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1.  Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities 
Aims
The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data however are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development.
Methods
We investigated the dorsal anterior cingulate cortex (dACC) in 13 males with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neuron and glial numbers, and glia/neuron (GNI) ratios in both layers II-III and V-VI.
Results
We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neuron numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development.
Conclusions
Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post-mortem histopathological studies and in vivo brain imaging findings in patients.
doi:10.1111/j.1365-2990.2012.01296.x
PMCID: PMC3508088  PMID: 22860626
dysmyelination; oligodendrocytes; white matter; morphology; cytoarchitecture; myelin
2.  Early failure of the default mode network and the pathogenesis of Alzheimer's disease 
CNS neuroscience & therapeutics  2014;20(7):692-698.
The default mode network (DMN) is a major resting-state network that supports most of the baseline brain activity. Recent studies revealed that DMN cortical hub regions, including the medial prefrontal cortex, parietal cortex, posterior cingulum, and precuneus are all affected early during Alzheimer’s disease (AD) and exhibit high amounts of Aβ deposits. The cells generating Aβ are chiefly cortical and some brainstem projection neurons. Because processing of the amyloid precursor protein is activity-dependent, it can be speculated that due to their constant activity, DMN neurons produce and release more Aβ than occurs elsewhere in the neocortex, thus leading to an increase in production, oligomerization and aggregation of Aβ as well as tau hyperphosphorylation, which presumably is caused by the released Aβ oligomers. DMN cortical regions are richly innervated by long projection fibers from the noradrenergic locus coeruleus (LC), the serotonergic dorsal raphe nucleus (DRN), as well as the cholinergic basal forebrain (nucleus basalis complex, NB), which all may release high amounts of Aβ in the vicinity of glutamatergic projection neurons in the DMN cortical regions that are vulnerable to tau pathology and neurofibrillary degeneration. Recent findings provide converging evidence that the amyloid accumulation and DMN functional alterations are closely linked with the changes of sleep-wake cycle (particularly in regard of lesser amount of short-wave deep sleep when metabolic demands are about 50% lower in comparison with awake state and when presumably less amyloid is produced) and pre-tangle changes of LC, thus opening new promising area for future research.
doi:10.1111/cns.12260
PMCID: PMC4062585  PMID: 24712393
Alzheimer's disease; amyloid beta; default mode network; energy metabolism; pathogenesis; tau protein
3.  Early Fear Memory Defects Are Associated with Altered Synaptic Plasticity and Molecular Architecture in the TgCRND8 Alzheimer's Disease Mouse Model 
The Journal of comparative neurology  2014;522(10):2319-2335.
Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here, we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wild-type littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss.
doi:10.1002/cne.23536
PMCID: PMC4251468  PMID: 24415002
Amyloid beta; mouse model of dementia; neuronal morphology; dendritic pathology; spine pathology
4.  Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice 
Molecular Autism  2015;6:41.
Background
The genetics of autism spectrum disorder (hereafter referred to as “autism”) are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. Previous electrophysiological studies in mice with Shank3 mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse.
Methods
To understand how variants in SHANK3 would lead to such impairments and manifest in the brain of patients with autism, we assessed the presence of synaptic pathology in Shank3-deficient mice at 5 weeks and 3 months of age, focusing on the stratum radiatum of the CA1 field. This study analyzed both Shank3 heterozygous and homozygous mice using an electron microscopy approach to determine whether there is a morphological correlate to the synaptic functional impairment.
Results
As both synaptic strength and plasticity are affected in Shank3-deficient mice, we hypothesized that there would be a reduction in synapse density, postsynaptic density length, and perforated synapse density. No differences were found in most parameters assessed. However, Shank3 heterozygotes had significantly higher numbers of perforated synapses at 5 weeks compared to 3 months of age and significantly higher numbers of perforated synapses compared to 5-week-old wildtype and Shank3 homozygous mice.
