the mouse (GNR: 0.4; nNNR: 0.6) but significantly higher in the human samples (GNR: 1.5; nNNR: 2.3). By overcoming the limitations of traditional stereological and tissue-homogenization techniques, this study provides a detailed laminar characterization of the cellular composition in these particular cortical regions (mouse S1HL and human BA21).
IntroductionLipopolysaccharide (LPS) induces neuronal injury by stimulating microglia, which release pro-inflammatory markers and neurotoxic factors. Folate deficiency induces microglial activation and modulates nuclear factor-κB (NF-κB) p65 and neurogenic locus Notch homolog protein 1 (Notch1) expression in the hippocampus. This study investigated the neuroprotective effect of folic acid against LPS-induced neurotoxicity in rats, focusing on its modulation of microglial activation and the Notch1, NF-κB, and p65 signaling pathways.MethodsA total of 24 Sprague–Dawley male rats were assigned to four groups: control, folic acid, LPS, and folic acid + LPS. After sacrifice, the left cerebral hemisphere was subjected to histopathological assessment using hematoxylin and eosin (H&E) staining and immunohistochemical assessment using anti-GFAP, anti-Iba1, anti-cyclooxygenase-2 (COX-2), anti-tumor necrosis factor-α (TNF-α), and anti-NF-κB antibodies. The hippocampus was extracted from the right hemisphere and used to assess the gene expression of Notch1, TNF-α, interleukin-6 (IL-6), and COX-2 markers using real-time reverse transcription PCR.ResultsFolic acid ameliorated LPS-induced neuronal damage in the hippocampus, suppressed microglial activation (GFAP and Iba-1), downregulated Notch1 and NF-κB p65, and improved neuroinflammatory responses (TNF-α, IL-6, and COX-2), regardless of the region.ConclusionFolic acid exerted an equivalent neuroprotective effect in both the CA1 and CA3 regions by suppressing microglial activation and modulating the Notch1/NF-κB signaling pathway, thereby reducing neuroinflammation. These findings suggest that folic acid may serve as a potential adjuvant neuroprotective agent against inflammation-mediated neuronal injury.
Introduction:Maternal environmental factors critically influence neural circuit maturation during early development. The maternal gut microbiota has emerged as an important upstream regulator of offspring neurodevelopment, yet its role in shaping the structural organization of enteric and cortical inhibitory circuits remains poorly defined. Here, we examined whether gestational disruption of the maternal gut microbiota is associated with alterations in parallel enteric and cortical inhibitory circuit development. Methods:Maternal gut dysbiosis was induced in pregnant GAD67-GFP mice by oral vancomycin administration during gestation. Maternal and offspring microbiota were analyzed using full-length 16S rRNA gene sequencing to assess microbial diversity and vertical transmission. Offspring were examined at postnatal day 14 for intestinal morphology, altered barrier integrity, and enteric nervous system (ENS) organization. Cortical inhibitory circuits were analyzed by quantifying GAD67-positive interneuron density and performing three-dimensional morphological reconstruction in layers II/III of the somatosensory cortex, motor cortex, medial entorhinal cortex, and CA1 region of the hippocampus. Results:Maternal dysbiosis significantly reduced microbial diversity and disrupted maternal-offspring microbial transmission. These changes were associated with impaired intestinal development, including reduced crypt height, thinning of the muscularis propria, fragmented Claudin-1 expression, and reduced Auerbach's plexus area without changes in neuronal density, indicating altered enteric network organization. In the brain, maternal dysbiosis induced region-specific cortical vulnerability, with reduced dendritic length and branching of GAD67-positive interneurons in the somatosensory and motor cortices, while interneuron morphology in the medial entorhinal cortex and hippocampus was preserved. Interneuron density was selectively reduced in the motor cortex. Discussion:These findings indicate that gestational maternal dysbiosis is associated with co-occurring structural alterations in intestinal and cortical inhibitory systems, selectively affecting inhibitory circuit architecture in sensorimotor regions. While the present model does not isolate microbiota-specific mechanisms from potential antibiotic-induced maternal physiological changes, the data support an association between disrupted maternal microbial ecology and offspring enteric and cortical neuroanatomical development during early postnatal life. These findings should be interpreted as descriptive associations and do not establish mechanistic gut-brain interactions.
The corticospinal tract (CST) and reticulospinal tract (RST) represent the core descending pathways within the central nervous system for motor control. This review elucidates the anatomical and functional interplay. Anatomically, the CST and RST fibers are spatially proximate within the spinal cord and are integrated into a continuous regulatory axis via the corticoreticular pathway. Functionally, they exhibit both synergy and specialization: the CST primarily governs contralateral distal limb fine motor control, whereas the RST, operating in a bilateral mode, regulates axial and proximal body movements, postural stability, and adaptation to strength training. Notably, following CST damage (e.g., stroke or spinal cord injury), the RST demonstrates remarkable plasticity and serves as a critical substrate for functional compensation and recovery. Furthermore, an imbalance in CST-RST function has been implicated in the pathophysiology of conditions such as post-stroke spasticity and multiple sclerosis. Therapeutic strategies targeting the CST-RST network, including neuromodulation and molecular interventions aimed at promoting axonal regeneration and modulating network excitability, present promising new directions for the treatment of neurological disorders. Future research should focus on deciphering the specific interactions at the spinal interneuron level to advance the development of precise rehabilitation strategies.
IntroductionMotion sickness is a common physiological disorder induced by with unusual movement exposure, characterized by conflicting motion signals that trigger vestibulo-sympathetic reflexes (VSR). These reflexes mediate autonomic responses to motion-induced stress. Previous studies have implicated the vestibular nucleus complex and the caudal ventrolateral medulla (CVLM) in VSR modulation. GABA (γ-aminobutyric acid), the primary inhibitory neurotransmitter in the central nervous system (CNS), plays a key role in both cardiovascular regulation and vestibular function. However, the specific contribution of GABAergic structures to motion sickness-related cardiovascular responses remains unclear.MethodsIn this study, we combined retrograde tracing and immunofluorescence labeling to investigate GABAergic pathways using complex double-axis rotation model. Fluoro-Gold (FG) was injected into the CVLM, while biotinylated dextran amine (BDA) was delivered to the medial vestibular nuclei (MVe).ResultsOur results revealed a bilateral distribution of GABAergic neurons, predominantly within the caudal raphe nuclei. Notably, a subset of these neurons was activated (as indicated by Fos immunoreactivity) and projected to the CVLM (as shown by retrograde labeling with FG) under complex double-axis rotation model. Furthermore, these same neurons also received direct inputs from the MVe, as evidenced by their labeling with BDA.DiscussionOur findings offer morphological evidence that GABAergic neurons in the caudal raphe nuclei participate in the cardiovascular responses evoked by motion sickness in a complex double-axis rotation model.
