Front Neuroanat
· 2025 · PMID 41169656
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Santiago Ramón y Cajal's pioneering work laid the foundations for modern neuroscience and continues to impact the development of artificial intelligence, particularly deep learning. His neuron theory, the principle of dy...Santiago Ramón y Cajal's pioneering work laid the foundations for modern neuroscience and continues to impact the development of artificial intelligence, particularly deep learning. His neuron theory, the principle of dynamic polarization, and his insights into brain plasticity and network organization have significantly influenced both our understanding of the nervous system and the design of artificial neural networks. This article reviews Cajal's key contributions, explores their role in the evolution of AI, and emphasizes the enduring links between neuroscience and machine learning in the digital era.
Hansson N, Fangerau H, De Sio F
… +2 more, Grell U, Amunts K
Front Neuroanat
· 2025 · PMID 41059389
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This article explores the complex and ultimately unsuccessful Nobel Prize trajectories of Oskar (1870-1959) and Cécile Vogt (1875-1962), as well as their ongoing scientific legacy. Their legacy sheds light on the backgro...This article explores the complex and ultimately unsuccessful Nobel Prize trajectories of Oskar (1870-1959) and Cécile Vogt (1875-1962), as well as their ongoing scientific legacy. Their legacy sheds light on the background to the decision from different perspectives. Despite multiple nominations, the couple never received the Nobel Prize in Physiology or Medicine. Drawing upon archival sources from the Nobel Forum and the Vogt Archive in Düsseldorf, we reconstruct the history of their candidacies, the reasons why they were proposed, and those behind the committee's repeated rejections. Their work on cyto- and myeloarchitectonics, the functional anatomy of the basal ganglia, and structure-function relationships in the cerebral cortex earned them international recognition. However, the Nobel Committee remained unconvinced, often citing issues of scientific priority, insufficient novelty, and the controversial nature of some of their claims. Despite their exclusion from the prize, the Vogts' research shaped the development of brain science across Europe and beyond, influencing later Nobel laureates and contributing to foundational concepts in neuroanatomy and -physiology. Their case invites reflection on the historical contingencies of scientific recognition and the shifting criteria for what counts as a "discovery" worthy of the Nobel Prize.
Pereira M, Venâncio C, Pinto ML
… +3 more, Félix LM, Alves-Pimenta S, Colaço B
Front Neuroanat
· 2025 · PMID 41059387
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INTRODUCTION: The olfactory system acts as an interface between the environment and the brain. Its direct neural connection makes it a target for xenobiotics and a suitable model for studying olfactory dysfunction and re...INTRODUCTION: The olfactory system acts as an interface between the environment and the brain. Its direct neural connection makes it a target for xenobiotics and a suitable model for studying olfactory dysfunction and related neurotoxic effects. This study aimed to characterize an animal model of olfactory dysfunction induced by nose-to-brain (NTB) delivery of vanadium pentoxide (VO). METHODS: Rats received 182 or 273 μg intranasally, thrice weekly over 4 weeks, followed by behavioral, histological, and biochemical analysis of the olfactory epithelium (OE), olfactory bulbs (OBs), and hippocampus. RESULTS: Behavioral tests showed significant olfactory deficits, longer latencies, and reduced investigation times in exposed groups. Histological analysis revealed coagulative necrosis in the OE, disrupted cellular organization, reduced number and size of OB glomeruli, and hippocampal neuronal loss with gliosis. Immunohistochemistry revealed increased proliferating cell nuclear antigen (PCNA) expression in the OE, dopaminergic neuron loss and astroglial proliferation in the OB, and hippocampal astroglial proliferation at the highest dose. Myelin basic protein (MBP) expression remained unchanged. Oxidative stress markers were largely unaltered, except for increased superoxide dismutase (SOD) in OBs and glutathione S-transferase (GST) in the hippocampus, especially at the high dose. DISCUSSION: The results reveal dose-dependent vanadium-induced neurotoxicity in the olfactory system. The higher dose induced pronounced structural damage, neuroinflammation, and oxidative stress, resulting in olfactory and cognitive impairments relevant to advanced olfactory dysfunction and neurodegeneration. The lower dose induced milder yet significant effects, supporting its use in early-stage dysfunction studies. This NTB-based model offers a valuable tool for investigating olfactory dysfunction mechanisms in toxicological and neurodegenerative contexts.