Conclusions
Although this finding represents preliminary evidence for ultrastructural alterations, it suggests that while major structural changes seem to be compensated for in Shank3-deficient mice, more subtle morphological alterations, affecting synaptic structure, may take place in an age-dependent manner.
doi:10.1186/s13229-015-0036-x
PMCID: PMC4486760  PMID: 26137200
Autism; Shank3; Electron microscopy; CA1; Hippocampus; Stratum radiatum; Synapse
5.  Functional Neural Correlates of Attentional Deficits in Amnestic Mild Cognitive Impairment 
PLoS ONE  2013;8(1):e54035.
Although amnestic mild cognitive impairment (aMCI; often considered a prodromal phase of Alzheimer’s disease, AD) is most recognized by its implications for decline in memory function, research suggests that deficits in attention are present early in aMCI and may be predictive of progression to AD. The present study used functional magnetic resonance imaging to examine differences in the brain during the attention network test between 8 individuals with aMCI and 8 neurologically healthy, demographically matched controls. While there were no significant behavioral differences between groups for the alerting and orienting functions, patients with aMCI showed more activity in neural regions typically associated with the networks subserving these functions (e.g., temporoparietal junction and posterior parietal regions, respectively). More importantly, there were both behavioral (i.e., greater conflict effect) and corresponding neural deficits in executive control (e.g., less activation in the prefrontal and anterior cingulate cortices). Although based on a small number of patients, our findings suggest that deficits of attention, especially the executive control of attention, may significantly contribute to the behavioral and cognitive deficits of aMCI.
doi:10.1371/journal.pone.0054035
PMCID: PMC3543395  PMID: 23326568
6.  Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation 
Alzheimer's disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.
doi:10.1155/2015/346783
PMCID: PMC4458271  PMID: 26090071
7.  SYNAPTOSOMAL LACTATE DEHYDROGENASE ISOENZYME COMPOSITION IS SHIFTED TOWARD AEROBIC FORMS IN PRIMATE BRAIN EVOLUTION 
Brain, behavior and evolution  2014;83:216-230.
With the evolution of a relatively large brain size in haplorhine primates (i.e., tarsiers, monkeys, apes and humans), there have been associated changes in the molecular machinery that delivers energy to the neocortex. Here we investigated variation in lactate dehydrogenase (LDH) expression and isoenzyme composition of the neocortex and striatum in primates using quantitative Western blotting and isoenzyme analysis of total homogenates and synaptosomal fractions. Analysis of isoform expression revealed that LDH in the synaptosomal fraction from both forebrain regions shifted towards a predominance of the heart-type, aerobic isoforms, LDHB, among haplorhines as compared to strepsirrhines (i.e., lorises and lemurs), while in total homogenate of neocortex and striatum there was no significant difference in the LDH isoenzyme composition between the primate suborders. The largest increase occurred in synapse-associated LDH-B expression in the neocortex, displaying an especially remarkable elevation in the ratio of LDH-B to LDH-A in humans. The phylogenetic variation in LDH-B to LDH-A ratio was correlated with species typical brain mass, but not encephalization quotient. A significant LDHB increase in the sub-neuronal fraction from haplorhine neocortex and striatum suggests a relatively higher rate of aerobic glycolysis that is linked to synaptosomal mitochondrial metabolism. Our results indicate that there is differential composition of LDH isoenzymes and metabolism in synaptic terminals that evolved in primates to meet increased energy requirements in association with brain enlargement.
doi:10.1159/000358581
PMCID: PMC4096905  PMID: 24686273
lactate dehydrogenase; strepsirrhines; haplorhines; brain; metabolism; synaptosome
8.  Vascular and Inflammatory Factors in the Pathophysiology of Blast-Induced Brain Injury 
Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI.
