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3D reconstruction of human brain volumes at high resolution is now possible thanks to advancements in tissue clearing methods and fluorescence microscopy techniques. Analyzing the massive data produced with these approaches requires automatic methods able to perform fast and accurate cell counting and localization. Recent advances in deep learning have enabled the development of various tools for cell segmentation. However, accurate quantification of neurons in the human brain presents specific challenges, such as high pixel intensity variability, autofluorescence, non-specific fluorescence and very large size of data. In this paper, we provide a thorough empirical evaluation of three techniques based on deep learning (StarDist, CellPose and BCFind-v2, an updated version of BCFind) using a recently introduced three-dimensional stereological design as a reference for large-scale insights. As a representative problem in human brain analysis, we focus on a 4 -cm 3 portion of the Broca's area. We aim at helping users in selecting appropriate techniques depending on their research objectives. To this end, we compare methods along various dimensions of analysis, including correctness of the predicted density and localization, computational efficiency, and human annotation effort. Our results suggest that deep learning approaches are very effective, have a high throughput providing each cell 3D location, and obtain results comparable to the estimates of the adopted stereological design., (© 2024. The Author(s).)

Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)-referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with a digital stereological approach on the 3D reconstruction at cellular resolution from a custom-made inverted confocal light-sheet fluorescence microscope (LSFM). Mesoscale optical coherence tomography enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system. The outcome is an integrated high-resolution cellular census of Broca's area in a human postmortem specimen, within a whole-brain reference space atlas.

The importance of assessing neurochemical processes in the cetacean brain as a tool for monitoring their cognitive health and to indirectly model human neurodegenerative conditions is increasingly evident, although available data are largely semiquantitative. High-resolution MRI for post-mortem brains and stereology allow for quantitative assessments of the cetacean brain. In this study, we scanned two brains of bottlenose dolphins in a 7-Tesla (7T) MR scanner and assessed the connectivity of the inferior colliculi and ventral cochlear nuclei using diffusion tensor imaging (DTI). Serial thick sections were investigated stereologically in one of the dolphins to generate rigorous quantitative estimates of identifiable cell types according to their morphology and expression of molecular markers, yielding reliable cell counts with most coefficients of error <10%. Fibronectin immunoreactivity in the dolphin resembled the pattern in a human chronic traumatic encephalopathy brain, suggesting that neurochemical compensation for insults such as hypoxia may constitute a noxious response in humans, while being physiological in dolphins. These data contribute to a growing body of knowledge on the morphological and neurochemical properties of the dolphin brain and highlight a stereological and neuroimaging workflow that may enable quantitative and translational assessment of pathological processes in the dolphin brain in the future.

While humans exhibit a significant degree of neuropathological changes associated with deficits in cognitive and memory functions during aging, non-human primates (NHP) present with more variable expressions of pathological alterations among individuals and species. As such, NHP with long life expectancy in captivity offer an opportunity to study brain senescence in the absence of the typical cellular pathology caused by age-related neurodegenerative illnesses commonly seen in humans. Age-related changes at neuronal population, single cell, and synaptic levels have been well documented in macaques and marmosets, while age-related and Alzheimer's disease-like neuropathology has been characterized in additional species including lemurs as well as great apes. We present a comparative overview of existing neuropathologic observations across the primate order, including classic age-related changes such as cell loss, amyloid deposition, amyloid angiopathy, and tau accumulation. We also review existing cellular and ultrastructural data on neuronal changes, such as dendritic attrition and spine alterations, synaptic loss and pathology, and axonal and myelin pathology, and discuss their repercussions on cellular and systems function and cognition., (© 2021 Wiley Periodicals LLC.)

Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans., (© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Over the last 15 years, research on canid cognition has revealed that domestic dogs possess a surprising array of complex sociocognitive skills pointing to the possibility that the domestication process might have uniquely altered their brains; however, we know very little about how evolutionary processes (natural or artificial) might have modified underlying neural structure to support species-specific behaviors. Evaluating the degree of cortical folding (i.e., gyrification) within canids may prove useful, as this parameter is linked to functional variation of the cerebral cortex. Using quantitative magnetic resonance imaging to investigate the impact of domestication on the canine cortical surface, we compared the gyrification index (GI) in 19 carnivore species, including six wild canid and 13 domestic dog individuals. We also explored correlations between global and local GI with brain mass, cortical thickness, white and gray matter volume and surface area. Our results indicated that GI values for domestic dogs are largely consistent with what would be expected for a canid of their given brain mass, although more variable than that observed in wild canids. We also found that GI in canids is positively correlated with cortical surface area, cortical thickness and total cortical gray matter volumes. While we found no evidence of global differences in GI between domestic and wild canids, certain regional differences in gyrification were observed., (© 2020 Wiley Periodicals LLC.)

