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Interlaminar astrocytes (ILA) in the cerebral cortex possess a soma in layer I and extend an interlaminar process that runs perpendicular to the pia into deeper cortical layers. We examined cerebral cortex from 46 species that encompassed most orders of therian mammalians, including 22 primate species. We described two distinct cell types with interlaminar processes that have been referred to as ILA, that we termed pial ILA and supial ILA. ILA subtypes differ in somatic morphology, position in layer I, and presence across species. We further described rudimentary ILA that have short GFAP(+) processes that do not exit layer I, and “typical” ILA with longer GFAP(+) processes that exit layer I. Pial ILA were present in all mammalian species analyzed, with typical ILA observed in Primates, Scandentia, Chiroptera, Carnivora, Artiodactyla, Hyracoidea, and Proboscidea. Subpial ILA were absent in Marsupialia, and typical subpial ILA were only found in Primate. We focused on the properties of pial ILA by investigating the molecular properties of pial ILA and confirming their astrocytic nature. We found that while the density of pial ILA somata only varied slightly, the complexity of ILA processes varied greatly across species. Primates, specifically bonobo, chimpanzee, orangutan, and human, exhibited pial ILA with the highest complexity. We showed that interlaminar processes contact neurons, pia, and capillaries, suggesting a potential role for ILA in the blood-brain barrier and facilitating communication among cortical neurons, astrocytes, capillaries, meninges, and cerebrospinal fluid.

Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.

We used inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male macaque monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hsyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD- transduced cells using stereological analysis of mCherry-immunolabeled cells. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared to monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.Significance StatementCognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N- oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.

Alzheimer’s disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate Aβ and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predomimantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular Aβ directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and Aβ in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/Aβ interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD. Keywords: p53, Aβ, tau, oxidative stress, neuronal apoptosis, Alzheimer's disease

All domesticated mammals exhibit marked reductions in overall brain size, however, it is unknown whether the corpus callosum, 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 mid‐sagittal cross‐sectional areas of the corpus callosum in 35 carnivore species, including eight wild canids and 13 domestic dogs. We segmented rostro‐caudal regions of interest for the corpus callosum and evaluated correlations with brain mass. The results of this study indicate that under the influence of domestication in canids, the corpus callosum 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 corpus callosum relative to overall brain size, however fibers passing through the rostrum, putatively connecting prefrontal cortex, are less constrained and therefore may contribute more towards 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.

A striking observation among veterans returning from the recent conflicts in Iraq and Afghanistan has been the co-occurrence of blast-related mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI might coexist due to additive effects of independent psychological and physical traumas experienced in a war zone. Alternatively blast injury might induce PTSD-related traits or damage brain structures that mediate responses to psychological stressors, increasing the likelihood that PTSD will develop following a subsequent psychological stressor. Rats exposed to repetitive low-level blasts consisting of three 74.5 kPa exposures delivered once daily for three consecutive days develop a variety of anxiety and PTSD-related behavioral traits that are present for at least 9 months after blast exposure. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxiety-related changes that are still present 45 days later. Because the blast injuries occur under general anesthesia, it appears that blast exposure in the absence of a psychological stressor can induce chronic PTSD-related traits. The reaction to a predator scent challenge delivered many months after blast exposure suggests that blast exposure in addition sensitizes the brain to react abnormally to subsequent psychological stressors. The development of PTSD-related behavioral traits in the absence of a psychological stressor suggests the existence of blast-induced “PTSD”. Findings that PTSD-related behavioral traits can be reversed by BCI-838, a group II metabotropic glutamate receptor antagonist offers insight into pathogenesis and possible treatment options for blast-related brain injury. This article is part of the Special Issue entitled “Novel Treatments for Traumatic Brain Injury”.

Autism spectrum disorder (ASD or autism) is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the genetic perturbations and underlying neuropathology of the disorder. While evidence from magnetic resonance imaging and other noninvasive techniques points to altered development and organization of the autistic brain, these tools lack the resolution for identifying the cellular and molecular underpinnings of the disorder. Postmortem studies of high-quality human brain tissue currently represent the only viable option to pursuing these types of studies. However, the availability of high-quality ASD brain tissue has been extremely limited. Here we describe the establishment of a privately funded tissue bank, Autism BrainNet, a network of brain collection sites that work in a coordinated fashion to develop an adequate library of human postmortem brain tissues. Autism BrainNet was initiated as a collaboration between the Simons Foundation and Autism Speaks, and is currently funded by the Simons Foundation Autism Research Initiative. Autism BrainNet has collection sites (nodes) in California, Texas, New York, and Massachusetts; an affiliated, international node is located in Oxford, England. All donations to this network become part of a consolidated pool of tissue that is distributed to qualified investigators worldwide to carry out autism research. An essential component of this program is a widespread outreach program that highlights the need for postmortem brain donations to families affected by autism, led by the Autism Science Foundation. Challenges include an outreach campaign that deals with a disorder beginning in early childhood, collecting an adequate number of donations to deal with the high level of biologic heterogeneity of autism, and preparing this limited resource for optimal distribution to the greatest number of investigators.

Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.

Background The rostral prefrontal cortex (RPFC) is involved in reflective thought processes such as self-knowledge and person perception. We hypothesized that childhood emotional abuse, which is disruptive of emotional regulation, would differentially impact neurometabolite concentrations of the RPFC, and related neocortical areas, in adults with generalized anxiety disorder (GAD) versus healthy controls. Methods GAD patients ( n =16; females=11) and medically healthy volunteers ( n =16; F =10) were assessed using the Childhood Trauma Questionnaire (CTQ), specifically the emotional abuse category. Proton magnetic resonance spectroscopy imaging examined 3 regions of interest (ROI) from the most rostral slice from the Duyn et al. (1993) multivoxel imaging modality: rostral prefrontal cortex (BA 10,9), premotor cortex (BA 6,8) and secondary somatosensory and associated parietal cortex (BA 5,7). Metabolites included N -acetyl-aspartate, creatine, and choline. Results GAD patients reported higher emotional abuse scores versus controls. An omnibus general linear model including 3 ROI, 3 metabolites, and laterality as dependent variables revealed a significant diagnosis by CTQ emotional abuse score interactive effect. In controls, all 3 ROI for all 3 metabolites on both sides demonstrated a significant inverse relationship with emotional abuse scores; none were significant in GAD patients. Limitations A major limitation is the uneven distribution of emotional abuse scores between the controls and GAD patients, with GAD patients reporting higher scores. Conclusion Unlike controls, GAD patients appear compromised in forming a molecular representation reflective of magnitude of childhood emotional abuse. The neurometabolites in GAD patients appear non-aligned to childhood emotional abuse, suggesting potential consequences for normative “theory of mind” processes and emotional function in certain anxiety disorders.

Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000 candidate genes associated with schizophrenia have been reported, most of which being mentioned only once. Alterations in cognitive processing - working memory, metacognition and mentalization - represent a core feature of schizophrenia, which indicates the involvement of the prefrontal cortex in the pathophysiology of this disorder. Hence we compared the gene expression in postmortem tissue from the left and right dorsolateral prefrontal cortex (DLPFC, Brodmann's area 46), and the medial part of the orbitofrontal cortex (MOFC, Brodmann's area 11/12), in six patients with schizophrenia and six control brains. Although in the past decade several studies performed transcriptome profiling in schizophrenia, this is the first study to investigate both hemispheres, providing new knowledge about possible brain asymmetry at the level of gene expression and its relation to schizophrenia. We found that in the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were differentially expressed in patients with schizophrenia compared to controls. In the right hemisphere there was only one gene differentially expressed in the MOFC. We reproduce the involvement of previously reported genes TARDBP and HNRNPC in the pathogenesis of schizophrenia, and report seven novel genes:SART1, KAT7, C1D, NPM1, EVI2A, XGY2, andTTTY15. As the differentially expressed genes only partially overlap with previous studies that analyzed other brain regions, our findings indicate the importance of considering prefrontal cortical regions, especially those in the left hemisphere, for obtaining disease-relevant insights.

We investigated the morphology of four primary neocortical projection areas (somatomotor, somatosensory, auditory, visual) qualitatively and quantitatively in the Indian river dolphins (Platanista gangetica gangetica, P. gangetica minor) with histological and stereological methods. For comparison, we included brains of other toothed whale species. Design-based stereology was applied to the primary neocortical areas (M1, S1, A1, V1) of the Indian river dolphins and compared to those of the bottlenose dolphin with respect to layers III and V. These neocortical fields were identified using existing electrophysiological and morphological data from marine dolphins as to their topography and histological structure, including the characteristics of the neuron populations concerned. In contrast to other toothed whales, the visual area (V1) of the ‘blind' river dolphins seems to be rather small. M1 is displaced laterally and the auditory area (A1) is larger than in marine species with respect to total brain size. The layering is similar in the cortices of all the toothed whale brains investigated; a layer IV could not be identified. Cell density in layer III is always higher than in layer V. The maximal neuron density in P. gangetica gangetica is found in layer III of A1, followed by layers III in V1, S1, and M1. The cell density in layer V is at a similar level in all primary areas. There are, however, some differences in neuron density between the two subspecies of Indian river dolphins. Taken as a whole, it appears that the neocortex of platanistids exhibits a considerable expansion of the auditory field. Even more than other toothed whales, they seem to depend on their biosonar abilities for navigation, hunting, and communication in their riverine habitat.

The dopaminergic innervation of the striatum has been implicated in learning processes and in the development of human speech and language. Several lines of evidence suggest that evolutionary changes in dopaminergic afferents of the striatum may be associated with uniquely human cognitive and behavioral abilities, including the association of the human-specific sequence of the FOXP2 gene with decreased dopamine in the dorsomedial striatum of mice. To examine this possibility, we quantified the density of tyrosine hydroxylase-immunoreactive axons as a measure of dopaminergic innervation within five basal ganglia regions in humans, great apes, and New and Old World monkeys. Our results indicate that humans differ from nonhuman primate species in having a significant increase in dopaminergic innervation selectively localized to the medial caudate nucleus. This region of the striatum is highly interconnected, receiving afferents from multiple neocortical regions, and supports behavioral and cognitive flexibility. The medial caudate nucleus also shows hyperactivity in humans lacking a functional FOXP2 allele and exhibits altered dopamine concentrations in humanized Foxp2 mice. Additionally, striatal dopaminergic input was not altered in chimpanzees that used socially learned attention-getting sounds versus those that did not. This evidence indicates that the increase in dopamine innervation of the medial caudate nucleus in humans is a species-typical characteristic not associated with experience-dependent plasticity. The specificity of this increase may be related to the degree of convergence from cortical areas within this region of the striatum and may also be involved in human speech and language. J. Comp. Neurol. 524:2117-2129, 2016. © 2015 Wiley Periodicals, Inc.

A central tenet in support of research reproducibility is the ability to uniquely identify research resources, i.e., reagents, tools, and materials that are used to perform experiments. However, current reporting practices for research resources are insufficient to identify the exact resources that are reported or to answer basic questions such as "How did other studies use resource X?" To address this issue, the Resource Identification Initiative was launched as a pilot project to improve the reporting standards for research resources in the Methods sections of articles and thereby improve identifiability and scientific reproducibility. The pilot engaged over 25 biomedical journal editors from most major publishers, as well as scientists and funding officials. Authors were asked to include Research Resource Identifiers (RRIDs) in their articles prior to publication for three resource types: antibodies, model organisms, and tools (i.e., software and databases). RRIDs are assigned by an authoritative database, for example, a model organism database for each type of resource. To make it easier for authors to obtain RRIDs, resources were aggregated from the appropriate databases and their RRIDs made available in a central Web portal (http://scicrunch.org/resources). RRIDs meet three key criteria: they are machine-readable, free to generate and access, and are consistent across publishers and journals. The pilot was launched in February of 2014 and over 300 articles have appeared that report RRIDs. The number of journals participating has expanded from the original 25 to more than 40, with RRIDs appearing in 62 different journals to date. Here we present an overview of the pilot project and its outcomes to date. We show that authors are able to identify resources and are supportive of the goals of the project. Identifiability of the resources post-pilot showed a dramatic improvement for all three resource types, suggesting that the project has had a significant impact on identifiability of research resources.