doi:10.3389/fneur.2015.00048
PMCID: PMC4360816  PMID: 25852632
animal models; blast; inflammation; traumatic brain injury; vascular pathology
9.  Variable temporo-insular cortex neuroanatomy in primates suggests a bottleneck effect in eastern gorillas 
In this study, we describe an atypical neuroanatomical feature present in several primate species that involves a fusion between the temporal lobe (often including Heschl’s gyrus in great apes) and the posterior dorsal insula, such that a portion of insular cortex forms an isolated pocket medial to the Sylvian fissure. We assessed the frequency of this fusion in 56 primate species (including apes, Old World monkeys, New World monkeys, and strepsirrhines) using either magnetic resonance images or histological sections. A fusion between temporal cortex and posterior insula was present in 22 species (7 apes, 2 Old World monkeys, 4 New World monkeys, and 9 strepsirrhines). The temporo-insular fusion was observed in most eastern gorilla (Gorilla beringei beringei and G. b. graueri) specimens (62% and 100% of cases, respectively) but less frequently in other great apes and was never found in humans. We further explored the histology of this fusion in eastern gorillas by examining the cyto- and myeloarchitecture within this region, and observed that the degree to which deep cortical layers and white matter are incorporated into the fusion varies among individuals within a species. We suggest that fusion between temporal and insular cortex is an example of a relatively rare neuroanatomical feature that has become more common in eastern gorillas, possibly as the result of a population bottleneck effect. Characterizing the phylogenetic distribution of this morphology highlights a derived feature of these great apes.
doi:10.1002/cne.23448
PMCID: PMC4195240  PMID: 23939630
cerebral cortex; cortical fusion; auditory cortex; ape
10.  Neuronal nucleus and cytoplasm volume deficit in children with autism and volume increase in adolescents and adults 
Introduction
Characterization of the type and topography of structural changes and their alterations throughout the lifespan of individuals with autism is essential for understanding the mechanisms contributing to the autistic phenotype. The aim of this stereological study of neurons in 16 brain structures of 14 autistic and 14 control subjects from 4 to 64 years of age was to establish the course of neuronal nuclear and cytoplasmic volume changes throughout the lifespan of individuals with autism.
Results
Our data indicate that a deficit of neuronal soma volume in children with autism is associated with deficits in the volume of the neuronal nucleus and cytoplasm. The significant deficits of neuronal nuclear and cytoplasmic volumes in 13 of 16 examined subcortical structures, archicortex, cerebellum, and brainstem in 4- to 8-year-old autistic children suggest a global nature of brain developmental abnormalities, but with region-specific differences in the severity of neuronal pathology. The observed increase in nuclear volumes in 8 of 16 structures in the autistic teenagers/young adults and decrease in nuclear volumes in 14 of 16 regions in the age-matched control subjects reveal opposite trajectories throughout the lifespan. The deficit in neuronal nuclear volumes, ranging from 7% to 42% in the 16 examined regions in children with autism, and in neuronal cytoplasmic volumes from 1% to 31%, as well as the broader range of interindividual differences for the nuclear than the cytoplasmic volume deficits, suggest a partial distinction between nuclear and cytoplasmic pathology.
Conclusions
The most severe deficit of both neuronal nucleus and cytoplasm volume in 4-to 8-year-old autistic children appears to be a reflection of early developmental alterations that may have a major contribution to the autistic phenotype. The broad range of functions of the affected structures implies that their developmental and age-associated abnormalities contribute not only to the diagnostic features of autism but also to the broad spectrum of clinical alterations associated with autism. Lack of clinical improvement in autistic teenagers and adults indicates that the observed increase in neuron nucleus and cytoplasm volume close to control level does not normalize brain function.
doi:10.1186/s40478-015-0183-5
PMCID: PMC4302585  PMID: 25595448
Autism; Neuropathology; Neuron development; Nucleus volume; Cytoplasm volume
11.  Abnormal autonomic and associated brain activities during rest in autism spectrum disorder 
Brain  2014;137(1):153-171.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
doi:10.1093/brain/awt294
PMCID: PMC3891443  PMID: 24424916
autism; autonomic nervous system; emotion; skin conductance; resting state
12.  Developmental changes in the spatial organization of neurons in the neocortex of humans and common chimpanzees 
The Journal of comparative neurology  2013;521(18):4249-4259.
