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Primate brains display a wide range of variation in size and cerebral gyrification, leading to the appearance of novel sulci in particular groups of species. We investigated sulcal organization in the medial frontal cortex of great apes, with a particular focus on the paracingulate sulcus (PCGS). Until recently, the presence of the PCGS was thought to be a structural feature unique to the human brain. However, upon closer examination, the PCGS has been observed as a variable feature that also may appear in chimpanzee brains. To understand the evolutionary origins of the sulcal anatomy in the medial frontal cortex of apes, we examined high-resolution MRI scans for the presence or absence of the PCGS and, when present, measured its length in a sample of ape brains (chimpanzees, bonobos, gorillas, orangutans, gibbons, and siamangs). We found that the PCGS is variable in its appearance among these species, being present in 23 to 50% of great ape individuals depending on the species, but not present in gibbons or siamangs. We did not find population level hemispheric lateralization patterns or sex differences in PCGS presence across species, and we did not detect a relationship between cerebral volume and PCGS occurrence or length. Our data suggest that the PCGS is a common sulcal variant present in great apes and humans due to a shared evolutionary ancestry. [ABSTRACT FROM AUTHOR]

Betz cells, named in honor of Volodymyr Betz (1834–1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α‐motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type‐specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT The isocortex of primates is disproportionately expanded relative to many other mammals, yet little is known about what the expansion of the isocortex entails for differences in cellular composition and connectivity patterns in primates. Across the depth of the isocortex, neurons exhibit stereotypical patterns of projections. Upper-layer neurons (i.e., layers II-IV) project within and across cortical areas, whereas many lower-layer pyramidal neurons (i.e., layers V-VI) favor connections to subcortical regions. To identify evolutionary changes in connectivity patterns, we quantified upper (i.e., layers II-IV)- and lower (i.e., layers V-VI)-layer neuron numbers in primates and other mammals such as rodents and carnivores. We also used MR tractography based on high-angular resolution diffusion imaging and diffusion spectrum imaging to compare anterior-to-posterior corticocortical tracts between primates and other mammals. We found that primates possess disproportionately more upper-layer neurons as well as an expansion of anterior-to-posterior corticocortical tracts compared with other mammals. Taken together, these findings demonstrate that primates deviate from other mammals in exhibiting increased cross-cortical connectivity. J. Comp. Neurol. 525:1075-1093, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT Homologizing between human and nonhuman area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to nonhuman species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and that areas v32/s32 have large and dense neurons in layer V, whereas a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to humans include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, with area s32 having the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable among humans, monkeys, and rats and were significantly lower than in mice. Layers I-III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV-VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture, and ligand binding studies demonstrate critical homologies among the four species. J. Comp. Neurol. 521:4189-4204, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people's emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta-analysis, 2) AIC is functionally dissociable from ACC, 3) AIC integrates stimulus-driven and top-down information, and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom-up interoceptive signals with top-down predictions to generate a current awareness state and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for emotional awareness. J. Comp. Neurol. 521:3371-3388, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A major focus of comparative neuroanatomy has been on whether the mammalian brain evolves in a concerted or a mosaic fashion. Workers have examined variation in the volume of different brain regions across taxa to test the degree to which selection is constrained by the timing of events in neural development. Whether a conserved neurogenetic program in the mammalian brain constrains the distribution of different cell types, however, has not yet been investigated. Here we tested for evidence of evolutionary constraints on the densities of different cell types in the primary visual cortex (V1) and the hippocampus in 37 primate and 21 carnivore species. Cellular densities in V1 and the hippocampus scale isometrically with respect to one another in carnivores, as predicted by the concerted evolution hypothesis. In primates, however, cellular distributions in the hippocampus and primary visual cortex show no correlations, which supports the hypothesis of mosaic brain evolution. We therefore provide evidence for the presence of constraints controlling the adult densities of different cell types in disparate regions of the mammalian brain, but also for specializations along the primate lineage. We propose that adaptations to modularity at the cellular level may carry a deep phylogenetic signal. [ABSTRACT FROM AUTHOR]

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'. [ABSTRACT FROM AUTHOR]

