Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole-brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high-resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and 1,356 large-format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto- and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127-3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Cholinergic innervation of the basal ganglia is important in learning and memory. Striatal cholinergic neurons integrate cognitive and motivational states with behavior. Given these roles, it is not surprising that deficits in cortical cholinergic innervation have been correlated with loss of cognitive function in Alzheimer's disease and schizophrenia. Such evidence suggests the potential significance of subcortical cholinergic innervation in the evolution of the human brain. To compare humans with other closely related primates, the present study quantified axons and interneurons immunoreactive for choline acetyltransferase (ChAT) in regions of the executive and motor loops of the basal ganglia of humans, great apes, and monkeys. We also compared ChAT-immunoreactive (ir) interneuron morphological types among species within striatal regions. The results indicate that humans and great apes differ from monkeys in having a preponderance of multipolar ChAT-ir interneurons in the caudate nucleus and putamen, whereas monkeys have a more heterogeneous representation of multipolar, bipolar, and unipolar interneurons. Cholinergic innervation, as measured by axon and interneuron densities, did not differ across species in the medial caudate nucleus. Differences were detected in the dorsal caudate nucleus, putamen, and globus pallidus but the observed variation did not associate with the phylogenetic structure of the species in the sample. However, combining the present results with previously published data for dopamine revealed a unique pattern of innervation for humans, with higher amounts of dopamine compared with acetylcholine in the striatum. Taken together, these findings indicate a potential evolutionary shift in basal ganglia neurotransmission in humans that may favor increased synaptic plasticity. J. Comp. Neurol. 525:319-332, 2017. © 2016 Wiley Periodicals, Inc.

Amyloid precursor protein (APP), the parent molecule to amyloid β peptide, is part of a larger gene family with two mammalian homologues, amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2). Initial knock-out studies demonstrated that while single APP family gene deletions produced relatively mild phenotypes, deficiency of APLP2 and one other member of the gene family resulted in perinatal lethality, suggesting vital roles masked by functional redundancy of the other homologues. Because of the importance of APP in Alzheimer's disease, the vast majority of studies to date have concentrated on the neuronal functions of APP, leaving limited data on its homologues. APLP2 is of particular interest as it contains high sequence homology with APP, is processed similarly, is expressed in overlapping spatial and temporal patterns, and is obligatory for lethality when combined with deficiency of either APLP1 or APP but does not contain the toxic amyloid β sequence. Here we sought to test the role of APLP2 on neuronal structure and function using a combined approach involving in vitro and in vivo techniques in young and aged animals. Surprisingly, we found that unlike APP, APLP2 appears not to be essential for maintenance of dendritic structure, spine density, or synaptic function. Thus, there is clear divergence in the functional redundancy between APP and APLP2.

The genetics of autism spectrum disorder (hereafter referred to as "autism") are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. Previous electrophysiological studies in mice with Shank3 mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse.

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.

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.

Cognitive control, with a limited capacity, is a core process in human cognition for the coordination of thoughts and actions. Although the regions involved in cognitive control have been identified as the cognitive control network (CCN), it is still unclear whether a specific region of the CCN serves as a bottleneck limiting the capacity of cognitive control (CCC). Here, we used a perceptual decision-making task with conditions of high cognitive load to challenge the CCN and to assess the CCC in a functional magnetic resonance imaging study. We found that the activation of the right anterior insular cortex (AIC) of the CCN increased monotonically as a function of cognitive load, reached its plateau early, and showed a significant correlation to the CCC. In a subsequent study of patients with unilateral lesions of the AIC, we found that lesions of the AIC were associated with a significant impairment of the CCC. Simulated lesions of the AIC resulted in a reduction of the global efficiency of the CCN in a network analysis. These findings suggest that the AIC, as a critical hub in the CCN, is a bottleneck of cognitive control.

Neuropeptide Y (NPY) plays a role in a variety of basic physiological functions and has also been implicated in regulating cognition, including learning and memory. A decrease in neocortical NPY has been reported for Alzheimer's disease, schizophrenia, bipolar disorder, and depression, potentially contributing to associated cognitive deficits. The goal of the present analysis was to examine variation in neocortical NPY-immunoreactive axon and varicosity density among haplorhine primates (monkeys, apes, and humans). Stereologic methods were used to measure the ratios of NPY-expressing axon length density to total neuron density (ALv/Nv) and NPY-immunoreactive varicosity density to neuron density (Vv/Nv), as well as the mean varicosity spacing in neocortical areas 10, 24, 44, and 22 (Tpt) of humans, African great apes, New World monkeys, and Old World monkeys. Humans and great apes showed increased cortical NPY innervation relative to monkey species for ALv/Nv and Vv/Nv. Furthermore, humans and great apes displayed a conserved pattern of varicosity spacing across cortical areas and layers, with no differences between cortical layers or among cortical areas. These phylogenetic differences may be related to shared life history variables and may reflect specific cognitive abilities.

Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non-demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion-specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (r(p) = -0.539, p = 0.021 for 5-mC and r(p) = -0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.

In human and nonhuman primates, the amygdala is known to play critical roles in emotional and social behavior. Anatomically, individual amygdaloid nuclei are connected with many neural systems that are either differentially expanded or conserved over the course of primate evolution. To address amygdala evolution in humans and our closest living relatives, the apes, we used design-based stereological methods to obtain neuron counts for the amygdala and each of four major amygdaloid nuclei (the lateral, basal, accessory basal, and central nuclei) in humans, all great ape species, lesser apes, and one monkey species. Our goal was to determine whether there were significant differences in the number or percent of neurons distributed to individual nuclei among species. Additionally, regression analyses were performed on independent contrast data to determine whether any individual species deviated from allometric trends. There were two major findings. In humans, the lateral nucleus contained the highest number of neurons in the amygdala, whereas in apes the basal nucleus contained the highest number of neurons. Additionally, the human lateral nucleus contained 59% more neurons than predicted by allometric regressions on nonhuman primate data. Based on the largest sample ever analyzed in a comparative study of the hominoid amygdala, our findings suggest that an emphasis on the lateral nucleus is the main characteristic of amygdala specialization over the course of human evolution.

Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable "learning" thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.

Like humans, chimpanzees display robust and consistent hand preferences during the performance of certain tasks. Although correlations have been demonstrated between gross anatomic measures of primary motor cortex asymmetry and handedness in captive chimpanzees, the relationship between histological architecture and behavioral lateralization has not yet been investigated. Therefore, we examined interhemispheric asymmetry of several different microstructural characteristics of the primary motor cortex in the region of hand representation from 18 chimpanzees tested on a coordinated bimanual task before death. At the population level our data showed leftward bias for higher layer II/III neuron density. Of note, however, there was no population-level asymmetry in the areal fraction of Nissl-stained cell bodies, a finding that differs from previous studies of this cortical region in humans. Nonetheless, we found that asymmetry in the density of layer II/III parvalbumin-immunoreactive interneurons was the best predictor of individual hand preference. These results suggest that histological asymmetries are related to handedness in chimpanzees, while overall patterns of asymmetry at the population level might differ from humans.

Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin-1β, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1α, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury.

Although it has been claimed that marsupials possess a lower density of isocortical neurons compared with other mammals, little is known about cross-cortical variation in neuron distributions in this diverse taxonomic group. We quantified upper-layer (layers II-IV) and lower-layer (layers V-VI) neuron numbers per unit of cortical surface area in three diprotodont marsupial species (two macropodiformes, the red kangaroo and the parma wallaby, and a vombatiform, the koala) and compared these results to eutherian mammals (e.g., xenarthrans, rodents, primates). In contrast to the notion that the marsupial isocortex contains a low density of neurons, we found that neuron numbers per unit of cortical surface area in several marsupial species overlap with those found in eutherian mammals. Furthermore, neuron numbers vary systematically across the isocortex of the marsupial mammals examined. Neuron numbers under a unit of cortical surface area are low toward the frontal cortex and high toward the caudo-medial (occipital) pole. Upper-layer neurons (i.e., layers II-IV) account for most of the variation in neuron numbers across the isocortex. The variation in neuron numbers across the rostral to the caudal pole resembles primates. These findings suggest that diprotodont marsupials and eutherian mammals share a similar cortical architecture despite their distant evolutionary divergence.

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS.