The human brain and human cognitive abilities are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure differences accounted for a total of 134 amino acids in proteins found in the gorilla that were absent from protein products of the orthologous human genes. Proteins varying in structure between human and gorilla were involved in immunity and energy metabolism, suggesting their relevance to phenotypic differences. This gorilla neocortical transcriptome comprises an empirical, not homology- or prediction-driven, resource for orthologous gene comparisons between human and gorilla. These findings provide a unique repository of the sequences and structures of thousands of genes transcribed in the gorilla brain, pointing to candidate genes that may contribute to the traits distinguishing humans from other closely related great apes.

Paul Broca's concept of the "great limbic lobe" has had a huge impact on neuroscience. In this commentary, which accompanies the first English translation of the original paper, we comment on Broca's contribution and its influence on the understanding of the brain bases of emotion.

Epigenetics is a quickly growing field encompassing mechanisms regulating gene expression that do not involve changes in the genotype. Epigenetics is of increasing relevance to neuroscience, with epigenetic mechanisms being implicated in brain development and neuronal differentiation, as well as in more dynamic processes related to cognition. Epigenetic regulation covers multiple levels of gene expression; from direct modifications of the DNA and histone tails, regulating the level of transcription, to interactions with messenger RNAs, regulating the level of translation. Importantly, epigenetic dysregulation currently garners much attention as a pivotal player in aging and age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, where it may mediate interactions between genetic and environmental risk factors, or directly interact with disease-specific pathological factors. We review current knowledge about the major epigenetic mechanisms, including DNA methylation and DNA demethylation, chromatin remodeling and non-coding RNAs, as well as the involvement of these mechanisms in normal aging and in the pathophysiology of the most common neurodegenerative diseases. Additionally, we examine the current state of epigenetics-based therapeutic strategies for these diseases, which either aim to restore the epigenetic homeostasis or skew it to a favorable direction to counter disease pathology. Finally, methodological challenges of epigenetic investigations and future perspectives are discussed.

Although neocortical neuronal morphology has been documented in the adult giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana), no research has explored the cortical architecture in newborns of these species. To this end, the current study examined the morphology of neurons from several cortical areas in the newborn giraffe and elephant. After cortical neurons were stained with a modified Golgi technique (N = 153), dendritic branching and spine distributions were analyzed by using computer-assisted morphometry. The results showed that newborn elephant neurons were considerably larger in terms of all dendritic and spine measures than newborn giraffe neurons. Qualitatively, neurons in the newborns appeared morphologically comparable to those in their adult counterparts. Neurons in the newborn elephant differed considerably from those observed in other placental mammals, including the giraffe, particularly with regard to the morphology of spiny projection neurons. Projection neurons were observed in both species, with a much larger variety in the elephant (e.g., flattened pyramidal, nonpyramidal multipolar, and inverted pyramidal neurons). Although local circuit neurons (i.e., interneurons, neurogliaform, Cajal–Retzius neurons) resembled those observed in other eutherian mammals, these were usually spiny, which contrasts with their adult, aspiny equivalents. Newborn projection neurons were smaller than the adult equivalents in both species, but newborn interneurons were approximately the same size as their adult counterparts. Cortical neuromorphology in the newborn giraffe is thus generally consistent with what has been observed in other cetartiodactyls, whereas newborn and adult elephant morphology appears to deviate substantially from what is commonly observed in other placental mammals. J. Comp. Neurol. 524:257–287, 2016. © 2015 Wiley Periodicals, Inc.

The field of paleoneurology emerged as an independ-ent discipline in the early years of the twentieth centuryand was directed at systematically analyzing the brainsof fossil species within an evolutionary framework. Thepioneer of this effort was Tilly (Johanna Gabrielle Ottilie)Edinger (1897–1967), a German-born vertebrate paleon-tologist, who combined her interests in both paleontol-ogy and comparative neuroanatomy to add a newdimension to evolutionary studies of the brain (Buch-holtz and Seyfarth, 1999, 2001). Her father, LudwigEdinger (1855–1917), was a prominent and pioneeringcomparative neuroanatomist and served as an editorialboard member of the Journal of Comparative Neurology(JCN) beginning with its eighth volume (Herrick, 1954).The 25th volume of JCN was dedicated to LudwigEdinger in honor of his 60th birthday (April 13, 1915),and his brain was the object of study for a 1950 JCNreport (Riese and Goldstein, 1950).Paleoneurologists generally depend on endocasts tostudy the external features of brains because brains them-selves do not fossilize (Edinger, 1927). Endocasts aremade by creating a cast of the interior surface of the skullto reveal external features that left impressions on thebones. Natural endocasts occur when the cranial cavity ofa deceased animal is filled with sediment that is solidifiedby calciferous solutions (Kochetkova, 1978). Prior to the1920s, endocasts had been documented for a variety ofspecies, but these existed as independent observationsthat were purely descriptive. Tilly Edinger compiled allaccounts of natural brain casts that were distributedthroughout the paleontology literature and compiled theminto one volume (Edinger, 1929). Edinger’s unique contri-bution to the study of brain evolution was to add a“longitudinal” view wherein changes in patterns and struc-ture could be reconstructed through evolutionary time(Edinger, 1949). This is in contrast to the necessarily“horizontal”’ comparisons that are made when studyingneuroanatomical features of extant species. She appliedher methods to well-represented fossil sequences, includ-ing those of reptiles (Edinger, 1955b), amphibians (Romerand Edinger, 1942), bats (Edinger, 1926), cetaceans(Edinger, 1955a), and sirenians (Edinger, 1933, 1948),among others. Through her work, Edinger discountedsome prevalent ideas of her time, including the notion thatan increase in brain size was necessary for a species toavoid extinction (Edinger, 1962), and she also developed aconcept of mosaic evolution, that changes in one func-tional system, in this case the central nervous system,were independent of changes in other systems, includingthe postcranial skeleton (Edinger, 1958). Edinger changedour approaches and understanding of comparative neurol-ogy by providing the important additional element of evolu-tionary time with recognition of the sequence of changesthat led to modern species.JCN has had a tradition of presenting the findingsfrom paleoneurological research, including one articlefrom Tilly Edinger (Romer and Edinger, 1942). Theearliest endocast articles in JCN were reporting featuresof the brains of early cetaceans, the archeocetes (Fig.1; Elliot Smith, 1903), and fossil fish, amphibian, andreptile species (Case, 1921, 1928; Moodie, 1915a,b,1920). In the same years, many studies on the endo-cranial and brain anatomy of fossil mammals, includinga hominin, in comparison with their extant relatives(Black, 1915, 1920; Dempster, 1935; Moodie, 1922)were published in JCN, as well as, in more recent years,some of the earliest evolutionary interpretations ofstructure in the context of systems neuroscience in thepioneering work of Leonard Radinsky (Radinsky, 1968),which recently culminated in a review of olfaction inthe evolution of the mammalian cerebral cortex (Roweand Shepherd, 2015).Although natural endocasts are rare, it is almostunheard of to have a naturally preserved brain (i.e., mum-mified) with external and internal structures maintained(but see Papageorgopoulou et al., 2010, for an accountof a remarkably preserved human brain). Our Journal is

