Astrocytes as brain interoceptors

Astrocytes form a vascular-neuronal interface and provide CNS neural networks with essential structural and metabolic support. They embrace all penetrating arterioles and capillaries, enwrap multiple neuronal somata, thousands of individual synapses, and upon activation release gliotransmitters (ATP, glutamate and D-serine) capable of modulating neuronal activity. The aim of this brief report is to review recent data implicating astrocytes in the brain mechanisms responsible for the detection of different sensory modalities and transmitting sensory information to the relevant neural networks controlling vital behaviours. The concept of astrocytes as brain interoceptors is strongly supported by our recent data obtained from studies of the central nervous mechanisms underlying the chemosensory control of breathing. At the level of the medulla oblongata, astrocytes indeed act as functional central respiratory chemoreceptors, sensing changes in the arterial blood and brain levels of /pH and then imparting these changes on the activity of the respiratory network to induce adaptive changes in lung ventilation.     

Comparative genetic approaches to the evolution of human brain and behavior

With advances in genomic technologies, the amount of genetic data available to scientists today is vast. Genomes are now available or planned for 14 different primate species and complete resequencing of numerous human individuals from numerous populations is underway. Moreover, high‐throughput deep sequencing is quickly making whole genome efforts within the reach of single laboratories allowing for unprecedented studies. Comparative genetic approaches to the identification of the underlying basis of human brain, behavior, and cognitive ability are moving to the forefront. Two approaches predominate: inter‐species divergence comparisons and intra‐species polymorphism studies. These methodological differences are useful for different time scales of evolution and necessarily focus on different evolutionary events in the history of primate and hominin evolution. Inter‐species divergence is more useful in studying large scale primate, or hominoid, evolution whereas intra‐species polymorphism can be more illuminating of recent hominin evolution. These differences in methodological utility also extend to studies of differing genetic substrates; current divergence studies focus primarily on protein evolution whereas polymorphism studies are substrate ambivalent. Some of the issues inherent in these studies can be ameliorated by current sequencing capabilities whereas others remain intractable. New avenues are also being opened that allow for the incorporation of novel substrates and approaches. In the post‐genomic era, the study of human evolution, specifically as it relates to the brain, is becoming more complete focusing increasingly on the totality of the system and better conceptualizing the entirety of the genetic changes that have lead to the human phenotype today. Am. J. Hum. Biol., 2011. © 2010 Wiley‐Liss, Inc.     

Astrocytes and microglia in human brain share an epitope recognized by a B-lymphocyte-specific monoclonal antibody (LN-1)

A B-lymphocyte-specific mouse monoclonal antibody, LN-1, recognizes two morphologic classes of glial cells in human brain. The nature and duration of tissue fixation and processing are critical in the detection of the two cell types. In tissue that is lightly fixed, LN-1 recognizes astrocytes. The astrocytic nature of the LN-1 reactive glial cell was confirmed by cytologic features, tissue distribution, immunoelectron microscopy, double labeling immunofluorescent microscopy, and staining of serial sections with antibodies to glial fibrillary acidic protein. In tissue that is fixed for longer periods or in Bouin's fixative, two glial cell types are recognized: astrocytes and microglia. The identity of the latter cell type as microglia was confirmed by morphologic features, tissue distribution, immunoelectron microscopy, and double staining with monoclonal antibodies or lectins to macrophage markers, including class II major histocompatibility antigens. The two cell types had different disposition in senile plaques of elderly individuals and of those with Alzheimer's disease. Astrocytes were present at the periphery of the plaques, whereas microglial cells were centrally placed, often in juxtaposition to amyloid. The results are discussed with respect to ontogeny of glial cells and the ability of monoclonal antibodies to recognize epitopes on unrelated proteins.     