The University of Geneva brain collection was founded at the beginning of the 20th century. Today, it consists of 10,154 formaldehyde- or buffered formaldehyde-fixed brains obtained from the autopsies of the Department of Psychiatry and, since 1971, from the Department of Geriatrics. More than 100,000 paraffin-embedded blocks and 200,000 histological slides have also been collected since 1901. From the time of its creation, this collection has served as an important resource for pathological studies and clinicopathological correlations, primarily in the field of dementing illnesses and brain aging research. These materials have permitted a number of original neuropathological observations, such as the classification of Pick's disease by Constantinidis, or the description of dyshoric angiopathy and laminar sclerosis by Morel. The large number of cases, including some very rare conditions, provides a unique resource and an opportunity for worldwide collaborations. [ABSTRACT FROM AUTHOR]

The human insular cortex is involved in a variety of viscerosensory, visceromotor, and interoceptive functions, and plays a role in complex processes such as emotions, music, and language. Across mammals, the insula has considerable morphologic variability. We review the structure and connectivity of the insula in laboratory animals (mouse, domestic cat, macaque monkey), and we present original data on the morphology and cytoarchitecture of insular cortex in less common species including a large carnivore (the Atlantic walrus, Odobenus rosmarus), two artiodactyls (the pigmy hippopotamus, Hexaprotodon liberiensis, and the Western bongo, Tragelaphus eurycerus), two cetaceans (the beluga whale, Delphinapterus leucas, and the minke whale, Balaenoptera acutorostrata), and a sirenian (the Florida manatee, Trichechus manatus latirostris). The insula shows substantial variability in shape, extent, and gyral and sulcal patterns, as well as differences in laminar organization, cellular specialization, and structural association with the claustrum. Our observations reveal that the insular cortex is extremely variable among mammals. These differences could be related to the role exerted by specific and selective pressures on cortical structure during evolution. We conclude that it is not possible to identify a general model of organization for the mammalian insular cortex. [ABSTRACT FROM AUTHOR]

Abstract: According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer''s disease. [Copyright &y& Elsevier]

The midline and intralaminar thalamic nuclei (MITN), locus coeruleus (LC) and cingulate cortex contain nociceptive neurons. The MITN that project to cingulate cortex have a prominent innervation by norepinephrinergic axons primarily originating from the LC. The hypothesis explored in this study is that MITN neurons that project to cingulate cortex receive a disproportionately high LC input that may modulate nociceptive afferent flow into the forebrain. Ten cynomolgus monkeys were evaluated for dopamine-β hydroxylase (DBH) immunohistochemistry, and nuclei with moderate or high DBH activity were analyzed for intermediate neurofilament proteins, calbindin (CB), and calretinin (CR). Sections of all but DBH were thionin counterstained to assure precise localization in the mediodorsal and MITN, and cytoarchitecture was analyzed with neuron-specific nuclear binding protein. Moderate–high levels of DBH-immunoreactive (ir) axons were generally associated with high densities of CB-ir and CR-ir neurons and low levels of neurofilament proteins. The paraventricular, superior centrolateral, limitans and central nuclei had relatively high and evenly distributed DBH, the magnocellular mediodorsal and paracentral nuclei had moderate DBH-ir, and other nuclei had an even and low level of activity. Some nuclei also have heterogeneities in DBH-ir that raised questions of functional segregation. The anterior multiformis part of the mediodorsal nucleus but not middle and caudal levels had high DBH activity. The posterior parafascicular nucleus (Pf) was heterogeneous with the lateral part having little DBH activity, while its medial division had most DBH-ir axons and its multiformis part had only a small number. These findings suggest that the LC may regulate nociceptive processing in the thalamus. The well established role of cingulate cortex in premotor functions and the projections of Pf and other MITN to the limbic striatum suggests a specific role in mediating motor outflow for the LC-innervated nuclei of the MITN. [ABSTRACT FROM AUTHOR]

