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Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. ----- Objective: To test the association of essential metals with APOE genotype. ----- Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. ----- Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. ----- Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

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

The hippocampal formation is important for higher brain functions such as spatial navigation and the consolidation of memory, and it contributes to abilities thought to be uniquely human, yet little is known about how the human hippocampal formation compares to that of our closest living relatives, the chimpanzees. To gain insight into the comparative organization of the hippocampal formation in catarrhine primates, we quantified neurons stereologically in its major subdivisions - the granular layer of the dentate gyrus, CA4, CA2–3, CA1, and the subiculum – in archival brain tissue from six chimpanzees ranging from 29 to 43 years of age. We also sought evidence of Aβ deposition and hyperphosphorylated tau in the hippocampus and adjacent neocortex. A 42-year-old animal had moderate cerebral Aβ-amyloid angiopathy and tauopathy, but Aβ was absent and tauopathy was minimal in the others. Quantitatively, granule cells of the dentate gyrus were most numerous, followed by CA1, subiculum, CA4, and CA2–3. In the context of prior investigations of rhesus monkeys and humans, our findings indicate that, in the hippocampal formation as a whole, the proportions of neurons in CA1 and the subiculum progressively increase, and the proportion of dentate granule cells decreases, from rhesus monkeys to chimpanzees to humans. Because CA1 and the subiculum engender key hippocampal projection pathways to the neocortex, and because the neocortex varies in volume and anatomical organization among these species, these findings suggest that differences in the proportions of neurons in hippocampal subregions of catarrhine primates may be linked to neocortical evolution.

Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior., Frontal top-down cortical neurons implement top-down attentional control of sensory regions. The authors reveal adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are functionally integrated into local excitatory circuitry.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.

Information processing under conditions of uncertainty requires the involvement of cognitive control. Despite behavioral evidence of the supramodal function (i.e., independent of sensory modality) of cognitive control, the underlying neural mechanism needs to be directly tested. This study used functional magnetic imaging together with visual and auditory perceptual decision-making tasks to examine brain activation as a function of uncertainty in the two stimulus modalities. The results revealed a monotonic increase in activation in the cortical regions of the cognitive control network (CCN) as a function of uncertainty in the visual and auditory modalities. The intrinsic connectivity between the CCN and sensory regions was similar for the visual and auditory modalities. Furthermore, multivariate patterns of activation in the CCN predicted the level of uncertainty within and across stimulus modalities. These findings suggest that the CCN implements cognitive control by processing uncertainty as abstract information independent of stimulus modality.

Background: Neuroinflammation plays an important role in Alzheimer's disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β-1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896), and TNFα -308A/G (rs1800629) polymorphisms with AD. ----- Objective: We aimed to investigate whether people with certain IL-1α, IL-1β, IL-6, IL-10, and TNFα genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p-tau199), and Thr 231 (p-tau231), and visinin-like protein 1 (VILIP-1). ----- Methods: The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. ----- Results: A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G, and GG TNFα -308A/G genotype. ----- Conclusion: These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G), and TNFIα (-308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

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

Traumatic brain injury (TBI) is a leading cause of neurologic impairment and death that remains poorly understood. Rodent models have yet to produce clinical therapies, and the exploration of larger and more diverse models remains relatively scarce. We investigated the potential for brain injury after headbutting in two combative bovid species by assessing neuromorphology and neuropathology through immunohistochemistry and stereological quantification. Postmortem brains of muskoxen (Ovibos moschatus, n = 3) and bighorn sheep (Ovis canadensis, n = 4) were analyzed by high-resolution MRI and processed histologically for evidence of TBI. Exploratory histological protocols investigated potential abnormalities in neurons, microglia, and astrocytes in the prefrontal and parietal cortex. Phosphorylated tau protein, a TBI biomarker found in the cerebrospinal fluid and in neurodegenerative lesions, was used to detect possible cellular consequences of chronic or acute TBI. MRI revealed no abnormal neuropathological changes; however, high amounts of tau-immunoreactive neuritic thread clusters, neurites, and neurons were concentrated in the superficial layers of the neocortex, preferentially at the bottom of the sulci in the muskoxen and occasionally around blood vessels. Tau-immunoreactive lesions were rare in the bighorn sheep. Additionally, microglia and astrocytes showed no grouping around tau-immunoreactive cells in either species. Our preliminary findings indicate that muskoxen and possibly other headbutting bovids suffer from chronic or acute brain trauma and that the males' thicker skulls may protect them to a certain extent.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations., An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

Significance The cerebral cortex of the human brain is a highly complex, heterogeneous tissue that contains many cell types that are exquisitely regulated at the level of gene expression by noncoding regulatory elements, presumably in a cell-type–dependent manner. However, assessing the regulatory elements in individual cell types is technically challenging, and therefore most of the previous studies on gene regulation were performed with bulk brain tissue. Here we analyze two major types of neurons isolated from the cerebral cortex of humans, chimpanzees, and rhesus macaques, and report complex patterns of cell-type–specific evolution of the regulatory elements in numerous genes. Many genes with evolving regulation are implicated in language abilities as well as psychiatric disorders., The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type–specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype–specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergoes subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type–dependent gene-expression programs, and provides a resource for further exploration of human brain evolution and function.