We performed high-throughput mass spectrometry at high spatial resolution from individual regions (anterior cingulate and primary motor, somatosensory, and visual cortices) and layers of the neocortex (layers III, IV, and V) and cerebellum (granule cell layer), as well as the caudate nucleus in humans and chimpanzees. A total of 39 mass spectrometry peaks were matched with probable protein identifications in both species, allowing for comparison in expression. We explored how the pattern of protein expression varies across regions and cortical layers to provide insights into the differences in molecular phenotype of these neural structures between species. The expression of proteins differed principally in a region- and layer-specific pattern, with more subtle differences between species. Specifically, human and chimpanzee brains were similar in their distribution of proteins related to the regulation of transcription and enzyme activity but differed in their expression of proteins supporting aerobic metabolism. Whereas most work assessing molecular expression differences in the brains of primates has been performed on gene transcripts, this dataset extends current understanding of the differential molecular expression that may underlie human cognitive specializations.

Although transcriptomic profiling has become the standard approach for exploring molecular differences in the primate brain, very little is known about how the expression levels of gene transcripts relate to downstream protein abundance. Moreover, it is unknown whether the relationship changes depending on the brain region or species under investigation. We performed high-throughput transcriptomic (RNA-Seq) and proteomic (liquid chromatography coupled with tandem mass spectrometry) analyses on two regions of the human and chimpanzee brain: The anterior cingulate cortex and caudate nucleus. In both brain regions, we found a lower correlation between mRNA and protein expression levels in humans and chimpanzees than has been reported for other tissues and cell types, suggesting that the brain may engage extensive tissue-specific regulation affecting protein abundance. In both species, only a few categories of biological function exhibited strong correlations between mRNA and protein expression levels. These categories included oxidative metabolism and protein synthesis and modification, indicating that the expression levels of mRNA transcripts supporting these biological functions are more predictive of protein expression compared with other functional categories. More generally, however, the two measures of molecular expression provided strikingly divergent perspectives into differential expression between human and chimpanzee brains: mRNA comparisons revealed significant differences in neuronal communication, ion transport, and regulatory processes, whereas protein comparisons indicated differences in perception and cognition, metabolic processes, and organization of the cytoskeleton. Our results highlight the importance of examining protein expression in evolutionary analyses and call for a more thorough understanding of tissue-specific protein expression levels.

Despite a not insignificant number of anatomical and experimental studies describing the distribution and movement of the cerebrospinal fluid several questions were answered controversially, leaving room for objections and doubts. Some of these controversies I have tried to address by new experiments. Before going on to describe these studies, some short anatomical notes on the membranes that cover the central nervous system may be appropriate. Bichat described the anatomical membranes as follows: in between the fibrous lining of the brain-vertebral cavity, the dura mater and the vascularized coat of the spinal cord (the pia mater) a space covered by a serous skin is interposed, the parietal part of which is integrated with the inner side of the dura mater; and the visceral part in contrast is detachable from the underlying pia mater. The watery fluid of the brain-spinal-cord cavity discovered by Cotugno received more attention by Magendie, who initially placed it [ the fluid ] within the serous space described by Bichat, convincing himself [Magendie] however later, that it [ the fluid ] is present in between the visceral sheet of the arachnoid and the pia mater.

The discovery of the ‘glymphatic’ pathway has shed new light on the cerebrospinal (CSF)–brain interstitial fluid (ISF) exchange process (Iliff et al., 2012). In new anatomically defined terms, the glymphatic pathway now represents a brain-wide pathway where CSF flows through the brain and spinal cord parenchyma and exchanges with ISF from periarterial to perivenous spaces in a route interconnected by aquaporin 4 water channels present on glial cells (Iliff et al., 2012). The new concept of the glymphatic pathway has evolved from the older concept of bulk flow of ISF from brain parenchyma to the ventricular CSF referred to as the “ependymal pathway” (Brightman, 1965a,b). The glymphatic pathway is important for detoxification of the brain (and spinal cord), a cleaning process that appears to be driven by adrenergic tone (Xie et al., 2013), arterial pulsatility (Iliff et al., 2013b), level of arousal (Xie et al., 2013), and aging (Kress et al., 2014). For decades, brain pulsations have been observed directly during neurosurgical procedures. Pulsation of the CSF was first qualitatively described in vivo using fluoroscopy (Du Boulay, 1966) and then validated using non-invasively using magnetic resonance imaging (MRI) (Sherman and Citrin, 1986; Sherman et al., 1986). A comprehensive review of this topic by Wagshul and coworkers was recently published (Wagshul et al., 2011). Phase-contrast MRI was later used to quantify CSF pulsation in selected parts of the ventricular CSF spaces, followed by quantitative flow visualization in the entire subarachnoid and ventricular spaces through computational flow reconstruction from phase-contrast MRI data (Gupta et al., 2010; Cheng et al., 2012; Siyahhan et al., 2014). Major aspects of CSF flow dynamics and outflow pathways are now more fully characterized (Wagshul et al., 2006; Oreskovic and Klarica, 2010; Bulat and Klarica, 2011). All of these experimental and mathematical modeling studies have led the conclusion that for example ‘pressure pulsatility’ in the brain functions as an internal biosensor of intracranial compliance (Wagshul et al., 2011) which is heightened in chronic hydrocephalus (Greitz, 2004). CSF reabsorption via the arachnoid villi into the dural sinuses to the blood or through the nasal lymphatics have been previously documented in seminal papers (Boulton et al., 1996; Abbott, 2004; Johnston et al., 2004). Nevertheless, important questions pertaining to CSF drainage remain unanswered. For example, the exact anatomy of the subarachnoid spaces along cranial and spinal nerves, the functional (quantitative and directional) relationship between influx of CSF into the brain and lymphatic drainage of CSF-ISF, and the potentially fluctuating outflow volumes at the various exit points along the complex outflow pathways, which under normal conditions may be dependent on posture, activity and state of consciousness. The influence of body posture and respiration on CSF outflow and transport has been characterized; and continues to be investigated using MRI techniques with improved temporal resolution (Bradbury et al., 1981; Bradbury and Westrop, 1983; Alperin et al., 2005; Yamada et al., 2013). However, another exceedingly important area that is only partially understood is how physiological movement and various motor activities affects CSF movements and outflow patterns. This lack of information is paradoxical because the influence of motor activity is clearly playing a prominent role on CSF-ISF exchange and clearance (Bechter, 2011). For example, local muscle tone change associated with yawning changes CSF dynamics (Walusinski, 2014). To our knowledge, one of the best studies on CSF flow and outflow pathways have been performed by Heinrich Quincke and described in a paper he published in “Archiv fur Anatomie, Physiologie und wissenschaftliche Medicin” in 1872 (Quincke, 1872). In his studies, Quincke experimented with freely moving animals, injecting the particulate dye cinnabar (Mercury(II) sulfide, HgS) into the intrathecal spaces of dogs, cats, and rabbits, all animals with high motor activity, and analyzed the dye’s distribution throughout the body after days, weeks or months postmortem.

Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ- icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ(1- 42)) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ- icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ(1-42) accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ(1-42)-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time- dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.

The relationship between primary age-related tauopathy (PART) and Alzheimer’s disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0–IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0–2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA–AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or “tangle-only dementia” [55].

It has always been difficult to account for the evolution of certain human characters such as language, empathy, and altruism via individual reproductive success. However, the striatum, a subcortical region originally thought to be exclusively motor, is now known to contribute to social behaviors and "personality styles" that may link such complexities with natural selection. We here report that the human striatum exhibits a unique neurochemical profile that differs dramatically from those of other primates. The human signature of elevated striatal dopamine, serotonin, and neuropeptide Y, coupled with lowered acetylcholine, systematically favors externally driven behavior and greatly amplifies sensitivity to social cues that promote social conformity, empathy, and altruism. We propose that selection induced an initial form of this profile in early hominids, which increased their affiliative behavior, and that this shift either preceded or accompanied the adoption of bipedality and elimination of the sectorial canine. We further hypothesize that these changes were critical for increased individual fitness and promoted the adoption of social monogamy, which progressively increased cooperation as well as a dependence on tradition-based cultural transmission. These eventually facilitated the acquisition of language by elevating the reproductive advantage afforded those most sensitive to social cues.

Amyloid deposits and tau-immunoreactive neurofibrillary tangles, together with neuronal and synaptic loss, are the neuropathological hallmarks of Alzheimer's disease (AD). Both proteins are present in the normal brain during aging. However, the temporal sequence of their involvement in the onset of AD pathology remains controversial. To define whether amyloid β protein deposits or tau protein lesions appear first during normal brain aging, we performed an immunohistological study on serial sections from 105 autopsy brains (age range: 40-104 years) from patients free of clinical signs of cognitive decline, using anti-tau (AT8) and anti-amyloid (4G8) antibodies in the hippocampus, entorhinal cortex, inferior temporal cortex (Brodmann area 20), prefrontal cortex (Brodmann area 9), occipital cortex (Brodmann areas 17 and 18), and in the brainstem. All cases older than 48 years displayed at least a few neurofibrillary tangles, which appeared more frequently in the entorhinal than in the transentorhinal cortex. Tau pathology in these areas preceded tau inclusions in the brainstem. Furthermore, the first site of the apparition of tau pathology is inconsistent, being the entorhinal cortex in most cases, and in fewer cases, the transentorhinal region. There was no case presenting with amyloid deposition in the absence of neurofibrillary tangles, lending evidence to the fact that neurofibrillary tangles appear earlier than amyloid plaques during normal brain aging. However, the role of amyloid in promoting tau deposition cannot be excluded in some cases but may not represent the sole mechanism of disease induction and progression.

Introduction: The pathological process of Alzheimer's disease (AD) in the brain likely begins 20-30 years earlier than the emergence of its first clinical symptoms and symptoms of AD often overlap with the symptoms of other primary causes of dementia. Therefore, it is crucially important to improve early and differential diagnosis of the disease. Event-related potentials (ERP) measured non-invasively by electroencephalography have shown diagnostic potential in AD. Aims: The aim of this study was to compare the efficiency of P300 and N200 potentials and reaction time (RT) with commonly used protein biomarkers measured in the cerebrospinal fluid (CSF), including amyloid β peptide (β1-42), total tau (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), tau protein phosphorylated at serine 199 (p-tau199), tau protein phosphorylated at threonine 231 (p-tau231), and visinin-like protein 1 (VILIP-1) in differential diagnosis of AD in mild cognitive impairment (MCI) and AD patients. Subjects: The study involved 49 AD patients, 28 patients with MCI, 4 healthy control subjects and 16 patients with other primary causes of dementia. Results: ERP (P300RT, N200RT, P300 counting and N200 counting) showed a moderate to strong correlation with protein CSF biomarkers. We confirmed previous observations of moderate to strong correlation between ERP and neuropsychological testing and showed that P300 latency and RT are shortened in AD patients on therapy with acetylcholinesterase inhibitors. Using ERP and RT, a predictive model for determination of AD likelihood in MCI patients was developed, detecting 56.3% of MCI patients with high risk for development of AD in our cohort. MCI patients with pathological levels of Aβ1-42 had prolonged P300 latency, indicating that a combination of ERP and CSF protein biomarkers could improve the differential diagnosis of AD in MCI patients. Additionally, the results suggested the potential of P300 latency in differentiating AD and FTD patients. Conclusion: Our data provide possible solutions for improvement of differential diagnosis of AD, and reveal that the diagnostic efficiency of CSF protein biomarkers t-tau, p-tau181, p-tau199, p-tau231 and VILIP-1 could be improved by adding ERP in clinical practice.