In adult humans, the prefrontal cortex possesses wider minicolumns and more neuropil space than other cortical regions. These aspects of prefrontal cortex architecture, furthermore, are increased in comparison to chimpanzees and other great apes. In order to determine the developmental appearance of this human cortical specialization, we examined the spatial organization of neurons in four cortical regions (frontal pole [Brodmann’s area 10], primary motor [area 4], primary somatosensory [area 3b], and prestriate visual cortex [area 18]) in chimpanzees and humans from birth to approximately the time of adolescence (11 years of age). Horizontal spacing distance (HSD) and gray level ratio (GLR) of layer III neurons were measured in Nissl-stained sections. In both human and chimpanzee area 10, HSD was significantly higher in the post-weaning specimens compared to the pre-weaning ones. No significant age-related differences were seen in the other regions in either species. In concert with other recent studies, the current findings suggest that there is a relatively slower maturation of area 10 in both humans and chimpanzees as compared to other cortical regions, and that further refinement of the spatial organization of neurons within this prefrontal area in humans takes place after the post-weaning periods included here.
doi:10.1002/cne.23412
PMCID: PMC4041080  PMID: 23839595
minicolumn; evolution; comparative neuroanatomy; biological anthropology
13.  An anatomically comprehensive atlas of the adult human brain transcriptome 
Nature  2012;489(7416):391-399.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
doi:10.1038/nature11405
PMCID: PMC4243026  PMID: 22996553
Neuroscience; Genetics; Genomics; Databases
14.  REPEATED STRESS ALTERS DENDRITIC SPINE MORPHOLOGY IN THE RAT MEDIAL PREFRONTAL CORTEX 
The Journal of comparative neurology  2008;507(1):1141-1150.
Anatomical alterations in the medial prefrontal cortex (mPFC) are associated with hypothalamo-pituitary adrenal (HPA) axis dysregulation, altered stress hormone levels, and psychiatric symptoms of stress-related mental illnesses. Functional imaging studies reveal impairment and shrinkage of the mPFC in such conditions, and these findings are paralleled by experimental studies showing dendritic retraction and spine loss following repeated stress in rodents. Here we extend this characterization to how repeated stress affects dendritic spine morphology in mPFC through the utilization of an automated approach which rapidly digitizes, reconstructs 3-dimensionally, and calculates geometric features of neurons. Rats were perfused after being subjected to 3 weeks of daily restraint stress (6 hours/day), and intracellular injections of Lucifer Yellow were made in layers II/III pyramidal neurons in the dorsal mPFC. To reveal spines in all angles of orientation, deconvolved high-resolution confocal laser scanning microscopy image stacks of dendritic segments were reconstructed and analyzed for spine volume, surface area, and length using a Rayburst-based automated approach (8,091 and 8,987 spines for control and stress, respectively). We found that repeated stress results in an overall decrease in mean dendritic spine volume and surface area, which was most pronounced in the distal portion of apical dendritic fields. Moreover, we observed an overall shift in the population of spines, manifested by a reduction in large spines and increase in small spines. These results suggest a failure of spines to mature and stabilize following repeated stress, and are likely to have major repercussions on function, receptor expression, and synaptic efficacy.
doi:10.1002/cne.21588
PMCID: PMC2796421  PMID: 18157834
dendritic spine; morphometry; plasticity; prefrontal cortex; stress
15.  Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease 
Neurobiology of aging  2007;29(9):1296-1307.
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer’s disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
doi:10.1016/j.neurobiolaging.2007.03.007
PMCID: PMC2569870  PMID: 17420070
Alzheimer’s disease; cognition; synapses; tangles
16.  Dendritic spine changes associated with normal aging 
Neuroscience  2012;251:21-32.
Given the rapid rate of population aging and the increased incidence of cognitive decline and neurodegenerative diseases with advanced age, it is important to ascertain the determinants that result in cognitive impairment. It is also important to note that some many of the aged population exhibit ‘successful’ cognitive aging, in which cognitive impairment is minimal. One main goal of normal aging studies is to distinguish the neural changes that occur in unsuccessful (functionally impaired) subjects from those of successful (functionally unimpaired) subjects. In this review, we present some of the structural adaptations that neurons and spines undergo throughout normal aging and discuss their likely contributions to electrophysiological properties and cognition. Structural changes of neurons and dendritic spines during aging, and the functional consequences of such changes, remain poorly understood. Elucidating the structural and functional synaptic age-related changes that lead to cognitive impairment may lead to the development of drug treatments that can restore or protect neural circuits and mediate cognition and successful aging.
doi:10.1016/j.neuroscience.2012.09.077
PMCID: PMC3654095  PMID: 23069756
17.  Anterior Insular Cortex and Emotional Awareness 
The Journal of comparative neurology  2013;521(15):3371-3388.