Rodríguez-Moldes I, Sueiro C, Carrera I
… +2 more, Quintana-Urzainqui I, Candal E
Front Neuroanat
· 2025 · PMID 40933510
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Comparative studies on the forebrain across different model organisms are necessary to investigate the origin and degree of evolutionary conservation of this brain region and its derivatives. The catshark has become a r...Comparative studies on the forebrain across different model organisms are necessary to investigate the origin and degree of evolutionary conservation of this brain region and its derivatives. The catshark has become a reliable model representative of cartilaginous fishes (Chondrichthyans), the oldest divergent lineage of extant gnathostomes (jawed vertebrates). Previous studies on the chemoarchitecture, connectivity, and development of the subpallium of revealed the existence of subdivisions with an embryological origin and genetic specification similar to those of tetrapods, supporting homology with their basal ganglia and certain amygdaloid components. To better understand the evolutionary origin of these subpallial components, we present here a summary of the main neuroanatomical, chemoarchitectural, and developmental features of the of , a nuclear aggrupation of the basal forebrain of all Chondrichthyans that has been related to the basal ganglia and the amygdala. Particular emphasis has been placed on characterizing the tyrosine hydroxylase-positive components of the subpallium to discern their involvement in the structural organization of putative basal ganglia homologs in the catshark. We propose a new interpretation that considers the as the central part of a subpallial complex formed also by its neighboring territories, where the basic components of the basal ganglia and the amygdala of gnathostomes would be integrated.
Corrales Parada CD, Udovičić I, Haschei G
… +1 more, Chagnaud BP
Front Neuroanat
· 2025 · PMID 40895598
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Animals use different communication modalities for social interactions, often showing sensory adaptations linked to their preferred signaling system. How such adaptations affect individual processing centers usually rema...Animals use different communication modalities for social interactions, often showing sensory adaptations linked to their preferred signaling system. How such adaptations affect individual processing centers usually remains elusive due to interspecies differences. One system in which such adaptations can be investigated are catfish. generally use acoustic signals for social communication, but in some species, they generate electric signals. This allows to investigate adaptations of networks associated with social signal detection in closely related species. We investigated potential sensory adaptations in two species ( - SG and - SN) with different communication channels. We tested their behavioral preferences toward different sensory modalities and found strong preferences for conspecifics. To investigate potential adaptations at the cellular level, we focused on the torus semicircularis (TS), a major midbrain sensory hub for auditory and electric sensory processing. We found an increase in projections from the anterior tuberal nucleus (AT) to the lateral TS (TSl, which processes electrosensory information) in SN, but no difference in the projections from the central TS (TSc) to AT in either species. An enhanced density of calcium binding proteins in the TSl was found only in SN. As electrocommunication is a derived communication channel in , our findings suggest that a shift to electric communication may have led to (i) stronger projections to and from sensory regions, and (ii) a change in neurochemical profile, which together might facilitate social signal detection.
Front Neuroanat
· 2025 · PMID 40880684
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Even though bats are the second most speciose group of mammals, neuroanatomical studies of their hippocampus are rare, particularly of small echolocating bats. Here, we provide a qualitative and quantitative neuroanatomi...Even though bats are the second most speciose group of mammals, neuroanatomical studies of their hippocampus are rare, particularly of small echolocating bats. Here, we provide a qualitative and quantitative neuroanatomical analysis of the hippocampus of small echolocating bats (Phyllostomidae and Vespertilionidae). Calcium-binding proteins revealed species- and family-specific patterns for calbindin and calretinin. Interneuron staining for both proteins was very rare in phyllostomids, while calretinin marked subpopulations of CA3 pyramidal neurons in both families. Parvalbumin expression was consistent across bats and similar to other species. A unique calretinin-positive calbindin-negative zone was observed at the superficial boundary of the CA3 pyramidal cell layer in phyllostomid bats. This zone defined a gap between pyramidal cells and the zinc-positive mossy fibers. We hypothesize that this gap might either stem from calretinin-positive afferents displacing the zinc-positive mossy fiber boutons, or from a complete segregation of neurochemically distinct mossy boutons. Furthermore, we observed a distinct dorsoventral shift in the length of the upper and lower blade of the granule cell layer in all species. In terms of hippocampal neuron numbers, bats were characterized by a rather small granule cell and subicular neuron population, but a well-developed CA3. In a correspondence analysis, preferred diet segregated phyllostomids into a hilus-dominant omnivorous and frugivorous species group, and a subiculum-dominant group containing vampire bats and nectivorous species. Although the two families overlapped considerably, the cellular composition of the phyllostomid hippocampus can be described as output dominant, while in vespertilionids neuron populations on the hippocampal input side are more dominant. Neuroanatomical and ecological variability and unique traits within echolocating bats as shown here can provide a rich source for investigating structure-function relationships.