Small untranslated BC1 and BC200 RNAs are translational regulators that are selectively targeted to somatodendritic domains of neurons. They are thought to operate as modulators of local protein synthesis in postsynaptic dendritic microdomains, in a capacity in which they would contribute to the maintenance of long-term synaptic plasticity. Because plasticity failure has been proposed to be a starting point for the neurodegenerative changes that are seen in Alzheimer's disease (AD), we asked whether somatodendritic levels of human BC200 RNA are deregulated in AD brains. We found that in normal aging, BC200 levels in cortical areas were reduced by >60% between the ages of 49 and 86. In contrast, BC200 RNA was significantly up-regulated in AD brains, in comparison with age-matched normal brains. This up-regulation in AD was specific to brain areas that are involved in the disease. Relative BC200 levels in those areas increased in parallel with the progression of AD, as reflected by Clinical Dementia Rating scores. In more advanced stages of the disease, BC200 RNA often assumed a clustered perikaryal localization, indicating that dendritic loss is accompanied by somatic overexpression. Mislocalization and overexpression of BC200 RNA may be reactive-compensatory to, or causative of, synaptodendritic deterioration in AD neurons. [ABSTRACT FROM AUTHOR]

Abstract: The trigeminal motor (Vmo), facial (VII), and hypoglossal (XII) nuclei of the brainstem comprise the final common output for neural control of most orofacial muscles. Hence, these cranial motor nuclei are involved in the production of adaptive behaviors such as feeding, facial expression, and vocalization. We measured the volume and Grey Level Index (GLI) of Vmo, VII, and XII in 47 species of primates and examined these nuclei for scaling patterns and phylogenetic specializations. Allometric regression, using medulla volume as an independent variable, did not reveal a significant difference between strepsirrhines and haplorhines in the scaling of Vmo volume. In addition, correlation analysis using independent contrasts did not find a relationship between Vmo size or GLI and the percent of leaves in the diet. The scaling trajectory of VII volume, in contrast, differed significantly between suborders. Great ape and human VII volumes, furthermore, were significantly larger than predicted by the haplorhine regression. Enlargement of VII in these taxa may reflect increased differentiation of the facial muscles of expression and greater utilization of the visual channel in social communication. The independent contrasts of VII volume and GLI, however, were not correlated with social group size. To examine whether the human hypoglossal motor system is specialized to control the tongue for speech, we tested human XII volume and GLI for departures from nonhuman haplorhine prediction lines. Although human XII volumes were observed above the regression line, they did not exceed prediction intervals. Of note, orang-utan XII volumes had greater residuals than humans. Human XII GLI values also did not differ from allometric prediction. In sum, these findings indicate that the cranial orofacial motor nuclei evince a mosaic of phylogenetic specializations for innervation of the facial muscles of expression in the context of a generally conservative scaling relationship with respect to medulla size. [Copyright &y& Elsevier]

The human brain is uniquely powerful with respect to cognitive abilities, yet the hippocampal and neocortical circuits that mediate such complex functions are highly vulnerable to aging. Their selective vulnerability is profoundly manifested in Alzheimer''s disease (AD), where degeneration of select neurons leads to a near complete loss of cognitive abilities. Most of us will avoid AD as we age. However, many will experience age-associated cognitive impairment – a decline in cognitive status presenting as deficits in memory and key capacities for strategic use of acquired information. Animal studies suggest that both AD and age-associated cognitive impairment reflect vulnerability of the same circuits. However, neuron death predominates in the former, whereas the latter is probably mediated by synaptic alterations in otherwise intact circuits. Fortunately, such age-related synaptic alterations could be reversible, as suggested by recent studies of hormone replacement. [Copyright &y& Elsevier]

The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer''s disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new β-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD. [Copyright &y& Elsevier]

We describe the synthesis of automated neuron branching morphology and spine detection algorithms to provide multiscale three-dimensional morphological analysis of neurons. The resulting software is applied to the analysis of a high-resolution (0.098 μm × 0.098 μm × 0.081 μm) image of an entire pyramidal neuron from layer III of the superior temporal cortex in rhesus macaque monkey. The approach provides a highly automated, complete morphological analysis of the entire neuron; each dendritic branch segment is characterized by several parameters, including branch order, length, and radius as a function of distance along the branch, as well as by the locations, lengths, shape classification (e.g., mushroom, stubby, thin), and density distribution of spines on the branch. Results for this automated analysis are compared to published results obtained by other computer-assisted manual means. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimer’s disease (AD), and is thus considered a tauopathy. Following reports of α-synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of α-synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinson’s disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of α-synuclein in the cerebellum of Guamanian PDC patients. Numerous α-synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing α-synuclein pathology in the amygdala. The average density of α-synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this α-synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar α-synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the α-synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes. [ABSTRACT FROM AUTHOR]