Molecular evolution of microcephalin, a gene determining human brain size

Microcephalin gene is one of the major players in regulating human brain development. It was reported that truncated mutations in this gene can cause primary microcephaly in humans with a brain size comparable with that of early hominids. We studied the molecular evolution of microcephalin by sequencing the coding region of microcephalin gene in humans and 12 representative non-human primate species covering great apes, lesser apes, Old World monkeys and New World monkeys. Our results showed that microcephalin is highly polymorphic in human populations. We observed 22 substitutions in the coding region of microcephalin gene in human populations, with 15 of them causing amino acid changes. The neutrality tests and phylogenetic analysis indicated that the rich sequence variations of microcephalin in humans are likely caused by the combination of recent population expansion and Darwinian positive selection. The synonymous/non-synonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes. The codon-based neutrality test also indicated the signal of positive selection on five individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin.     

颅脑有限元模型演化规律及其生物力学研究进展

交通事故中头颈部损伤因其较高的致命性,已成为最严重的损伤类型。有限元模型在创伤性脑损伤生物力学机理研究中得到日益广泛应用。回顾头颈部有限元模型的生物力学研究历史和现状,并阐述车辆碰撞交通事故中人体颅脑典型交通伤演化规律和生物力学研究进展,探索头颈部损伤安全防护的方法,以期为车辆碰撞事故中人体颅脑损伤生物力学研究和相应的汽车安全防护装置研制提供理论依据。     

An integrative view of dynamic genomic elements influencing human brain evolution and individual neurodevelopment

An increasing number of reports of rearranged and aneuploid chromosomes in brain cells suggest an unexpected link between developmental chromosomal instability and brain genome diversity. Unstable chromosomal fragile sites (FS), endogenously or exogenously induced by replicative stressors, participate in genetic rearrangement and may be key features of epigenetically modified neuroplasticity. Certain common chromosomal FS are known to function as signals for RAG complex targets. Recombinase activation gene RAG-1 directed V(D)J recombination affecting specific recognition sequences allows the immune system to encode memories of a vast array of antigens. The finding that RAG-1 is transcribed in the central nervous system raised the consideration that immunoglobulin-like somatic DNA recombination could be involved in recognition and memory processes in brain development and function. Cognitive stress induced somatic hypermutation in neurons, similar to what happens after antigenic challenge in lymphocytes, could underly a massive increase in the synthesis of novel macromolecules to function as coded information bits which get selected for memory storage. This process may involve mobile element activation, which may also play a role in recombinational repair. As a source of tested, successful new open reading frames, somatic hypermutation may confer a selective advantage if somatically acquired information is fed back to germline V gene arrays and the human brain could have adopted a similar process to manage the information captured in rearranged sequences. In neuroevolution and individual brain development, germline information could thus represent a crucial component. The brain itself may, from an evolutionary genetic point of view, represent nothing more than a highly specialized and individually diversified information accrual and memory system to increase the overall phenotypically validated information content of the immortal germline. In the evolution of rapid evolvability, exceeding the narrow margins within which genetic instability is useful, would be expected to be associated with penalties in terms of neuropathology and malignancy risk. The utilisation of genetic instability to obtain diversification under stress is an ancient principle, but may have reached unprecedented levels in humans, which, in turn, fed back to creation of more unstable environments. Since increased genomic instability is likely to have been introduced to the genomes of other life forms by some of the extremely genotoxic environments created by H sapiens, a better understanding of the implications of borderline genomic instability may be an important priority to ensure long term biological survival, including that of our own species.     

Neanderthal, chimp and human genomes: hypotheses wanted for research into brain evolution

The recent sequencing of Neanderthal DNA and the release of drafts of human and chimp genomes in 2001 and 2005, respectively, provide an opportunity to better understand why our brain is different from those of extinct and living relatives. However, it is not clear that hypothesis-free analysis of genetic differences alone will shed light on the complex "big bang" evolution of human brains that is thought to have taken place about 100,000 years ago. Rather than pursuing black box genomics, we suggest that genetic analyses should be guided by hypotheses. One plausible candidate in this regard is the"fat-utilization" hypothesis proposed by the late David Horrobin.     