Mydeen AB, Nakhal MM, Nafees F
… +12 more, Almazrouei R, Alkamali R, Alsulaimi M, Aleissaee O, Alzaabi A, Alfahim M, Almansoori H, BaniYas S, Al Houqani S, Elkashlan M, Shehab S, Hamad MIK
Front Neuroanat
· 2025 · PMID 40880682
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INTRODUCTION: The gut microbiota plays a critical role in regulating brain structure and function via the microbiota-gut-brain axis. Antibiotic-induced gut dysbiosis (AIGD) has been linked to neuroanatomical changes and...INTRODUCTION: The gut microbiota plays a critical role in regulating brain structure and function via the microbiota-gut-brain axis. Antibiotic-induced gut dysbiosis (AIGD) has been linked to neuroanatomical changes and cognitive deficits. However, its impact on neuronal morphology in layer II of the medial entorhinal cortex (mECII), a region central to spatial memory, remains poorly understood. This study examines how AIGD affects dendritic architecture in mECII stellate and pyramidal island cells. METHODS: Mice received a broad-spectrum oral antibiotic cocktail to induce AIGD. Gut microbiota composition was analyzed using 16S rRNA sequencing. Golgi-stained neurons in mECII were assessed for dendritic complexity via Sholl analysis. Iba1 staining evaluated microglial activation in mECII. Intestinal sections were stained with NeuN and CD8 to assess enteric neuron density and inflammation. Microbial abundance was correlated with dendritic parameters. RESULTS: AIGD resulted in significant dysbiosis, including depletion of butyrate-producing taxa (, ) and enrichment of proinflammatory bacteria (, , ). Stellate cells showed marked dendritic atrophy, while pyramidal island cells were unaffected. Dendritic complexity positively correlated with and negatively with . No microglial activation was detected in mECII, but CD8 + T-cell infiltration increased in the gut without changes in NeuN-labeled enteric neurons. DISCUSSION: These findings suggest AIGD selectively alters mECII stellate cell morphology through peripheral immune signaling or microbial metabolites, independent of local microglial activation. This study highlights the role of gut microbiota in shaping neuronal architecture and supports microbiome-targeted strategies to counteract dysbiosis-associated neuroanatomical changes.
Yang T, Ren K, Chen X
… +5 more, Toriumi T, Li R, Li J, Tokita K, Yi SQ
Front Neuroanat
· 2025 · PMID 40880683
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BACKGROUND: Pacinian corpuscles (PCs) are pressure- and vibration-sensitive mechanoreceptors found in hairless skin, external genitalia, joints, ligaments, lymph nodes, prostate, bladder, etc. While they are documented i...BACKGROUND: Pacinian corpuscles (PCs) are pressure- and vibration-sensitive mechanoreceptors found in hairless skin, external genitalia, joints, ligaments, lymph nodes, prostate, bladder, etc. While they are documented in the pancreas of cats, their presence in the normal pancreas remains speculative. PURPOSE: The present study therefore investigated the distribution of PCs in the normal human pancreas and compared the findings with those in several other animal species. METHODS: The study subjects included 74 human cadaver specimens, 3 , 2 , 1 , and 10 . Pancreatic tissues were prepared as paraffin sections for histological and immunohistochemical analyses of the main constituents of PCs (central axon, inner core, and outer core capsule). RESULTS: PCs were found in the pancreas of five human cadavers (7%), as well as in one , one and one but not in . The PCs varied in size, with the largest in the human pancreas measuring up to 1,106 μm-far exceeding those in animal pancreata, but less numerous than those in animals. Morphologically, animal PCs were mainly typical oval shapes, whereas PCs in the human pancreas were mostly irregular in shape. In addition, we found that PCs in animals and human pancreata had similar structures, with consistent expression of protein gene product 9.5, in axonic profiles, and diffuse vimentin immunoreactivity in the inner core, outer core, and capsule. CONCLUSION: This study confirmed the presence of PCs in a small number of healthy humans and some animal pancreata. The number, distribution characteristics, and morphology of PCs in the pancreata of animals and humans are quite different; however, their structures and immunohistochemical profiles are similar. The presence of PCs in the normal human pancreas is also a mystery, and the physiological role of PCs in the human pancreas requires further clarification.