Recent design-based stereologic studies have shown that the early postnatal (

Autism spectrum disorder (ASD or autism) is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the genetic perturbations and underlying neuropathology of the disorder. While evidence from magnetic resonance imaging and other noninvasive techniques points to altered development and organization of the autistic brain, these tools lack the resolution for identifying the cellular and molecular underpinnings of the disorder. Postmortem studies of high-quality human brain tissue currently represent the only viable option to pursuing these types of studies. However, the availability of high-quality ASD brain tissue has been extremely limited. Here we describe the establishment of a privately funded tissue bank, Autism BrainNet, a network of brain collection sites that work in a coordinated fashion to develop an adequate library of human postmortem brain tissues. Autism BrainNet was initiated as a collaboration between the Simons Foundation and Autism Speaks, and is currently funded by the Simons Foundation Autism Research Initiative. Autism BrainNet has collection sites (nodes) in California, Texas, New York, and Massachusetts; an affiliated, international node is located in Oxford, England. All donations to this network become part of a consolidated pool of tissue that is distributed to qualified investigators worldwide to carry out autism research. An essential component of this program is a widespread outreach program that highlights the need for postmortem brain donations to families affected by autism, led by the Autism Science Foundation. Challenges include an outreach campaign that deals with a disorder beginning in early childhood, collecting an adequate number of donations to deal with the high level of biologic heterogeneity of autism, and preparing this limited resource for optimal distribution to the greatest number of investigators.

SUMMARY Peripheral nerve lesions provoke apoptosis in the dorsal horn of the spinal cord. The cause of cell death, the involvement of neurons, and the relevance for the processing of somatosensory information are controversial. Here, we demonstrate in a mouse model of sciatic nerve injury that glutamate-induced neurodegeneration and loss of γ-aminobutyric acid (GABA)ergic interneurons in the superficial dorsal horn promote the transition from acute to chronic neuropathic pain. Conditional deletion of Grin1, the essential subunit of N-methyl-D-aspartate-type glutamate receptors (NMDARs), protects dorsal horn neurons from excitotoxicity and preserves GABAergic inhibition. Mice deficient in functional NMDARs exhibit normal nociceptive responses and acute pain after nerve injury, but this initial increase in pain sensitivity is reversible. Eliminating NMDARs fully prevents persistent pain-like behavior. Reduced pain in mice lacking proapoptotic Bax confirmed the significance of neurodegeneration. We conclude that NMDAR-mediated neuron death contributes to the development of chronic neuropathic pain., In Brief Dorsal horn neurons process somatosensory information, including pain. Inquimbert et al. utilized spatially restricted Grin1 knockout to show that NMDA-receptor-mediated excitatory input causes the degeneration of some dorsal horn neurons after nerve injury. Irreversible loss of GABAergic interneurons leads to a deficit in inhibition that promotes persistent pain hypersensitivity., Graphical Abstract

This review highlights relevant issues about applications and improvements of atomic force microscopy (AFM) toward a better understanding of neurodegenerative changes at the molecular level with the hope of contributing to the development of effective therapeutic strategies for neurodegenerative illnesses. The basic principles of AFM are briefly discussed in terms of evaluation of experimental data, including the newest PeakForce Quantitative Nanomechanical Mapping (QNM) and the evaluation of Young’s modulus as the crucial elasticity parameter. AFM topography, revealed in imaging mode, can be used to monitor changes in live neurons over time, representing a valuable tool for high-resolution detection and monitoring of neuronal morphology. The mechanical properties of living cells can be quantified by force spectroscopy as well as by new AFM. A variety of applications are described, and their relevance for specific research areas discussed. In addition, imaging as well as non-imaging modes can provide specific information, not only about the structural and mechanical properties of neuronal membranes, but also on the cytoplasm, cell nucleus, and particularly cytoskeletal components. Moreover, new AFM is able to provide detailed insight into physical structure and biochemical interactions in both physiological and pathophysiological conditions.

Within afrotherians, sirenians are unusual due to their aquatic lifestyle, large body size and relatively large lissencephalic brain. However, little is known about the neuron type distributions of the cerebral cortex in sirenians within the context of other afrotherians and aquatic mammals. The present study investigated two cortical regions, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2), in the presumptive primary somatosensory cortex (S1) in Florida manatees (Trichechus manatus latirostris) to characterize cyto- and chemoarchitecture. The mean neuron density for both cortical regions was 35,617 neurons/mm3 and fell within the 95% prediction intervals relative to brain mass based on a reference group of afrotherians and xenarthrans. Densities of inhibitory interneuron subtypes labeled against calcium-binding proteins and neuropeptide Y were relatively low compared to afrotherians and xenarthrans and also formed a small percentage of the overall population of inhibitory interneurons as revealed by GAD67 immunoreactivity. Nonphosphorylated neurofilament protein-immunoreactive (NPNFP-ir) neurons comprised a mean of 60% of neurons in layer V across DL1 and CL2. DL1 contained a higher percentage of NPNFP-ir neurons than CL2, although CL2 had a higher variety of morphological types. The mean percentage of NPNFP-ir neurons in the two regions of the presumptive S1 were low compared to other afrotherians and xenarthrans but were within the 95% prediction intervals relative to brain mass, and their morphologies were comparable to those found in other afrotherians and xenarthrans. Although this specific pattern of neuron types and densities sets the manatee apart from other afrotherians and xenarthrans, the manatee isocortex does not appear to be explicitly adapted for an aquatic habitat. Many of the features that are shared between manatees and cetaceans are also shared with a diverse array of terrestrial mammals and likely represent highly conserved neural features. A comparative study across manatees and dugongs is necessary to determine whether these traits are specific to one or more of the manatee species, or can be generalized to all sirenians.