Humans, non-human primates and rodents show declines in spatial memory abilities with increased age. Some of these declines in mice are related to changes in the expression of the epsilon2 (ϵ2) (NR2B) subunit of the N-methyl-d-aspartate receptor. The purpose of this study was to determine whether primates show changes during aging in the mRNA expression of the NR2B subunit. In situ hybridization was performed on tissue sections from three different ages of Rhesus monkeys (Macaca mulatta; 6–8, 10–12, and 24–26 years). There was a significant decrease in the mRNA expression of the NR2B subunit overall in the prefrontal cortex and in the caudate nucleus between young and old monkeys. There were no significant changes in NR2B mRNA expression in the hippocampus or the parahippocampal gyrus. The results in the prefrontal cortex, caudate and hippocampus were similar to those seen previously in C57BL/6 mice during aging, which suggests that mice may be useful as a model for primates to further examine the age-related changes in the expression of the NR2B subunit of the NMDA receptor in several important regions of the brain. [Copyright &y& Elsevier]

: BackgroundBrain imaging, molecular genetic, and ultrastructural evidence indicate the existence of pathologic alterations in the cortical and subcortical white matter of schizophrenic patients.: MethodsWe performed a stereologic analysis of numbers, densities, and spatial distribution of oligodendrocytes in layer III and in the gyral white matter of Brodmann’s area 9 in the superior frontal gyrus to assess whether these cells are affected in schizophrenia. Counts were obtained on Nissl-stained materials and on sections immunolabeled for the oligodendrocyte marker 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in seven schizophrenic and seven age-matched control cases.: ResultsA 28% decrease in total numbers (or densities) of cortical layer III oligodendrocytes and a 27% decrease in the white matter were detected in schizophrenic compared with control cases based on CNPase immunostaining. Nissl and CNPase immunohistochemistry yielded comparable results. The spatial distribution of oligodendrocytes in area 9 white matter exhibited a less clustered arrangement in schizophrenic cases.: ConclusionsThese results suggest a severe pathology of oligodendrocytes in schizophrenia and provide a quantitative cellular correlate of the white matter changes observed by brain imaging in vivo, showing reduced fractional anisotropy in schizophrenia. The data support recent evidence that several genes encoding myelin-related proteins consistently exhibit reduced expression in schizophrenia. [Copyright &y& Elsevier]

In this paper, we review the key pathologic events in human hippocampus and neocortex that underlie Alzheimer''s disease, and contrast these events with those of normal aging in these same brain regions of animal models. Alzheimer''s disease is characterized by senile plaque and neurofibrillary tangle formation, and more importantly, extensive yet selective neuron death and synapse loss in the hippocampus and neocortex. Particular subsets of pyramidal cells and their projections, such as the connection between entorhinal cortex and hippocampus and corticocortical interconnections in neocortex, are particularly vulnerable. The extensive degeneration of these circuits leads directly to dementia. Normal aging can be accompanied by a more modest disruption of memory, yet neuron death is unlikely to be a significant contributor to age-associated memory impairment. While the death of neurons is minimal in normal aging, the same hippocampal and neocortical circuits that die in Alzheimer''s disease are vulnerable to sublethal age-related shifts in morphology, neurochemical phenotype and synaptic alterations that might impair function. The response of these circuits to circulating estrogen levels is also discussed, since the critical interactions between reproductive senescence and brain aging may affect excitatory synaptic transmission in the hippocampus as well. Thus, subtle changes in the aging spine and synapse may be the key to age-related memory decline, whereas degeneration of entire circuits is the more prominent substrate for functional decline in Alzheimer''s disease. [Copyright &y& Elsevier]

The amyotrophic lateral sclerosis/parkinsonism-dementia complex is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. The cortical pathology of the disease is characterized by the widespread occurrence of cortical neurofibrillary tangles that exhibit a specific laminar and regional distribution different from that seen in Alzheimer''s disease (AD). In spite of the major motor symptomatology, the degree to which the primary motor cortex is affected in this disease has not been investigated in detail. We report here that the primary motor cortex in Guamanian cases contains high numbers of neurofibrillary tangles, contrasting sharply with the situation in AD and in non-Chamorro cases of amyotrophic lateral sclerosis. Furthermore, the cases with predominant parkinsonism-dementia are more severely affected than amyotrophic lateral sclerosis cases. These data suggest that the regional and cellular pathology of Guamanian cases differs radically from that commonly observed in neurodegenerative diseases outside Guam and point to the existence of subgroups in the spectrum of clinical manifestations seen in Guamanian patients. [Copyright &y& Elsevier]