Afrin M, Islam MN, Meher MM
… +5 more, Jahan MR, Nozaki K, Masumoto KH, Yanai A, Shinoda K
Front Neuroanat
· 2025 · PMID 40766770
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Huntingtin-associated protein 1 (HAP1) is a crucial component of the stigmoid body (STB) and is recognized as a neuroprotective interactor with causative proteins for several neurodegenerative disorders (NDs). Due to HAP...Huntingtin-associated protein 1 (HAP1) is a crucial component of the stigmoid body (STB) and is recognized as a neuroprotective interactor with causative proteins for several neurodegenerative disorders (NDs). Due to HAP1 protectivity, brain regions rich in STB/HAP1 are typically shielded from neurodegeneration, whereas areas with little or no STB/HAP1 are often affected in NDs. Mounting evidence suggests that serotonin (5-HT) neuron dysfunction contributes to various NDs. While the raphe nuclei denote the origin of 5-HT neurons, HAP1 protectivity has yet to be determined there. To accomplish this, the present study evaluated the expression and detailed neuroanatomical distribution of HAP1 throughout the rostral and caudal clusters of raphe nuclei in adult mice brains and their morphological relationships with 5-HT by employing Western blotting and immunohistochemistry. Our results indicated that in the rostral cluster, HAP1-ir cells were extensively distributed across the caudal linear raphe, median raphe, dorsal raphe, supralemniscal raphe, caudal part of the dorsal raphe, pre-pontine and pontine raphe nuclei. In the caudal cluster, HAP1-ir neurons were disseminated throughout the raphe magnus, raphe obscurus, raphe pallidus, parapyramidal, and raphe interpositus nuclei. Our double-immunofluorescence labeling results confirmed that most of the 5-HT neurons contained HAP1 immunoreactivity throughout the rostral and caudal clusters of the raphe nuclei. These suggest that HAP1 is crucial for modulating/protecting serotonergic functions, plausibly by upholding 5-HT neuronal plasticity/integrity by raising the threshold for neurodegeneration. Our current findings might provide a fundamental basis for further research aimed at elucidating the role of STB/HAP1 in the pathophysiology of serotonin neurons.
Front Neuroanat
· 2025 · PMID 40747269
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The glial fibrillary acidic protein (GFAP) is the principal intermediate filament protein and histochemical marker for astroglia. It appears contradictory that there are extended GFAP-poor or even GFAP-free areas in the...The glial fibrillary acidic protein (GFAP) is the principal intermediate filament protein and histochemical marker for astroglia. It appears contradictory that there are extended GFAP-poor or even GFAP-free areas in the brains of various vertebrate clades: cartilaginous and ray-finned fishes, and amniotes. The "Relevant Subsections: Extended GFAP-free areas in various vertebrates" section in this study reviews our GFAP mapping studies on the brains of 58 species within these clades, as well as mappings from other authors, and demonstrates that these areas appeared independently from one another in the more advanced groups of different clades; it raises the supposition that the lack of GFAP is an apomorphic phenomenon. The GFAP expression has withdrawn mainly relatively: the GFAP-immunonegative areas increased more than the immunopositive ones. Primarily, regions that expanded and increased in complexity during evolution lack GFAP immunopositivity (except for their perivascular glia). The absence of GFAP expression, however, does not indicate the lack of astroglia. In the areas immunonegative to GFAP, astrocytes were visualized using other markers, such as glutamine synthetase or S-100 protein. In birds and mammals, lesions induced GFAP expression in these areas. It shows that the ability to express GFAP is not lost but has become facultative. These data suggest that the lack of GFAP production may provide an evolutionary advantage. The "Discussion" section relates the GFAP "withdrawal" to other steps of evolution: the increasing complexity and thickening of the brain wall, as well as the appearance of the astrocytes, particularly protoplasmic astrocytes, and then examines the proposed evolutionary advantages and disadvantages of the absence of GFAP. The role of the relative "withdrawal" of GFAP expression in brain evolution remains to be definitively answered. The most probable candidates may include the absence of synthesizing an unnecessary protein, improved adaptation of astrocytes to the demands of neurons, and an increased capacity for synaptic plasticity. In contrast, one must consider that the withdrawal of GFAP may not be a primary phenomenon but rather a consequence of the evolution of neural networks.