Astrocytes in sensory circumventricular organs of the rat brain express functional binding sites for endothelin

Sensory circumventricular organs bordering the anterior third cerebral ventricle, the subfornical organ and the organum vasculosum laminae terminalis, lack blood-brain barrier characteristics and are therefore accessible to circulating peptides like endothelins. Astrocytes of the rat subfornical organ and organum vasculosum laminae terminalis additionally showed immunocytochemical localization of endothelin-1/endothelin-3-like peptides, possibly acting as circumventricular organ-intrinsic modulators. Employing [125I]endothelin-1 as radioligand, quantitative autoradiography demonstrated specific binding sites throughout the rat organum vasculosum laminae terminalis and subfornical organ, and competitive displacement studies revealed expression of both ET(A) and ET(B) receptor subtypes for either circumventricular organ. ET(B) receptor binding prevailed for the whole brain and ET(A) receptors could be labelled in the peripheral vascular system. To characterize endothelin-specific receptors in astrocytes of both circumventricular organs, alterations in the intracellular calcium concentration due to endothelin-1/endothelin-3 stimulation were studied in primary culture of subfornical organ and organum vasculosum laminae terminalis cells obtained from early postnatal rat pups. Endothelin-1 and endothelin-3 induced Ca(2+) transients in 9-13% of either subfornical organ or organum vasculosum laminae terminalis astrocytes, respectively, and some glial cells (subfornical organ: 2%, organum vasculosum laminae terminalis: 5%) responded to both endothelin analogues. The antagonistic action of BQ123 specific for ET(A) receptors (74% of all astrocytes tested), and the pronounced responsiveness to the ET(B) receptor agonist [4Ala]ET-1 (subfornical organ: 27%, organum vasculosum laminae terminalis: 35%) demonstrated glial expression of both endothelin receptor subtypes. Agonist-induced elevations in the intracellular calcium concentration proved to be independent of extracellular Ca(2+).In summary, the results indicate that endothelin(s) interact(s) with circumventricular organ astrocytes. Competitive receptor binding techniques using brain tissue sections as well as a fura-2 loaded primary cell culture system of the subfornical organ and organum vasculosum laminae terminalis demonstrate glial expression of functional ET(A) and ET(B) receptors, with calcium as intracellular messenger emerging primarily from intracellular stores. Endothelin(s) of both circulating and circumventricular organ-intrinsic origin may afferently transfer information important for cardiovascular homeostasis to circumventricular organs serving as "windows to the brain".     

Grandmothers and the evolution of human longevity

Great apes, our closest living relatives, live longer and mature later than most other mammals and modern humans are even later‐maturing and potentially longer‐lived. Evolutionary life‐history theory seeks to explain cross‐species differences in these variables and the covariation between them. That provides the foundation for a hypothesis that a novel role for grandmothers underlies the shift from an ape‐like ancestral pattern to one more like our own in the first widely successful members of genus Homo. This hypothesis links four distinctive features of human life histories: 1) our potential longevity, 2) our late maturity, 3) our midlife menopause, and 4) our early weaning with next offspring produced before the previous infant can feed itself. I discuss the problem, then, using modern humans and chimpanzees to represent, respectively, genus Homo and australopithecines, I focus on two corollaries of this grandmother hypothesis: 1) that ancestral age‐specific fertility declines persisted in our genus, while 2) senescence in other aspects of physiological performance slowed down. The data are scanty but they illustrate similarities in age‐specific fertility decline and differences in somatic durability that are consistent with the hypothesis that increased longevity in our genus is a legacy of the “reproductive” role of ancestral grandmothers. Am. J. Hum. Biol. 15:380–400, 2003. © 2003 Wiley‐Liss, Inc.     