How much information can be encoded in synaptic connectivity patterns through formation and elimination of dendritic spines? To answer this question, we perform geometrical analysis and derive an expression for the number of potential synapses, i.e. the number of axons that pass within a spine length of a given dendrite. We evaluate this expression by using our measurements and existing anatomical data, and find that the ratio of actual to potential synapses is 0.26 in mouse neocortex, 0.18 in rat hippocampus, and 0.12–0.23 in macaque visual cortex. Consequently, mammalian synaptic connectivity patterns may encode up to 3–5 bits per synapse. [Copyright &y& Elsevier]

α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate excitatory neurotransmission in the central nervous system, and contain combinations of four subunits (GluR1-4). We developed a GluR3-specific monoclonal antibody and quantified the cellular distribution of GluR3 in rat hippocampus. GluR3 immunoreactivity was detected in all pyramidal neurons and most interneurons. In addition, we found a subset of parvalbumin (PV)-containing interneurons in the hippocampus and neocortex that was notable for its intense GluR3 immunoreactivity and lack of GluR2 immunoreactivity. Such an expression pattern of AMPA receptor subunits is likely to make these interneurons selectively vulnerable to excitotoxicity. [Copyright &y& Elsevier]

Changes in synaptic connectivity patterns through the formation and elimination of dendritic spines may contribute to structural plasticity in the brain. We characterize this contribution quantitatively by estimating the number of different synaptic connectivity patterns attainable without major arbor remodeling. This number depends on the ratio of the synapses on a dendrite to the axons that pass within a spine length of that dendrite. We call this ratio the filling fraction and calculate it from geometrical analysis and anatomical data. The filling fraction is 0.26 in mouse neocortex, 0.22–0.34 in rat hippocampus. In the macaque visual cortex, the filling fraction increases by a factor of 1.6–1.8 from area V1 to areas V2, V4, and 7a. Since the filling fraction is much smaller than 1, spine remodeling can make a large contribution to structural plasticity. [Copyright &y& Elsevier]

A distinct subpopulation of neurons forming long corticocortical projections in the association neocortex is highly vulnerable to the degenerative process in Alzheimer’s disease. However, the degree to which age-related molecular and morphologic alterations of identifiable neuronal populations reflects early cellular degeneration leading to functional deficits has not yet been fully investigated in the aging brain. We performed an immunohistochemical analysis of neurons forming short and long corticocortical projections in young and old monkeys using antibodies to the GluR2 and NMDAR1 glutamate receptor subunit proteins. Projection neurons differed in their expression of these receptor subunits, as GluR2 was less prevalent than NMDAR1 among retrogradely labeled neurons. Long and short corticocortical pathways in old animals demonstrated a considerable decrease in the proportions of projection neurons containing GluR2 and NMDAR1, an observation that was particularly consistent in the case of GluR2. No age-related differences were observed in distribution of neurofilament protein in either type of projection neurons. These data suggest that cortical neurons furnishing long and short corticocortical projections display consistent neurochemical changes during aging and that a differential decrease in cellular expression of glutamate receptor subunit proteins occurs. The fact that in aging these neurons have lower levels of GluR2 than in young individuals, but comparatively higher levels of NMDAR1 than GluR2, may render them prone to calcium-mediated excitotoxicity, which in humans may be related to the selective vulnerability of such neurons during the course of Alzheimer’s disease. Also, it is apparent that age-related neuronal changes are quite subtle and involve subcellular components of the cortical circuits rather than major morphologic alterations. [Copyright &y& Elsevier]