Autism spectrum disorder (ASD) is defined by impairments in social communication, along with the presence of restricted and repetitive behaviors. Approximately half of affected children also suffer from intellectual disability (ID), which is defined by cognitive and adaptive functioning at least two standard deviations below the mean (e.g., standard scores

BACKGROUND: The diagnosis of either Alzheimer's disease (AD) or vascular dementia (VaD) is still largely based on clinical guidelines and exclusion of other diseases that may lead to dementia. AIMS: In this study, we assessed whether the use of sensitive and specific biomarkers such as phosphorylated tau proteins could contribute to an earlier and more accurate diagnosis of AD and VaD, as well as to their differentiation. MATERIAL AND METHODS: A total of 198 patients, of which 152 had AD, 28 VaD, and 18 were healthy controls (HC), were included in the analyses. We analyzed cerebrospinal fluid (CSF) levels of total tau protein (t‐tau), tau protein phosphorylated at threonine 231 (p‐tau231), and factor score (FS) determined by combination of p‐tau231 and Mini‐Mental State Examination (MMSE) in patients with AD and VaD, as well as in HC. We tested the diagnostic accuracy of these biomarkers in the CSF and FS (p‐tau231, MMSE) in differentiating AD from VaD and HC. RESULTS: Total tau levels were significantly elevated in subjects with AD compared to HC, as well as in VaD subjects compared to HC. DISCUSSION: p‐tau(231) levels were significantly higher in patients with AD vs HC as well in patients with VaD vs HC. p‐tau231 levels did not distinguish AD from VaD patients. Importantly, FS(p‐tau231 and MMSE) showed statistically significant differences in the distribution of subjects with AD and VaD. CONCLUSION: These results indicate that FS (p‐tau231 and MMSE) has a strong potential to provide an early distinction between AD and VaD.

In human life, social context requires the engagement in complex interactions among individuals as the dynamics of social networks. The evolution of the brain as the neurological basis of the mind must be crucial in supporting social networking. Although the relationship between social networking and the amygdala, a small but core region for emotion processing, has been reported, other structures supporting sophisticated social interactions must be involved and need to be identified. In this study, we examined the relationship between morphology of the anterior insular cortex (AIC), a structure involved in basic and high-level cognition, and social networking. Two independent cohorts of individuals (New York group n = 50, Beijing group n = 100) were recruited. Structural magnetic resonance images were acquired and the social network index (SNI), a composite measure summarizing an individual's network diversity, size, and complexity, was measured. The association between morphological features of the AIC, in addition to amygdala, and the SNI was examined. Positive correlations between the measures of the volume as well as sulcal depth of the AIC and the SNI were found in both groups, while a significant positive correlation between the volume of the amygdala and the SNI was only found in the New York group. The converging results from the two groups suggest that the AIC supports network-level social interactions.

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. This article is protected by copyright. All rights reserved.

The mammalian cochlear nuclei (CN) consist of two major subdivisions, the dorsal (DCN) and ventral (VCN) nuclei. We previously reported differences in the structural and neurochemical organization of the human DCN from that in several other species. Here we extend this analysis to the VCN, considering both the organization of subdivisions and the types and distributions of neurons. Classically, the VCN in mammals is composed of two subdivisions, the anteroventral (VCA) and posteroventral cochlear nuclei (VCP). Anatomical and electrophysiological data in several species have defined distinct neuronal types with different distributions in the VCA and VCP. We asked if VCN subdivisions and anatomically defined neuronal types might be distinguished by patterns of protein expression in humans. We also asked if the neurochemical characteristics of the VCN are the same in humans as in other mammalian species, analyzing data from chimpanzees, macaque monkeys, cats, rats and chinchillas. We examined Nissl- and immunostained sections, using antibodies that had labeled neurons in other brainstem nuclei in humans. Nissl-stained sections supported the presence of both VCP and VCA in humans and chimpanzees. However, patterns of protein expression did not differentiate classes of neurons in humans; neurons of different soma shapes and dendritic configurations all expressed the same proteins. The patterns of immunostaining in macaque monkey, cat, rat, and chinchilla were different from those in humans and chimpanzees and from each other. The results may correlate with species differences in auditory function and plasticity. Anat Rec, 301:862-886, 2018. © 2017 Wiley Periodicals, Inc.

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.

Gorillas include separate eastern (Gorilla beringei) and western (Gorilla gorilla) African species that diverged from each other approximately 2 million years ago. Although anatomical, genetic, behavioral, and socioecological differences have been noted among gorilla populations, little is known about variation in their brain structure. This study examines neuroanatomical variation between gorilla species using structural neuroimaging. Postmortem magnetic resonance images were obtained of brains from 18 captive western lowland gorillas (Gorilla gorilla gorilla), 15 wild mountain gorillas (Gorilla beringei beringei), and 3 Grauer's gorillas (Gorilla beringei graueri) (both wild and captive). Stereologic methods were used to measure volumes of brain structures, including left and right frontal lobe gray and white matter, temporal lobe gray and white matter, parietal and occipital lobes gray and white matter, insular gray matter, hippocampus, striatum, thalamus, each hemisphere and the vermis of the cerebellum, and the external and extreme capsules together with the claustrum. Among the species differences, the volumes of the hippocampus and cerebellum were significantly larger in G. gorilla than G. beringei. These anatomical differences may relate to divergent ecological adaptations of the two species. Specifically, G. gorilla engages in more arboreal locomotion and thus may rely more on cerebellar circuits. In addition, they tend to eat more fruit and have larger home ranges and consequently might depend more on spatial mapping functions of the hippocampus.

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

The dorsal cochlear nucleus (DCN) is a brainstem structure that receives input from the auditory nerve. Many studies in a diversity of species have shown that the DCN has a laminar organization and identifiable neuron types with predictable synaptic relations to each other. In contrast, studies on the human DCN have found a less distinct laminar organization and fewer cell types, although there has been disagreement among studies in how to characterize laminar organization and which of the cell types identified in other animals are also present in humans. We have reexamined DCN organization in the human using immunohistochemistry to analyze the expression of several proteins that have been useful in delineating the neurochemical organization of other brainstem structures in humans: nonphosphorylated neurofilament protein (NPNFP), nitric oxide synthase (nNOS), and three calcium-binding proteins. The results for humans suggest a laminar organization with only two layers, and the presence of large projection neurons that are enriched in NPNFP. We did not observe evidence in humans of the inhibitory interneurons that have been described in the cat and rodent DCN. To compare humans and other animals directly we used immunohistochemistry to examine the DCN in the macaque monkey, the cat, and three rodents. We found similarities between macaque monkey and human in the expression of NPNFP and nNOS, and unexpected differences among species in the patterns of expression of the calcium-binding proteins.