In recent years, new human magnetic resonance imaging systems operating at static magnetic fields strengths of 7 Tesla or higher have become available, providing better signal sensitivity compared with lower field strengths. However, imaging human-sized objects at such high field strength and associated precession frequencies is limited due to the technical challenges associated with the wavelength effect, which substantially disturb the transmit field uniformity over the human body when conventional coils are used. Here we report a novel passive inductively-coupled radiofrequency resonator array design with a simple structure that works in conjunction with conventional coils and requires only to be tuned to the scanner’s operating frequency. We show that inductive-coupling between the resonator array and the coil improves the transmit efficiency and signal sensitivity in the targeted region. The simple structure, flexibility, and cost-efficiency make the proposed array design an attractive approach for altering the transmit field distribution specially at high field systems, where the wavelength is comparable with the tissue size.

Background: Mutations and deletions in the SHANK3 synaptic gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS). The SHANK3 gene encodes a key structural component of excitatory synapses that is important for synaptogenesis. PMS is characterized by intellectual disability, autism spectrum disorder, cognitive deficits, physical dysmorphic features, sensory hyporeactivity, and alterations in the size of multiple brain regions. Clinical assessments and limited imaging studies have revealed a reduction in volume of multiple brain regions. They have also found white matter thinning and microstructural alterations to be persistent in patients with PMS. While many of these impairments have been replicated in mouse models of PMS, the brain structure of a rat model has not yet been studied. Methods: We assessed the brain structure of haploinsufficient and homozygous Shank3-deficient rats that model the behavioral deficits of PMS with magnetic resonance and diffusion tensor imaging, and compared their brain structure to wild type littermates.Results: Both gray and white matter structures were smaller in Shank3-deficient rats, leading to an overall reduction in brain size compared to wild type littermates. The largest region to be diminished in size was the neocortex. Some regions involved in sensory processing and white matter regions were also reduced in size. Lastly, the microstructure of two white matter tracts, the external capsule and fornix, was abnormal.Conclusions: Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in individuals with PMS. Therefore, the brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.

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.

Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

BackgroundDeletion or mutations ofSHANK3lead to Phelan–McDermid syndrome and monogenic forms of autism spectrum disorder (ASD).SHANK3encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency ofShank3in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC).MethodsWe assessed dendrite and spine morphology and spine density in mPFC layer III neurons inShank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses.ResultsBasal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes inShank3-Het compared to WT andShank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses inShank3-Het rats, but notShank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger inShank3-Het rats compared toShank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy ofShank3and mimic the heterozygous loss ofSHANK3in Phelan–McDermid syndrome.LimitationsTheShank3deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in maleShank3-deficient rats.ConclusionsWe observed increased HD and PSD area inShank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan–McDermid syndrome.

Many military veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently have chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Besides static symptoms, new symptoms may emerge or existing symptoms may worsen. TBI is also a risk factor for later development of neurodegenerative diseases. In rats exposed to repetitive low-level blast overpressure (BOP), robust and enduring cognitive and PTSD-related behavioral traits develop that are present for at least one year after blast exposure. Here we determined the time-course of the appearance of these traits by testing rats in the immediate post-blast period. Three cohorts of rats examined within the first eight weeks exhibited no behavioral phenotype or, in one cohort, features of anxiety. None showed the altered cued fear responses or impaired novel object recognition characteristic of the fully developed phenotype. Two cohorts retested 36 to 42 weeks after blast exposure exhibited the expanded behavioral phenotype including anxiety as well as altered cued fear learning and impaired novel object recognition. Combined with previous work, the chronic behavioral phenotype has been observed in six cohorts of blast-exposed rats studied at 3–4 months or longer after blast injury, and the three cohorts studied here document the progressive nature of the cognitive/behavioral phenotype. These studies suggest the existence of a latent, delayed emerging and progressive blast-induced cognitive and behavioral phenotype. The delayed onset has implications for the evolution of post-blast neurobehavioral syndromes in military veterans and its modeling in experimental animals.

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (A β ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial A β plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed A β and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains ( n = 28, ages 12–62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue ‘Evolution of the primate ageing process’.