Most of the available data on the cytoarchitecture of the cerebral cortex in mammals rely on Nissl, Golgi, and myelin stains and few studies have explored the differential morphologic and neurochemical phenotypes of neuronal populations. In addition, the majority of studies addressing the distribution and morphology of identified neuronal subtypes have been performed in common laboratory animals such as the rat, mouse, cat, and macaque monkey, as well as in postmortem analyses in humans. Several neuronal markers, such as neurotransmitters or structural proteins, display a restricted cellular distribution in the mammalian brain, and recently, certain cytoskeletal proteins and calcium-binding proteins have emerged as reliable markers for morphologically distinct subpopulations of neurons in a large number of mammalian species. In this article, we review the morphologic characteristics and distribution of three calcium-binding proteins, parvalbumin, calbindin, and calretinin, and of the neurofilament protein triplet, a component of the neuronal cytoskeleton, to provide an overview of the presence and cellular typology of these proteins in the neocortex of various mammalian taxa. Considering the remarkable diversity in gross morphological patterns and neuronal organization that occurred during the evolution of mammalian neocortex, the distribution of these neurochemical markers may help define taxon-specific patterns. In turn, such patterns can be used as reliable phylogenetic traits to assess the degree to which neurochemical specialization of neurons, as well as their regional and laminar distribution in the neocortex, represent derived or ancestral features, and differ in certain taxa from the laboratory species that are most commonly studied.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Investigating evolutionary changes in frontal cortex microstructure is crucial to understanding how modifications of neuron and axon distributions contribute to phylogenetic variation in cognition. In the present study, we characterized microstructural components of dorsolateral prefrontal cortex, orbitofrontal cortex, and primary motor cortex from 14 primate species using measurements of neuropil fraction and immunohistochemical markers for fast-spiking inhibitory interneurons, large pyramidal projection neuron subtypes, serotonergic innervation, and dopaminergic innervation. Results revealed that the rate of evolutionary change was similar across these microstructural variables, except for neuropil fraction, which evolves more slowly and displays the strongest correlation with brain size. We also found that neuropil fraction in orbitofrontal cortex layers V–VI was associated with cross-species variation in performance on experimental tasks that measure self-control. These findings provide insight into the evolutionary reorganization of the primate frontal cortex in relation to brain size scaling and its association with cognitive processes. [ABSTRACT FROM AUTHOR]

Presents results of a study which investigated the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss. Traits of neurodegenerative disorders; Functional decline in normal aging; Neuron death in normal aging; Age-related changes in hippocampal circuits; Neurobiological substrates for functional impairment in aging; Human entorhinal cortex; Neurofilament protein; Neuronal viability; Role of estrogen.

In this novel large-scale multiplexed immunofluorescence study we comprehensively characterized and compared layer-specific proteomic features within regions of interest of the widely divergent dorsolateral prefrontal cortex (A46) and primary visual cortex (A17) of adult rhesus monkeys. Twenty-eight markers were imaged in rounds of sequential staining, and their spatial distribution precisely quantified within gray matter layers and superficial white matter. Cells were classified as neurons, astrocytes, oligodendrocytes, microglia, or endothelial cells. The distribution of fibers and blood vessels were assessed by quantification of staining intensity across regions of interest. This method revealed multivariate similarities and differences between layers and areas. Protein expression in neurons was the strongest determinant of both laminar and regional differences, whereas protein expression in glia was more important for intra-areal laminar distinctions. Among specific results, we observed a lower glia-to-neuron ratio in A17 than in A46 and the pan-neuronal markers HuD and NeuN were differentially distributed in both brain areas with a lower intensity of NeuN in layers 4 and 5 of A17 compared to A46 and other A17 layers. Astrocytes and oligodendrocytes exhibited distinct marker-specific laminar distributions that differed between regions; notably, there was a high proportion of ALDH1L1-expressing astrocytes and of oligodendrocyte markers in layer 4 of A17. The many nuanced differences in protein expression between layers and regions observed here highlight the need for direct assessment of proteins, in addition to RNA expression, and set the stage for future protein-focused studies of these and other brain regions in normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Although the mammalian cerebral cortex is most often described as a hexalaminar structure, there are cortical areas (primary motor cortex) and species (elephants, cetaceans, and hippopotami), where a cytoarchitecturally indistinct, or absent, layer 4 is noted. Thalamocortical projections from the core, or first order, thalamic system terminate primarily in layers 4/inner 3. We explored the termination sites of core thalamocortical projections in cortical areas and in species where there is no cytoarchitecturally distinct layer 4 using the immunolocalization of vesicular glutamate transporter 2, a known marker of core thalamocortical axon terminals, in 31 mammal species spanning the eutherian radiation. Several variations from the canonical cortical column outline of layer 4 and core thalamocortical inputs were noted. In shrews/microchiropterans, layer 4 was present, but many core thalamocortical projections terminated in layer 1 in addition to layers 4 and inner 3. In primate primary visual cortex, the sublaminated layer 4 was associated with a specialized core thalamocortical projection pattern. In primate primary motor cortex, no cytoarchitecturally distinct layer 4 was evident and the core thalamocortical projections terminated throughout layer 3. In the African elephant, cetaceans, and river hippopotamus, no cytoarchitecturally distinct layer 4 was observed and core thalamocortical projections terminated primarily in inner layer 3 and less densely in outer layer 3. These findings are contextualized in terms of cortical processing, perception, and the evolutionary trajectory leading to an indistinct or absent cortical layer 4. [ABSTRACT FROM AUTHOR]