The present study documents the morphology of neurons in several regions of the neocortex from the bottlenose dolphin (Tursiops truncatus), the North Atlantic minke whale (Balaenoptera acutorostrata), and the humpback whale (Megaptera novaeangliae). Golgi-stained neurons (n = 210) were analyzed in the frontal and temporal neocortex as well as in the primary visual and primary motor areas. Qualitatively, all three species exhibited a diversity of neuronal morphologies, with spiny neurons including typical pyramidal types, similar to those observed in primates and rodents, as well as other spiny neuron types that had more variable morphology and/or orientation. Five neuron types, with a vertical apical dendrite, approximated the general pyramidal neuron morphology (i.e., typical pyramidal, extraverted, magnopyramidal, multiapical, and bitufted neurons), with a predominance of typical and extraverted pyramidal neurons. In what may represent a cetacean morphological apomorphy, both typical pyramidal and magnopyramidal neurons frequently exhibited a tri-tufted variant. In the humpback whale, there were also large, star-like neurons with no discernable apical dendrite. Aspiny bipolar and multipolar interneurons were morphologically consistent with those reported previously in other mammals. Quantitative analyses showed that neuronal size and dendritic extent increased in association with body size and brain mass (bottlenose dolphin

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 birth of the cytoarchitectonics (in Korbinian Brod- mann's own words cytoarchitectonics should be defined as "the localization of the individual histological ele- ments, their layering, and their parcellation in the adult brain") of the human cerebral cortex is credited to Mey- nert, who in 186721868, by using one of the first syn- thetic colors, Prussian (Berlin) blue (in painting, Parisian blue, Fe4(Fe(CN)6)3, derived from hydrogen cyanide or "blue acid"), noticed regional variations in the nerve cells stratification in different parts of the gray matter of the cerebral hemispheres (Meynert, 1868). During the 20th century, many investigators, including Camp- bell (1903), Brodmann (1909, 1910; for review see Judaet al., 2012), Elliot Smith (1907), von Economo and Koskinas (1925), Vogt and Vogt (1926), Bailey and von Bonin (1951), Sarkisov et al. (1955), and others, have produced cytoarchitectural maps of the human cerebral cortex by dividing it into a number of areas or fields. For this purpose, they were generally used the Nissl staining method, which is based on "defatting" brain tissue sections by passing through graded dilu- tions of ethanol, rehydrating through decreasing ethanol concentrations, and staining in a water solution of a cationic dye (such as methylene blue, cresyl violet, thio- nin, toluidine blue). The ethanol solutions act to differ- entiate the stain, causing myelin and other components to lose color and be "stripped off the cells", whereas negatively charged molecules within cell bodies retain the coloration (Nissl, 1894). Although many maps have been produced in attempts to make a definitive parti- tion of the human cerebral cortex, Brodmann's map and especially his numerical system attached to cytoarchitecture is by far the most widely recognized in current use. The last (final) Brodmann's map of the human cerebral cortex is shown in Figure 1A2C, and the list of cortical areas defined by Brodmann is pro- vided in Table 1. There is a common agreement that the popularity of Brodmann's numbering system is due to its simplicity to recall, its relatively sharp delineations of the borders between adjacent areas, its detail not so exhaustive to be impossible to refer to, and the fact that Brodmann's observations of cytoarchitecture have stood the test of time. In addition, Brodmann's map is also the closest to the modern definition of the cortical area (field), by which an area, among several other features, is receiv- ing afferent fibers from a particular (principal) nucleus of the thalamus (Jones, 1985, 2009). Thalamic inputs, except for the so-called nonspecific thalamic nuclei, stop abruptly at an areal border, and there appears to be no overlap between inputs from different specific thalamic nuclei to adjacent fields (Jones, 1985, 2009). Moreover, the chemoarchitectural borders, as defined by a characteristic pattern of histochemical or immuno- cytochemical staining, also commonly coincide with the cytoarchitecture defined by Brodmann. It is therefore not surprising that modified versions of Brodmann's map, often based on its extrapolation onto the Talairach and Tournoux brain atlas (Talairach and Tournoux, 1988), are so frequently used in neuroimaging studies to describe the localization of activation (Zilles and Amunts, 2010). In practice, however, this led to the occurrence of consistent mistakes and misinterpreta- tions in relation to usage and quotation of Brodmann's maps and numbers. Brodmann published a series of comparative neuroana- tomical works on more than 60 mammalian species in the Journal f € Psychologie und Neurologie between 1903 and 1908. These findings were summarized in his famous book (Brodmann, 1909) and extended in two chapters, which he contributed to contemporary handbooks (Brodmann, 1910, 1914). The first ("original") Brodmann's cytoarchitectonic map was first published in one of his monographs (Brodmann, 1908a) and then reproduced in his 1909 book, when he also added the map of the

Von Economo neurons (VENs) are specialized projection neurons with a characteristic spindle-shaped soma and thick basal and apical dendrites. VENs have been described in restricted cortical regions, with their most frequent appearance in layers III and V of the anterior cingulate cortex, anterior insula, and frontopolar cortex of humans, great apes, macaque monkeys, elephants, and some cetaceans. Recently, a ubiquitous distribution of VENs was reported in various cortical areas in the pygmy hippopotamus, one of the closest living relatives of cetaceans. That finding suggested that VENs might not be unique to only a few species that possess enlarged brains. In the present analysis, we assessed the phylogenetic distribution of VENs within species representative of the superordinal clade that includes cetartiodactyls and perissodactyls, as well as afrotherians. In addition, the distribution of fork cells that are often found in close proximity to VENs was also assessed. Nissl-stained sections from the frontal pole, anterior cingulate cortex, anterior insula, and occipital pole of bowhead whale, cow, sheep, deer, horse, pig, rock hyrax, and human were examined using stereologic methods to quantify VENs and fork cells within layer V of all four cortical regions. VENs and fork cells were found in each of the species examined here with species-specific differences in distributions and densities. The present results demonstrated that VENs and fork cells were not restricted to highly encephalized or socially complex species, and their repeated emergence among distantly related species seems to represent convergent evolution of specialized pyramidal neurons. The widespread phylogenetic presence of VENs and fork cells indicates that these neuron morphologies readily emerged in response to selective forces,whose variety and nature are yet to be identified.