Astrocytes and human cognition: Modeling information integration and modulation of neuronal activity

Recent research focusing on the participation of astrocytes in glutamatergic tripartite synapses has revealed mechanisms that support cognitive functions common to human and other mammalian species, such as learning, perception, conscious integration, memory formation/retrieval and the control of voluntary behavior. Astrocytes can modulate neuronal activity by means of release of glutamate, d-serine, adenosine triphosphate and other signaling molecules, contributing to sustain, reinforce or depress pre- and post-synaptic membranes. We review molecular mechanisms present in tripartite synapses and model the cognitive role of astrocytes. Single protoplasmic astrocytes operate as a “Local Hub”, integrating information patterns from neuronal and glial populations. Two mechanisms, here modeled as the “domino” and “carousel” effects, contribute to the formation of intercellular calcium waves. As waves propagate through gap junctions and reach other types of astrocytes (interlaminar, polarized, fibrous and varicose projection), the active astroglial network functions as a “Master Hub” that integrates results of distributed processing from several brain areas and supports conscious states. Response of this network would define the effect exerted on neuronal plasticity (membrane potentiation or depression), behavior and psychosomatic processes. Theoretical results of our modeling can contribute to the development of new experimental research programs to test cognitive functions of astrocytes.     

Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain.

Amyloid beta-protein (Abeta) is the major component of senile plaques that emerge in the cortex during aging and appear most abundantly in Alzheimer's disease. In the course of our immunocytochemical study on a large number of autopsy cases, we noticed, in many aged nondemented cases, the presence of unique diffuse plaques in the cortex distinct from ordinary diffuse plaques by immunocytochemistry. The former were amorphous, very faintly Abeta-immunoreactive plaques resembling diffuse plaques, but they stained for Abeta40 and were associated with small cells containing Abeta-positive granules. A panel of amino- and carboxyl-terminal-specific Abeta antibodies showed that such Abeta40-positive diffuse plaques and cell-associated granules were composed exclusively of amino-terminally deleted Abeta terminating at Abeta40, -42, and -43. Double immunostaining also showed that those Abeta-immunoreactive granules are located in astrocytes and not in microglia or neurons. Immunoelectron microscopy revealed that nonfibrillar Abeta immunoreactivity was located within lipofuscin-like granules in somewhat swollen astrocytes. These findings raise the possibility that astrocytes take up Abeta and attempt to degrade it in lysosomes in the aged brain.     

Polygamy and the evolution of human longevity.

An alternative to previous explanations of the rapid increase in man's longevity and intelligence during the several million years of his recent evolution from pre-hominid, clearly shorter-lived and less intelligent, primate ancestors is presented. The general thesis is that a very greatly accelerated rate of incorporation of favorable genes or gene combinations can be achieved in surprisingly few generations among social animals provided that dominant males become the patriarchs of many descendents by virtue of their partial or complete monopoly on available females. The conclusion is that man probably differs from his ancesters of 0.5 to 5 million years ago by many thousands of genes (both structural and regulatory) rather than the dozens or few hundreds that have been postulated on the basis of more classical treatments of selection pressures, gene frequency changes and mutation rates. The concepts developed here formally apply only to two alternative alleles, rather than to groups of genes which segregate independently, or to characters determined by multiple alleles. The appropriate mathematical treatment of the latter real situation is not readily visualized; nor is account taken of the likelihood that different tribes of pre-humans developed different specializations via the above mechanisms which were then (later) combined into an emerging human stock through matings between members of different tribes. The very great variability both in longevity and in intelligence between different races of animals such as dogs, which have been the objects of deliberate genetic selection by humans for particular heritable traits, may parallel our own recent history, even though the selection mechanism (deliberate human selection vs. polygamous dominance) is quite different in the two cases. The onset of civilizations consisting of amalgums between smaller, previously competing tribes, together with the humanitarian responsibilities to each other we share as a species, ironically has probably arrested further evolution of human longevity (and perhaps of intelligence) in the modern world. Possibly even retrogressive changes are occurring, except in those rare sub-populations in which special social and cultural practices tend to favor selective perpetuation of characteristics which are usually viewed as beneficial.