Background: The primary histological characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which are large aggregates of tau protein. Aging is the primary risk factor for the development of Alzheimer's disease, however, the underlying causes of tau protein aggregation and toxicity are unclear. Aims: Here we investigated tau aggregation and toxicity under the conditions of compromised protein homeostasis. Methods: We used heterologous expression of human tau protein in the unicellular eukaryote yeast Saccharomyces cerevisiae with evolutionarily conserved protein quality control pathways and examined tau‐dependent toxicity and aggregation using growth assays, fluorescence microscopy, and a split luciferase‐based reporter NanoBiT. Results: Tau protein expressed in yeast under mild proteotoxic stress, or in mutants with impaired pathways for proteotoxic stress response, did not lead to synthetic toxicity or the formation of obvious aggregates. Chronologically old cells also did not develop observable tau aggregates. Our examination of tau oligomerization in living cells using NanoBiT reporter suggests that tau does not form significant levels of oligomers under basal conditions or under mild proteotoxic stress. Conclusion: Together our data suggest that human tau protein does not represent a major burden to the protein quality control system in yeast cells. When expressed in yeast Saccharomyces cerevisiae cell model under the conditions of compromised protein homeostasis, human tau protein does not form visible aggregates or result in toxicity. [ABSTRACT FROM AUTHOR]

The evolutionary history of canids and felids is marked by a deep time separation that has uniquely shaped their behavior and phenotype toward refined predatory abilities. The caudate nucleus is a subcortical brain structure associated with both motor control and cognitive, emotional, and executive functions. We used a combination of three‐dimensional imaging, allometric scaling, and structural analyses to compare the size and shape characteristics of the caudate nucleus. The sample consisted of MRI scan data obtained from six canid species (Canis lupus lupus, Canis latrans, Chrysocyon brachyurus, Lycaon pictus, Vulpes vulpes, Vulpes zerda), two canid subspecies (Canis lupus familiaris, Canis lupus dingo), as well as three felids (Panthera tigris, Panthera uncia, Felis silvestris catus). Results revealed marked conservation in the scaling and shape attributes of the caudate nucleus across species, with only slight deviations. We hypothesize that observed differences in caudate nucleus size and structure for the domestic canids are reflective of enhanced cognitive and emotional pathways that possibly emerged during domestication. [ABSTRACT FROM AUTHOR]

Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution. Author summary: Humans are distinguished from other species by several aspects of cognition. While much comparative evolutionary neuroscience has focused on the neocortex, increasing recognition of the cerebellum's role in cognition and motor processing has inspired considerable new research. Comparative molecular studies, however, generally continue to focus on the neocortex. We sought to characterize potential genetic regulatory traits distinguishing the human cerebellum by undertaking genome-wide epigenetic profiling of the lateral cerebellum, and compared this to the prefrontal cortex of humans, chimpanzees, and rhesus macaque monkeys. We found that humans showed greater differential CpG methylation–an epigenetic modification of DNA that can reflect past or present gene expression–in the cerebellum than the prefrontal cortex, highlighting the importance of this structure in human brain evolution. Humans also specifically show methylation differences at genes involved in neurodevelopment, neuroinflammation, synaptic plasticity, and lipid metabolism. These differences are relevant for understanding processes specific to humans, such as extensive plasticity, as well as pronounced and prevalent neurodegenerative conditions associated with aging. [ABSTRACT FROM AUTHOR]