The African wild dog is endemic to sub-Saharan Africa and belongs to the family Canidae which includes domestic dogs and their closest relatives (i.e., wolves, coyotes, jackals, dingoes, and foxes). The African wild dog is known for its highly social behavior, co-ordinated pack predation, and striking vocal repertoire, but little is known about its brain and whether it differs in any significant way from that of other canids. We employed gross anatomical observation, magnetic resonance imaging, and classical neuroanatomical staining to provide a broad overview of the structure of the African wild dog brain. Our results reveal a mean brain mass of 154.08 g, with an encephalization quotient of 1.73, indicating that the African wild dog has a relatively large brain size. Analysis of the various structures that comprise their brains and their topological inter-relationships, as well as the areas and volumes of the corpus callosum, ventricular system, hippocampus, amygdala, cerebellum and the gyrification index, all reveal that the African wild dog brain is, in general, similar to that of other mammals, and very similar to that of other carnivorans. While at this level of analysis we do not find any striking specializations within the brain of the African wild dog, apart from a relatively large brain size, the observations made indicate that more detailed analyses of specific neural systems, particularly those involved in sensorimotor processing, sociality or cognition, may reveal features that are either unique to this species or shared among the Canidae to the exclusion of other Carnivora., (© 2020 Wiley Periodicals LLC.)

Background: Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC)., Methods: We assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses., Results: Basal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan-McDermid syndrome., Limitations: The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats., Conclusions: We observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan-McDermid syndrome.

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

The present study examines cortical neuronal morphology in the African lion (Panthera leo leo), African leopard (Panthera pardus pardus), and cheetah (Acinonyx jubatus jubatus). Tissue samples were removed from prefrontal, primary motor, and primary visual cortices and investigated with a Golgi stain and computer-assisted morphometry to provide somatodendritic measures of 652 neurons. Although neurons in the African lion were insufficiently impregnated for accurate quantitative dendritic measurements, descriptions of neuronal morphologies were still possible. Qualitatively, the range of spiny and aspiny neurons across the three species was similar to those observed in other felids, with typical pyramidal neurons being the most prominent neuronal type. Quantitatively, somatodendritic measures of typical pyramidal neurons in the cheetah were generally larger than in the African leopard, despite similar brain sizes. A MARsplines analysis of dendritic measures correctly differentiated 87.4% of complete typical pyramidal neurons between the African leopard and cheetah. In addition, unbiased stereology was used to compare the soma size of typical pyramidal neurons (n = 2,238) across all three cortical regions and gigantopyramidal neurons (n = 1,189) in primary motor and primary visual cortices. Both morphological and stereological analyses indicated that primary motor gigantopyramidal neurons were exceptionally large across all three felids compared to other carnivores, possibly due to specializations related to the felid musculoskeletal systems. The large size of these neurons in the cheetah which, unlike lions and leopards, does not belong to the Panthera genus, suggests that exceptionally enlarged primary motor gigantopyramidal neurons evolved independently in these felid species., (© 2019 Wiley Periodicals, Inc.)