Obsessive-compulsive disorder (OCD) is characterized by excessive absorption with internally-generated distressing thoughts and urges, with difficulty incorporating external information running counter to their fears and concerns. In the present study, we experimentally probed this core feature of OCD through the use of a novel attention switching task that investigates transitions between internally focused (IF) and externally focused (EF) attentional states. Eighteen OCD patients and 18 controls imagined positive and negative personal event scenarios (IF state) or performed a color-word Stroop task (EF state). The IF/EF states were followed by a target detection (TD) task requiring responses to external stimuli. Compared to controls, OCD patients made significantly more errors and showed reduced activation of superior and inferior occipital cortex, thalamus, and putamen during TD following negative IF, with the inferior occipital hypoactivation being significantly greater for TD following negative IF compared to TD following the other conditions. Patients showed stronger functional connectivity between the inferior occipital region and dorsomedial prefrontal cortex. These findings point to an OCD-related impairment in the visual processing of external stimuli specifically when they follow a period of negative internal focus, and suggest that future treatments may wish to target the transition between attentional states.

MRI-negative epilepsy patients could benefit from advanced imaging techniques such as high-resolution diffusion magnetic resonance imaging (dMRI). Our aim was to perform hippocampal subfield-specific tractography and quantify connectivity of the subfields in MRI-negative patients. Abnormal connectivity of the hippocampal subfields may help inform seizure focus hypothesis and provide information to guide surgical intervention.

Cognitive control is the coordination of mental operations under conditions of uncertainty in accordance with goal-directed behaviors, and plays a key role in the domains of executive control, working memory, and decision-making. Although there is emerging evidence of common involvement of the cognitive control network (CCN) of the brain in these domains, this network has mostly been linked to the processing of conflict, which is just one case of an increase in uncertainty. Here, we conducted an activation-likelihood-estimation-based large-scale meta-analysis of 289 functional magnetic resonance imaging studies in the three domains to examine the common involvement of the CCN in uncertainty processing by contrasting the high-uncertainty versus low-uncertainty conditions. We found a general association between increase in uncertainty and an activation increase in regions of the CCN, including the frontoparietal network (comprising the frontal eye fields, the areas near and along the intraparietal sulcus, and the dorsolateral prefrontal cortex), the cingulo-opercular network (including the anterior cingulate cortex extending to the supplementary motor area, and the anterior insular cortex), and a subcortical structure (the striatum). These results demonstrate that the CCN is a domain-general construct underlying uncertainty processing to support goal-directed behaviors.

Employing a range of neuroanatomical stains, we detail the organization of the main and accessory olfactory systems of the African wild dog. The organization of both these systems follows that typically observed in mammals, but variations of interest were noted. Within the main olfactory bulb, the size of the glomeruli, at approximately 350 μm in diameter, are on the larger end of the range observed across mammals. In addition, we estimate that approximately 3,500 glomeruli are present in each main olfactory bulb. This larger main olfactory bulb glomerular size and number of glomeruli indicates that enhanced peripheral processing of a broad range of odorants is occurring in the main olfactory bulb of the African wild dog. Within the accessory olfactory bulb, the glomeruli did not appear distinct, rather forming a homogenous syncytia-like arrangement as seen in the domestic dog. In addition, the laminar organization of the deeper layers of the accessory olfactory bulb was indistinct, perhaps as a consequence of the altered architecture of the glomeruli. This arrangement of glomeruli indicates that rather than parcellating the processing of semiochemicals peripherally, these odorants may be processed in a more nuanced and combinatorial manner in the periphery, allowing for more rapid and precise behavioral responses as required in the highly social group structure observed in the African wild dog. While having a similar organization to that of other mammals, the olfactory system of the African wild dog has certain features that appear to correlate to their environmental niche.

The genus Macaca is an ideal model for investigating the biological basis of primate social behavior from an evolutionary perspective. A significant amount of behavioral diversity has been reported among the macaque species, but little is known about the neural substrates that support this variation. The present study compared neural cell density and serotonergic innervation of the amygdala among four macaque species using histological and immunohistochemical methods. The species examined included rhesus (Macaca mulatta), Japanese (M. fuscata), pigtailed (M. nemestrina), and moor macaques (M. maura). We anticipated that the more aggressive rhesus and Japanese macaques would have lower serotonergic innervation within the amygdala compared to the more affiliative pigtailed and moor macaques. In contrast to our prediction, pigtailed macaques had higher serotonergic innervation than Japanese and moor macaques in the basal and central amygdala nuclei when controlling for neuron density. Our analysis of neural cell populations revealed that Japanese macaques possess significantly higher neuron and glia densities relative to the other three species, however we observed no glia-to-neuron ratio differences among species. The results of this study revealed serotonergic innervation and cell density differences among closely related macaque species, which may play a role in modulating subtle differences in emotional processing and species-typical social styles.