Alonso-Almorox P, Blanco A, Fiorito C
… +4 more, Gómez-Villamandos JC, Risalde MA, Almunia J, Fernández A
Front Neuroanat
· 2025 · PMID 40747268
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The pituitary gland is central to endocrine regulation in vertebrates, coordinating key physiological processes such as growth, reproduction, and stress responses. In cetaceans, and particularly in large odontocetes like...The pituitary gland is central to endocrine regulation in vertebrates, coordinating key physiological processes such as growth, reproduction, and stress responses. In cetaceans, and particularly in large odontocetes like orcas (Orcinus orca), understanding pituitary structure is essential for advancing neuroendocrine research and informing welfare and health assessments. Despite their ecological, cognitive, and conservation significance, detailed morphological studies of the orca pituitary gland remain scarce. In this study, we conducted a comprehensive structural and ultrastructural analysis of the orca pituitary gland using postmortem samples from four captive individuals. We combined computed tomography, histology, immunohistochemistry, and transmission electron microscopy to examine the gland's anatomical organization and cellular composition. Our results reveal features consistent with other cetaceans as well as species-specific characteristics, including the distribution and morphology of endocrine cells within the adenohypophysis and neurohypophysis. These findings provide the first integrated anatomical and ultrastructural reference for the orca pituitary gland, offering valuable insights into cetacean neuroendocrinology and supporting improved species-specific welfare evaluation, health monitoring, and management practices for orcas under human care.
Hercher C, Ellerbeck K, Toutée L
… +9 more, Ye X, Mpai R, Belliveau C, Davoli MA, Farmer WT, Watt AJ, Murai KK, Turecki G, Mechawar N
Front Neuroanat
· 2025 · PMID 40687434
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INTRODUCTION: The cerebellar cortex is now recognized as a functionally heterogeneous brain region involved not only in traditional motor functioning but also in higher-level emotional and cognitive processing. Similarly...INTRODUCTION: The cerebellar cortex is now recognized as a functionally heterogeneous brain region involved not only in traditional motor functioning but also in higher-level emotional and cognitive processing. Similarly, cerebellar astrocytes also display a high degree of morphological and functional diversity based on their location. Yet, the morphological features and distribution of cerebellar astrocytes have yet to be quantified in the human brain. METHODS: To address this, we performed a comprehensive postmortem examination of cerebellar astrocytes in the healthy human brain using microscopy-based techniques. Purkinje cells (PCs) were also quantified due to their close relationship with Bergmann glia (BG). Using canonical astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase-1 family member L1 (ALDH1L1), we first mapped astrocytes within a complete cerebellar hemisphere. RESULTS: Astrocytes were observed to be differentially distributed across cerebellar layers with their processes displaying known morphological features unique to humans. Stereological quantifications in three functionally distinct lobules demonstrated that the vermis lobule VIIA, folium displayed the lowest densities of ALDH1L1+ astrocytes compared with lobule III and crus I. Assessing cerebellar layers showed that the PC layer had the highest ALDH1L1+ densities while GFAP+ densities and astrocytes colocalizing (ALDH1L1+ GFAP+) were highest in the granule cell layer yet displayed the smallest GFAP-defined territories. PC parameters revealed subtle differences across lobules, with vermis folium VIIA having the lowest PC densities while a trend for the highest BG:PC ratio was observed in the cognitive lobule crus I. Lastly, to determine if these features differ from those of cerebellar astrocytes and PCs in species used to model human illnesses, we performed comparative analyses in mice and macaques showing both divergence and commonalities across species. DISCUSSION: The present study highlights the heterogeneity of astrocytes in the human cerebellum and serves as a valuable resource on cerebellar astrocyte and PC properties in the healthy human brain.
Krishnan M, Mydeen AB, Nakhal MM
… +5 more, Ibrahim MF, Jayaraj RL, Ljubisavljevic MR, Hamad MIK, Ismail FY
Front Neuroanat
· 2025 · PMID 40630552
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INTRODUCTION: Mutations in the methyl-CpG-binding protein-2 gene (), which cause Rett syndrome (RTT), disrupt neuronal activity; however, the impact of the loss-of-function on the cytoarchitecture of medial entorhinal c...INTRODUCTION: Mutations in the methyl-CpG-binding protein-2 gene (), which cause Rett syndrome (RTT), disrupt neuronal activity; however, the impact of the loss-of-function on the cytoarchitecture of medial entorhinal cortex layer II (MECII) neurons-crucial for spatial memory and learning-remains poorly understood. METHODS: In this study, we utilized Golgi staining and neuron tracing in the 2 mouse model of RTT to investigate the pyramidal and stellate cell alterations in MECII. RESULTS AND DISCUSSION: Our findings revealed that pyramidal cells displayed a significant reduction in apical dendritic length, soma size, and spine density, while basal dendrites showed increased dendritic complexity and branching. On the other hand, stellate cells exhibited dendritic hypertrophy along with increased soma size, primary dendrites, and localized increase in dendritic intersections, despite an overall reduction in total dendritic length and spine density. These findings underscore the notion that loss-of-function can disrupt MECII pyramidal and stellate cell cytoarchitecture in a cell-type-specific manner, emphasizing its critical role in maintaining proper dendritic morphology in circuits, which is crucial for learning and memory.