Few studies exist of the bowhead whale brain and virtually nothing is known about its cortical cytoarchitecture or how it compares to other cetaceans. Bowhead whales are one of the least encephalized cetaceans and occupy a basal phylogenetic position among mysticetes. Therefore, the bowhead whale is an important specimen for understanding the evolutionary specializations of cetacean brains. Here, we present an overview of the structure and cytoarchitecture of the bowhead whale cerebral cortex gleaned from Nissl-stained sections and magnetic resonance imaging (MRI) in comparison with other mysticetes and odontocetes. In general, the cytoarchitecture of cetacean cortex is consistent in displaying a thin cortex, a thick, prominent layer I, and absence of a granular layer IV. Cell density, composition, and width of layers III, V, and VI vary among cortical regions, and cetacean cortex is cell-sparse relative to that of terrestrial mammals. Notably, all regions of the bowhead cortex possess high numbers of von Economo neurons and fork neurons, with the highest numbers observed at the apex of gyri. The bowhead whale is also distinctive in having a significantly reduced hippocampus that occupies a space below the corpus callosum within the lateral ventricle. Consistent with other balaenids, bowhead whales possess what appears to be a blunted temporal lobe, which is in contrast to the expansive temporal lobes that characterize most odontocetes. The present report demonstrates that many morphological and cytoarchitectural characteristics are conserved among cetaceans, while other features, such as a reduced temporal lobe, may characterize balaenids among mysticetes. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 302:745-760, 2019. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

All domesticated mammals exhibit marked reductions in overall brain size, however, it is unknown whether the corpus callosum (CC), an integral white matter fiber pathway for interhemispheric cortical communication, is affected by domestication differentially or strictly in coordination with changes in brain size. To answer this question, we used quantitative magnetic resonance imaging to compare the midsagittal cross-sectional areas of the CC in 35 carnivore species, including eight wild canids and 13 domestic dogs. We segmented rostro-caudal regions of interest for the CC and evaluated correlations with brain mass. The results of this study indicate that under the influence of domestication in canids, the CC scales to brain size in an allometric relationship that is similar to that of wild canids and other carnivores, with relatively high correlation coefficients observed for all regions, except the rostrum. These results indicate that architectural and energetic considerations are likely to tightly constrain variation in caudal components of the CC relative to overall brain size, however fibers passing through the rostrum, putatively connecting prefrontal cortex, are less constrained and therefore may contribute more toward species-specific differences in connectivity. Given the species diversity of the Canidae and the resurgence of interest in the brain of the domestic dog, further studies aimed at characterizing the neural architecture in domesticated species is likely to provide new insights into the effects of domestication, or artificial selection, on the brain., (© 2018 Wiley Periodicals, Inc.)

Gigantopyramidal neurons, referred to as Betz cells in primates, are characterized by large somata and extensive basilar dendrites. Although there have been morphological descriptions and drawings of gigantopyramidal neurons in a limited number of species, quantitative investigations have typically been limited to measures of soma size. The current study thus employed two separate analytical approaches: a morphological investigation using the Golgi technique to provide qualitative and quantitative somatodendritic measures of gigantopyramidal neurons across 19 mammalian species from 7 orders; and unbiased stereology to compare the soma volume of layer V pyramidal and gigantopyramidal neurons in primary motor cortex between 11 carnivore and 9 primate species. Of the 617 neurons traced in the morphological analysis, 181 were gigantopyramidal neurons, with deep (primarily layer V) pyramidal (n = 203) and superficial (primarily layer III) pyramidal (n = 233) neurons quantified for comparative purposes. Qualitatively, dendritic morphology varied considerably across species, with some (sub)orders (e.g., artiodactyls, perissodactyls, feliforms) exhibiting bifurcating, V-shaped apical dendrites. Basilar dendrites exhibited idiosyncratic geometry across and within taxonomic groups. Quantitatively, most dendritic measures were significantly greater in gigantopyramidal neurons than in superficial and deep pyramidal neurons. Cluster analyses revealed that most taxonomic groups could be discriminated based on somatodendritic morphology for both superficial and gigantopyramidal neurons. Finally, in agreement with Brodmann, gigantopyramidal neurons in both the morphological and stereological analyses were larger in feliforms (especially in the Panthera species) than in other (sub)orders, possibly due to specializations in muscle fiber composition and musculoskeletal systems., (© 2017 Wiley Periodicals, Inc.)

Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of SYNJ1 ( PARK20 ), a gene that is associated with recessive Parkinsonism. Combining SYNJ1 +/- and LRRK2 G2019S does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1 in vitro , resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of LRRK2 and SYNJ1 pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis. SIGNIFICANCE STATEMENT Understanding midbrain dopaminergic (DAergic) neuron-selective vulnerability in PD is essential for the development of targeted therapeutics. We report, for the first time, a nerve terminal impairment in SV trafficking selectively in MB neurons but not cortical neurons caused by two PARK genes: LRRK2 (PARK8) and SYNJ1 (PARK20). We demonstrate that the enhanced kinase activity resulting from the most frequent G2019S mutation in LRRK2 is the key to this impairment. We provide evidence suggesting that LRRK2 G2019S and SYNJ1 loss of function share a similar pathogenic pathway in deregulating DAergic neuron SV endocytosis and that they play additive roles in facilitating each other's pathogenic functions in PD., (Copyright © 2017 the authors 0270-6474/17/3711366-11$15.00/0.)