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.
doi:10.1002/cne.23368
PMCID: PMC3999437  PMID: 23749500
anterior insular cortex; emotional awareness; empathy; fMRI; meta-analysis; top-down; bottom-up; predictive coding
18.  Dendritic Morphology of Pyramidal Neurons in the Chimpanzee Neocortex: Regional Specializations and Comparison to Humans 
Cerebral Cortex (New York, NY)  2012;23(10):2429-2436.
The primate cerebral cortex is characterized by regional variation in the structure of pyramidal neurons, with more complex dendritic arbors and greater spine density observed in prefrontal compared with sensory and motor cortices. Although there are several investigations in humans and other primates, virtually nothing is known about regional variation in the morphology of pyramidal neurons in the cerebral cortex of great apes, humans' closest living relatives. The current study uses the rapid Golgi stain to quantify the dendritic structure of layer III pyramidal neurons in 4 areas of the chimpanzee cerebral cortex: Primary somatosensory (area 3b), primary motor (area 4), prestriate visual (area 18), and prefrontal (area 10) cortex. Consistent with previous studies in humans and macaque monkeys, pyramidal neurons in the prefrontal cortex of chimpanzees exhibit greater dendritic complexity than those in other cortical regions, suggesting that prefrontal cortical evolution in primates is characterized by increased potential for integrative connectivity. Compared with chimpanzees, the pyramidal neurons of humans had significantly longer and more branched dendritic arbors in all cortical regions.
doi:10.1093/cercor/bhs239
PMCID: PMC3767963  PMID: 22875862
area 10; dendrites; evolution; Golgi; primate cerebral cortex
19.  Linking White and Grey Matter in Schizophrenia: Oligodendrocyte and Neuron Pathology in the Prefrontal Cortex 
Neuronal circuitry relies to a large extent on the presence of functional myelin produced in the brain by oligodendrocytes. Schizophrenia has been proposed to arise partly from altered brain connectivity. Brain imaging and neuropathologic studies have revealed changes in white matter and reduction in myelin content in patients with schizophrenia. In particular, alterations in the directionality and alignment of axons have been documented in schizophrenia. Moreover, the expression levels of several myelin-related genes are decreased in postmortem brains obtained from patients with schizophrenia. These findings have led to the formulation of the oligodendrocyte/myelin dysfunction hypothesis of schizophrenia. In this review, we present a brief overview of the neuropathologic findings obtained on white matter and oligodendrocyte status observed in schizophrenia patients, and relate these changes to the processes of brain maturation and myelination. We also review recent data on oligodendrocyte/myelin genes, and present some recent mouse models of myelin deficiencies. The use of transgenic and mutant animal models offers a unique opportunity to analyze oligodendrocyte and neuronal changes that may have a clinical impact. Lastly, we present some recent morphological findings supporting possible causal involvement of white and grey matter abnormalities, in the aim of determining the morphologic characteristics of the circuits whose alteration leads to the cortical dysfunction that possibly underlies the pathogenesis of schizophrenia.
doi:10.3389/neuro.05.009.2009
PMCID: PMC2713751  PMID: 19636386
myelin; myelin-related genes; development; anterior cingulate cortex; cingulum bundle
20.  Pepsin Pretreatment Allows Collagen IV Immunostaining of Blood Vessels in Adult Mouse Brain 
Journal of neuroscience methods  2007;163(1):76-82.