Andújar-Castillo E, Carrillo-Molina C, Alonso F
… +9 more, Villanueva-Iza C, Fernández-Pajarín G, Sesar A, Jiménez-Martín I, Martín-Rodriguez JF, Lama MJ, Mir P, Perez-Hernandez E, Otero CN
Front Neuroanat
· 2025 · PMID 40611917
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INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms and heterogeneous cognitive impairments influenced by factors such as age, disease duration, and severity...INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms and heterogeneous cognitive impairments influenced by factors such as age, disease duration, and severity. Traditional neuropsychological assessments often fall short in capturing the multifaceted nature of PD-related cognitive dysfunction due to their reliance on single test metrics. This study provides empirical support for the implementation of domain-based cognitive assessments, structured in line with Movement Disorder Society recommendations, to provide a multidimensional evaluation of cognitive profiles in PD patients. METHODS: Neuropsychological and clinical data were analyzed from 316 PD patients recruited from three Spanish hospitals-Hospital Clínico San Carlos (Madrid), the University Complejo Universitario de Santiago de Compostela (Galicia), and Hospital Virgen del Rocío (Sevilla)- and a control group of 96 older individuals, whose age difference from the PD group was statistically significant. Five cognitive domains were constructed, addressing attention/working memory, executive functions, memory, visuospatial abilities, and language, using composite z-scores derived from standardized neuropsychological tests. RESULTS: Latent Cluster Analysis identified three distinct cognitive profiles: (1) a fronto-striatal profile characterized by mild deficits in executive and attention functions and intact visuospatial abilities, (2) a posterior cortical profile marked by severe memory and visuospatial impairments but strong language performance, and (3) a preserved profile displaying mild deficits across multiple domains. Comparisons between PD clusters and controls revealed significant differences in cognitive trajectories, emphasizing the value of a domain-based approach for differentiating neurodegenerative patterns from normal aging. DISCUSSION: The findings highlight the potential of domain-based assessments to unify data across diverse samples, fostering standardized cross-cohort comparisons and facilitating large-scale research initiatives. By enabling methodological consistency, this approach provides a robust framework for advancing the understanding of cognitive dysfunctions in PD and improving clinical decision-making.
Ciccone C, Dötterer SE, Vold Jensen S
… +5 more, Geßner C, West AC, Wood SH, Hazlerigg DG, Folkow LP
Front Neuroanat
· 2025 · PMID 40585892
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For most non-diving mammals, lack of O (hypoxia) has detrimental effects on brain function. Seals, however, display a series of systemic, cellular, and molecular adaptations that enable them to tolerate repeated episodes...For most non-diving mammals, lack of O (hypoxia) has detrimental effects on brain function. Seals, however, display a series of systemic, cellular, and molecular adaptations that enable them to tolerate repeated episodes of severe hypoxia. One as yet unresolved question is whether seal neurons in part employ anaerobic metabolism during diving: the "reverse astrocyte-neuron lactate shuttle" (rANLS) hypothesis postulates that seal neurons, by shuttling lactate to the astrocytes, may be relieved (1) from the lactate burden and (2) from subsequent ROS-production as lactate is oxidized by astrocytes upon re-oxygenation after the dive. Here, we have investigated this possibility, through histological and functional comparisons of the metabolic characteristics of neocortical neurons and astrocytes from the deep-diving hooded seal (), using mice () as a non-diving control. We found that seal astrocytes have higher mitochondrial density and larger mitochondria than seal neurons, and that seal neurons have an atypical and significantly higher representation of the monocarboxylate lactate exporter MCT4 compared to mouse neurons. Also, measurements of mitochondrial O consumption suggest that the aerobic capacity of primary seal astrocytes is at least equal to that of primary seal neurons. Transcriptomics data from seals vs. mice suggest that specific adaptations to the electron transport system in seals may contribute to enhance hypoxia tolerance. These observations are consistent with the rANLS hypothesis.