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls.

The anterior cingulate cortex, which is involved in cognitive and affective functioning, is important in investigating disorders in which individuals exhibit impairments in higher-order functions. In this study, we examined the anterior midcingulate cortex (aMCC) at the cellular level in patients with autism and in controls. We focused our analysis on layer V of the aMCC because it contains von Economo neurons, specialized cells thought to be involved in emotional expression and focused attention. Using a stereologic approach, we determined whether there were neuropathologic changes in von Economo neuron number, pyramidal neuron number, or pyramidal neuron size between diagnostic groups. When the groups were subdivided into young children and adolescents, pyramidal neuron and von Economo neuron numbers positively correlated with autism severity in young children, as measured by the Autism Diagnostic Interview-Revised. Young children with autism also had significantly smaller pyramidal neurons than their matched controls. Because the aMCC is involved in decision-making during uncertain situations, decreased pyramidal neuron size may reflect a potential reduction in the functional connectivity of the aMCC.

Background: Blast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy., Results: We describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure., Conclusions: These studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.

Although the basic morphological characteristics of neurons in the cerebellar cortex have been documented in several species, virtually nothing is known about the quantitative morphological characteristics of these neurons across different taxa. To that end, the present study investigated cerebellar neuronal morphology among eight different, large-brained mammalian species comprising a broad phylogenetic range: afrotherians (African elephant, Florida manatee), carnivores (Siberian tiger, clouded leopard), cetartiodactyls (humpback whale, giraffe) and primates (human, common chimpanzee). Specifically, several neuron types (e.g., stellate, basket, Lugaro, Golgi, and granule neurons; N = 317) of the cerebellar cortex were stained with a modified rapid Golgi technique and quantified on a computer-assisted microscopy system. There was a 64-fold variation in brain mass across species in our sample (from clouded leopard to the elephant) and a 103-fold variation in cerebellar volume. Most dendritic measures tended to increase with cerebellar volume. The cerebellar cortex in these species exhibited the trilaminate pattern common to all mammals. Morphologically, neuron types in the cerebellar cortex were generally consistent with those described in primates (Fox et al., 1967) and rodents (Palay and Chan-Palay, 1974), although there was substantial quantitative variation across species. In particular, Lugaro neurons in the elephant appeared to be disproportionately larger than those in other species. To explore potential quantitative differences in dendritic measures across species, MARSplines analyses were used to evaluate whether species could be differentiated from each other based on dendritic characteristics alone. Results of these analyses indicated that there were significant differences among all species in dendritic measures.

Background: While most neuropathologic studies focus on regions involved in behavioral abnormalities in autism, it is also important to identify whether areas that appear functionally normal are devoid of pathologic alterations. In this study we analyzed the posteroinferior occipitotemporal gyrus, an extrastriate area not considered to be affected in autism. This area borders the fusiform gyrus, which is known to exhibit functional and cellular abnormalities in autism., Findings: No studies have implicated posteroinferior occipitotemporal gyrus dysfunction in autism, leading us to hypothesize that neuropathology would not occur in this area. We indeed observed no significant differences in pyramidal neuron number or size in layers III, V, and VI in seven pairs of autism and controls., Conclusions: These findings are consistent with the hypothesis that neuropathology is unique to areas involved in stereotypies and social and emotional behaviors, and support the specificity of the localization of pathology in the fusiform gyrus.