Synapses are involved in the communication of information from one neuron to another. However, a systematic analysis of synapse density in the neocortex from a diversity of species is lacking, limiting what can be understood about the evolution of this fundamental aspect of brain structure. To address this, we quantified synapse density in supragranular layers II–III and infragranular layers V–VI from primary visual cortex and inferior temporal cortex in a sample of 25 species of primates, including humans. We found that synapse densities were relatively constant across these levels of the cortical visual processing hierarchy and did not significantly differ with brain mass, varying by only 1.9-fold across species. We also found that neuron densities decreased in relation to brain enlargement. Consequently, these data show that the number of synapses per neuron significantly rises as a function of brain expansion in these neocortical areas of primates. Humans displayed the highest number of synapses per neuron, but these values were generally within expectations based on brain size. The metabolic and biophysical constraints that regulate uniformity of synapse density, therefore, likely underlie a key principle of neuronal connectivity scaling in primate neocortical evolution.

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

Purpose 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. Methods Hippocampal structural imaging and dMRI was acquired in 25 drug resistant MRI-negative patients and 25 healthy volunteers. The hippocampi of each subject was segmented on high-resolution structural images and dMRI-based probabilistic tractography was performed in each subfield. The degrees of connectivity and fiber densities of the hippocampal subfields were quantified and compared between epilepsy patients and healthy volunteers. Results We were able to perform subfield-specific hippocampal tractography in each subject that participated in this study. These methods identified some hippocampal subfields that are abnormally connected in MRI-negative patients. In particular patients suspected of left temporal seizure focus exhibited increased connectivity of certain ipsilateral subfields, especially the subiculum, presubiculum, and parasubiculum, and reduced connectivity of some contralateral subfields, such as CA1 and subiculum. Conclusions Our data suggest that the hippocampal subfields are connected in distinct ways in different types of epilepsy. These results may provide important information that could help inform seizure focus hypothesis and in the surgical treatment of MRI-negative patients. These observations suggest that high-resolution dMRI-based tractography of the hippocampal subfields can detect subtle abnormalities in otherwise normal-appearing MRI-negative patients.

Despite being closely related, bonobos and chimpanzees exhibit several behavioral differences. For instance, studies indicate that chimpanzees are more aggressive, territorial, and risk-taking, while bonobos exhibit greater social tolerance and higher rates of socio-sexual interactions. To elucidate the potential neuroanatomical variation that accompanies these differences, we examined the microstructure of selected brain areas by quantifying the neuropil fraction, a measure of the relative tissue area occupied by structural elements of connectivity (e.g., dendrites, axons, and synapses) versus cell bodies. In bonobos and chimpanzees, we compared neuropil fractions in the nucleus accumbens (NAc; core and shell), amygdala (whole, accessory basal, basal, central and lateral nuclei), anterior cingulate cortex (ACC; dorsal and subgenual), anterior insular cortex (AIC), and primary motor cortex (M1). In the dorsal ACC and frontoinsular cortex (FI) we also quantified numbers of von Economo neurons (VENs), a unique subset of neurons thought to be involved in rapid information processing during social interactions. We predicted that the neuropil fraction and number of VENs in brain regions associated with socio-emotional processing would be higher in bonobos. In support of this hypothesis, we found that bonobos had significantly greater neuropil in the central and accessory basal nuclei of the amygdala, as well as layers V–VI of the subgenual ACC. However, we did not find a difference in the numbers of VENs between the two species. These findings support the conclusion that bonobo and chimpanzee brains differ in the anatomical organization of socio-emotional systems that may reflect species-specific variation in behavior.

Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation that are disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence, a period when cannabis use in humans has been linked to subsequent vulnerability to psychiatric disorders such as addiction and schizophrenia. Here, we investigated in a rat model the effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), a psychoactive component of cannabis, on the morphological architecture and transcriptional profile of layer III pyramidal neurons—using cell type- and layer-specific high-resolution microscopy, laser capture microdissection and next-generation RNA-sequencing. The results confirmed known normal expansions in basal dendritic arborization and dendritic spine pruning during the transition from late adolescence to early adulthood that were accompanied by differential expression of gene networks associated with neurodevelopment in control animals. In contrast, THC exposure disrupted the normal developmental process by inducing premature pruning of dendritic spines and allostatic atrophy of dendritic arborization in early adulthood. Surprisingly, there was minimal overlap of the developmental transcriptomes between THC- and vehicle-exposed rats. THC altered functional gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization. Marked developmental network disturbances were evident for epigenetic regulators with enhanced co-expression of chromatin- and dendrite-related genes in THC-treated animals. Dysregulated PFC co-expression networks common to both the THC-treated animals and patients with schizophrenia were enriched for cytoskeletal and neurite development. Overall, adolescent THC exposure altered the morphological and transcriptional trajectory of PFC pyramidal neurons, which could enhance vulnerability to psychiatric disorders.

Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Aβ) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37–62 years) for evidence of Aβ and tau lesions in brain regions affected by AD in humans. Aβ was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Aβ deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Aβ plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain.

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.

Autism spectrum disorder (ASD) is marked by both socio-communicative difficulties and abnormalities in sensory processing. Much of the work on sensory deficits in ASD has focused on tactile sensations and the perceptual aspects of somatosensation, such as encoding of stimulus intensity and location. Although aberrant pain processing has often been noted in clinical observations of patients with ASD, it remains largely uninvestigated. Importantly, the neural mechanism underlying higher order cognitive aspects of pain processing such as pain anticipation also remains unknown. Here we examined both pain perception and anticipation in high-functioning adults with ASD and matched healthy controls (HC) using an anticipatory pain paradigm in combination with functional magnetic resonance imaging (fMRI) and concurrent skin conductance response (SCR) recording. Participants were asked to choose a level of electrical stimulation that would feel moderately painful to them. Compared to HC group, ASD group chose a lower level of stimulation prior to fMRI. However, ASD participants showed greater activation in both rostral and dorsal anterior cingulate cortex during the anticipation of stimulation, but not during stimulation delivery. There was no significant group difference in insular activation during either pain anticipation or perception. However, activity in the left anterior insula correlated with SCR during pain anticipation. Taken together, these results suggest that ASD is marked with aberrantly higher level of sensitivity to upcoming aversive stimuli, which may reflect abnormal attentional orientation to nociceptive signals and a failure in interoceptive inference.

The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine - hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181, p-tau199, and p-tau231), amyloid-42 (A42), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in A42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. A42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes., GHRH neurons in the arcuate nucleus are activated by glucose deprivation; however, repeated hypoglycemia blunts activation, remodels inputs, and disrupts mitochondrial fusion.

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.

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.

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

In Alzheimer's disease (AD), the brain's primary immune cells, microglia, become activated and are found in close apposition to amyloid beta (Aβ) protein plaques and neurofibrillary tangles (NFT). The present study evaluated microglia density and morphology in a large group of aged chimpanzees (n = 20, ages 37-62 years) with varying degrees of AD-like pathology. Using immunohistochemical and stereological techniques, we quantified the density of activated microglia and morphological variants (ramified, intermediate, and amoeboid) in postmortem chimpanzee brain samples from prefrontal cortex, middle temporal gyrus, and hippocampus, areas that show a high degree of AD pathology in humans. Microglia measurements were compared to pathological markers of AD in these cases. Activated microglia were consistently present across brain areas. In the hippocampus, CA3 displayed a higher density than CA1. Aβ42 plaque volume was positively correlated with higher microglial activation and with an intermediate morphology in the hippocampus. Aβ42-positive vessel volume was associated with increased hippocampal microglial activation. Activated microglia density and morphology were not associated with age, sex, pretangle density, NFT density, or tau neuritic cluster density. Aged chimpanzees displayed comparable patterns of activated microglia phenotypes as well as an association of increased microglial activation and morphological changes with Aβ deposition similar to AD patients. In contrast to human AD brains, activated microglia density was not significantly correlated with tau lesions. This evidence suggests that the chimpanzee brain may be relatively preserved during normal aging processes but not entirely protected from neurodegeneration as previously assumed.

INTRODUCTION: Alzheimer's disease (AD) is the world leading cause of dementia. Early detection of AD is essential for faster and more efficacious usage of therapeutics and preventive measures. Even though it is well known that one ε4 allele of apolipoprotein E gene increases the risk for sporadic AD five times, and that two ε4 alleles increase the risk 20 times, reliable genetic markers for AD are not yet available. Previous studies have shown that microtubule-associated protein tau (MAPT) gene polymorphisms could be associated with increased risk for AD. ----- METHODS: The present study included 113 AD patients and 53 patients with mild cognitive impairment (MCI), as well as nine healthy controls (HC) and 53 patients with other primary causes of dementia. The study assessed whether six MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, and rs7521) and MAPT haplotypes are associated with AD pathology, as measured by cerebrospinal fluid (CSF) AD biomarkers amyloid β1-42 (Aβ1-42 ), total tau (t-tau), tau phosphorylated at epitopes 181 (p-tau181 ), 199 (p-tau199 ), and 231 (p-tau231 ), and visinin-like protein 1 (VILIP-1). ----- RESULTS: Significant increases in t-tau and p-tau CSF levels were found in patients with AG and AA MAPT rs1467967 genotype, CC MAPT rs2471738 genotype and in patients with H1H2 or H2H2 MAPT haplotype. ----- CONCLUSIONS: These results indicate that MAPT haplotype-tagging polymorphisms and MAPT haplotypes should be further tested as potential genetic biomarkers of AD.

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.

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.

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.

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.

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.

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.

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

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.

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 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