While the brain vasculature can be imaged with many methods, immunohistochemistry has distinct advantages due to its simplicity and applicability to archival tissue. However, immunohistochemical staining of the murine brain vasculature in aldehyde fixed tissue has proven elusive and inconsistent using current protocols. Here we investigated whether antigen retrieval methods could improve vascular staining in the adult mouse brain. We found that pepsin digestion prior to immunostaining unmasked widespread collagen IV staining of the cerebrovasculature in the adult mouse brain. Pepsin treatment also unmasked widespread vascular staining with laminin, but only marginally improved isolectin B4 staining and did not enhance vascular staining with fibronectin, perlecan or CD146. Collagen IV immunoperoxidase staining was easily combined with cresyl violet counterstaining making it suitable for stereological analyses of both vascular and neuronal parameters in the same tissue section. This method should be widely applicable for labeling the brain vasculature of the mouse in aldehyde fixed tissue from both normal and pathological states.
doi:10.1016/j.jneumeth.2007.02.020
PMCID: PMC1931483  PMID: 17403541
adult; antigen retrieval; blood vessels; brain; collagen IV; immunohistochemistry; mouse; pepsin
21.  The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer’s disease 
Aims
Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid β protein (Aβ) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer’s disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a one-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva.
Materials and methods
Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal, and occipital cortex, using an antibody against Aβ, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established.
Results
CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters.
Conclusion
The present data show that CAA plays a role in the development of microvascular lesions in the aging brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contributes importantly to the pathogenesis of microvascular changes.
doi:10.1111/nan.12003
PMCID: PMC3637988  PMID: 23163235
amyloid angiopathy; cortical microinfarcts; Alzheimer’s disease; vascular; neuropathology; immunohistochemistry
22.  Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease 
Croatian Medical Journal  2014;55(4):347-365.
Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.
doi:10.3325/cmj.2014.55.347
PMCID: PMC4157375  PMID: 25165049
23.  Slc25a12 disruption alters myelination and neurofilaments: A model for a hypomyelination syndrome and childhood neurodevelopmental disorders 
Biological psychiatry  2009;67(9):887-894.
Background
SLC25A12, a susceptibility gene for autism spectrum disorders (ASDs) that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate/glutamate carrier (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and ATP production.
Methods
We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies.
Results
Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In P13-14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cellautonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetyl aspartate (NAA) and/or alterations in the NADH/NAD+ ratio, resulting in myelin defects.
Conclusions
Our data implicate AGC1 activity in myelination and in neuronal structure, and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development contributing to increased autism susceptibility.
doi:10.1016/j.biopsych.2009.08.042
PMCID: PMC4067545  PMID: 20015484
Malate/aspartate shuttle; mitochondria; N-acetyl aspartate (NAA); neuron-oligodendrocyte interactions; pyruvate
24.  Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury 
Background
Blast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy.
Results
We describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure.
Conclusions
These studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.
doi:10.1186/2051-5960-2-67
PMCID: PMC4229875  PMID: 24938728
Blast; Rat; Traumatic brain injury; Vascular pathology
25.  Exceptional Evolutionary Divergence of Human Muscle and Brain Metabolomes Parallels Human Cognitive and Physical Uniqueness 
PLoS Biology  2014;12(5):e1001871.
Accelerated evolution of the human brain and muscle metabolomes reflects our unique cognitive and physical capacities.
Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.
Author Summary
Physiological processes that maintain our tissues' functionality involve the generation of multiple products and intermediates known as metabolites—small molecules with a weight of less than 1,500 Daltons. Changes in concentrations of these metabolites are thought to be closely related to changes in phenotype. Here, we assessed concentrations of more than 10,000 metabolites in three brain regions and two non-neural tissues (skeletal muscle and kidney) of humans, chimpanzees, macaque monkeys, and mice using mass spectrometry-based approaches. We found that the evolution of the metabolome largely reflects genetic divergence between species and is not greatly affected by environmental factors. In the human lineage, however, we observed an exceptional acceleration of metabolome evolution in the prefrontal cortical region of the brain and in skeletal muscle. Based on additional behavioral tests, we further show that metabolic changes in human muscle seem to be paralleled by a drastic reduction in muscle strength. The observed rapid metabolic changes in brain and muscle, together with the unique human cognitive skills and low muscle performance, might reflect parallel mechanisms in human evolution.
doi:10.1371/journal.pbio.1001871
PMCID: PMC4035273  PMID: 24866127

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