While the neural basis for linguistic communication has been linked to brain structural asymmetries found only in humans (wider connective spacing is found between the minicolumns of neurons in the left hemisphere language areas), it is unknown if the opposite microanatomical asymmetry exists in the fusiform gyrus which typically supports a right hemisphere bias for face processing. Unlike language, face processing is an ability shared with chimpanzees and, as Darwin observed, the widespread use of facial expressions in animal communication suggests a biological basis. We tested the principle that minicolumn asymmetry follows typical functional dominance in humans, and tested its evolutionary continuity, by measuring minicolumn width, neuronal size and density in the mid-fusiform cortex in 14 humans and 14 chimpanzees. We found that microanatomical asymmetry distinguishes humans from chimpanzees although the direction of asymmetry is the same as in language areas-the right hemisphere contained narrower minicolumns and smaller pyramidal neurons, as in auditory language areas. Uniformly narrow minicolumns in chimpanzees and in the human right hemisphere are consistent with mechanistic predictions supporting the apparent bias towards holistic face processing. Wider minicolumns and larger neurons in the human left hemisphere may be consistent with a language function such as word-form processing. Microanatomical asymmetry in the neocortex therefore provides a correlate of hemispheric specialisation.

Autism is a neurodevelopmental disorder characterized by deficits in social interaction and social communication, as well as by the presence of repetitive and stereotyped behaviors and interests. Brodmann areas 44 and 45 in the inferior frontal cortex, which are involved in language processing, imitation function, and sociality processing networks, have been implicated in this complex disorder. Using a stereologic approach, this study aims to explore the presence of neuropathological differences in areas 44 and 45 in patients with autism compared to age- and hemisphere-matched controls. Based on previous evidence in the fusiform gyrus, we expected to find a decrease in the number and size of pyramidal neurons as well as an increase in volume of layers III, V, and VI in patients with autism. We observed significantly smaller pyramidal neurons in patients with autism compared to controls, although there was no difference in pyramidal neuron numbers or layer volumes. The reduced pyramidal neuron size suggests that a certain degree of dysfunction of areas 44 and 45 plays a role in the pathology of autism. Our results also support previous studies that have shown specific cellular neuropathology in autism with regionally specific reduction in neuron size, and provide further evidence for the possible involvement of the mirror neuron system, as well as impairment of neuronal networks relevant to communication and social behaviors, in this disorder.

The presence of von Economo neurons (VENs) in the frontoinsular cortex (FI) has been linked to a possible role in the integration of bodily feelings, emotional regulation, and goal-directed behaviors. They have also been implicated in fast intuitive evaluation of complex social situations. Several studies reported a decreased number of VENs in neuropsychiatric diseases in which the "embodied" dimension of social cognition is markedly affected. Neuropathological analyses of VENs in patients with autism are few and did not report alterations in VEN numbers. In this study we re-evaluated the possible presence of changes in VEN numbers and their relationship with the diagnosis of autism. Using a stereologic approach we quantified VENs and pyramidal neurons in layer V of FI in postmortem brains of four young patients with autism and three comparably aged controls. We also investigated possible autism-related differences in FI layer V volume. Patients with autism consistently had a significantly higher ratio of VENs to pyramidal neurons (p=0.020) than control subjects. This result may reflect the presence of neuronal overgrowth in young patients with autism and may also be related to alterations in migration, cortical lamination, and apoptosis. Higher numbers of VENs in the FI of patients with autism may also underlie a heightened interoception, described in some clinical observations., (Copyright © 2010 Elsevier B.V. All rights reserved.)

There is growing clinical and neuropathologic evidence suggesting that cognitive decline in early Alzheimer's disease (AD) is aggravated by a synergistic relationship between AD and cerebrovascular disease associated with cardiovascular risk factors such as diabetes and hypertension. Here we used the stereologic "Space Balls" method to investigate the relationships between AD pathology and cardiovascular risk factors in postmortem human brains of patients with hypertension and diabetes in two groups - one consisting of cases with AD diagnosis and one of cases without. Hippocampal CA1 and CA3 microvasculature length density estimates were generated to characterize quantitatively the contribution of cardiovascular risk factors to the severity of neuropathologic changes. Our main finding is that the mean and variance of length density values in the AD group were significantly increased from the non-AD group, regardless of the absence or presence of a cardiovascular risk factor. An additional finding is that in the AD group without a risk factor, dementia severity correlated with amount of length density change in the CA1 field-this correlation did not exist in the AD groups with risk factors. Our findings suggest a role for cardiovascular risk factors in quantifiable change of hippocampal CA1 field microvasculature, as well as suggest a possible role of cardiovascular risk factors in altering microvasculature pathology in the presence of AD.