The way the central nervous system (CNS) responds to diverse stimuli is contingent upon the specific brain state of the individual, including sleep and wakefulness. Despite the wealth of readout parameters and data delineating the brain states, the primary mechanisms are yet to be identified. Here we highlight the role of astrocytes, with a specific emphasis on chloride (Cl−) homeostasis as a modulator of brain states. Neuronal activity is regulated by the concentration of ions that determine excitability. Astrocytes, as the (...) CNS homeostatic cells, are recognised for their proficiency in maintaining dynamic homeostasis of ions, known as ionostasis. Nevertheless, the contribution of astrocyte‐driven ionostasis to the genesis of brain states or their response to sleep‐inducing pharmacological agents has been overlooked. Our objective is to underscore the significance of astrocytic Cl− homeostasis, elucidating how it may underlie the modulation of brain states. We endeavour to contribute to a comprehensive understanding of the interplay between astrocytes and brain states. (shrink)

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding (...) synaptic and extrasynaptic receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed. (shrink)

The identification of neural substrates underlying the long lasting debilitating impact of drug cues is critical for developing novel therapeutic tools. Metabolic coupling has long been considered a key mechanism through which astrocytes and neurons actively interact in response of neuronal activity, but recent findings suggested that disrupting metabolic coupling may represent an innovative approach to prevent memory formation, in particular drug‐related memories. Here, we review converging evidence illustrating how memory and addiction share neural circuitry and molecular mechanisms implicating lactate‐mediated (...) metabolic coupling between astrocytes and neurons. With several aspects of addiction depending on mnemonic processes elicited by drug experience, disrupting lactate transport involved in the formation of a pathological learning, linking the incentive, and motivational effects of drugs with drug‐conditioned stimuli represent a promising approach to encourage abstinence. (shrink)

What is the biological basis for human cognition? Our understanding why human brains make us smarter than other animals is still in its infancy. In recent years, astrocytes have been shown to be indispensable for neuronal survival, growth, synapse formation, and synapse function. Now, in a new study from Maiken Nedergaard and Steven Goldman's groups (Han et al., 2013), human glia progenitor cells have been transplanted into mouse forebrains. These progenitors survived, migrated widely, and gave rise to astrocytes that displayed (...) the characteristics of human astrocytes in the rodent host brains. Strikingly, the mice with transplanted human cells displayed improved long term potentiation (LTP) and learning, suggesting the potential importance of human astrocytes in the unique cognitive abilities of human brains. This landmark paper is an important first step toward future investigations of whether and how human astrocytes play a role in distinguishing the cognitive abilities of humans from those of other animals. (shrink)

Brain function depends on the cooperation between highly specialized cells. Neurons generate electrical signals and glial cells provide structural and metabolic support. Here, I propose a new kind of job‐sharing between neurons and astrocytes. Recent studies on primary cultures of highly purified neurons from the rodent central nervous system (CNS) suggest that, during development, neurons reduce or even abandon cholesterol synthesis to save energy and import cholesterol from astrocytes via lipoproteins. The cholesterol shuttle may be restricted to compartments distant from (...) the soma including synapses and may be regulated by electrical activity. Testing these hypotheses will help to improve our still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration. BioEssays 25:72–78, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

For the epic journey of autumn migration, long-distance migratory birds use innate and learned information and follow strict schedules imposed by genetic and epigenetic mechanisms, the details of which remain largely unknown. In addition, bird migration requires integrated action of different multisensory systems for learning and memory, and the hippocampus appears to be the integration center for this task. In previous studies we found that contrasting long-distance migratory flights differentially affected the morphological complexity of two types of hippocampus astrocytes. Recently, (...) a significant association was found between the latitude of the reproductive site and the size of the ADCYAP1 allele in long distance migratory birds. We tested for correlations between astrocyte morphological complexity, migratory distances, and size of the ADCYAP1 allele in three long-distance migrant species of shorebird and one non-migrant. Significant differences among species were found in the number and morphological complexity of the astrocytes, as well as in the size of the microsatellites of the ADCYAP1 gene. We found significant associations between the size of the ADCYAP1 microsatellites, the migratory distances, and the degree of morphological complexity of the astrocytes. We suggest that associations between astrocyte number and morphological complexity, ADCYAP1 microsatellite size, and migratory behavior may be part of the adaptive response to the migratory process of shorebirds. (shrink)

The discovery of participation of astrocytes as active elements in glutamatergic tripartite synapses (composed by functional units of two neurons and one astrocyte) has led to the construction of models of cognitive functioning in the human brain, focusing on associative learning, sensory integration, conscious processing and memory formation/retrieval. We have modelled human cognitive functions by means of an ensemble of functional units (tripartite synapses) connected by gap junctions that link distributed astrocytes, allowing the formation of intra- and intercellular calcium (...) waves that putatively mediate large-scale cognitive information processing. The model contains a diagram of molecular mechanisms present in tripartite synapses and contributes to explain the physiological bases of cognitive functions. It can be potentially expanded to explain emotional functions and psychiatric phenomena. (shrink)

In the present paper we formulate the hypothesis that brain glycogen is a critical determinant in the modulation of carbohydrate supply at the cellular level. Specifically, we propose that mobilization of astrocytic glycogen after an increase in AMP levels during enhanced neuronal activity controls the concentration of glucose phosphates in astrocytes. This would result in modulation of glucose phosphorylation by hexokinase and upstream cell glucose uptake. This mechanism would favor glucose channeling to activated neurons, supplementing the already rich neuron‐astrocyte (...) metabolic and functional partnership with important implications for the energy compounds used to sustain neuronal activity. The hypothesis is based on recent modeling evidence suggesting that rapid glycogen breakdown can profoundly alter the short‐term kinetics of glucose delivery to neurons and astrocytes. It is also based on review of the literature relevant to glycogen metabolism during physiological brain activity, with an emphasis on the metabolic pathways identifying both the origin and the fate of this glucose reserve. (shrink)

Brain arteriovenous malformations (bAVMs) are abnormal vessels that are prone to rupture, causing life-threatening intracranial bleeding. The mechanism of bAVM formation is poorly understood. Nevertheless, animal studies revealed that gene mutation in endothelial cells (ECs) and angiogenic stimulation are necessary for bAVM initiation. Evidence collected through analyzing bAVM specimens of human and mouse models indicate that cells other than ECs also are involved in bAVM pathogenesis. Both human and mouse bAVMs vessels showed lower mural cell-coverage, suggesting a role of pericytes (...) and vascular smooth muscle cells (vSMCs) in bAVM pathogenesis. Perivascular astrocytes also are important in maintaining cerebral vascular function and take part in bAVM development. Furthermore, higher inflammatory cytokines in bAVM tissue and blood demonstrate the contribution of inflammatory cells in bAVM progression, and rupture. The goal of this paper is to provide our current understanding of the roles of different cellular loci in bAVM pathogenesis. (shrink)

De Sousa's comprehensive two-part review of a diversity of contemporary approaches to the study of consciousness is highly welcome. He makes us aware of a proliferation of theoretical and empirical approaches targeting a common theme, but diverging in many ways. He skilfully accomplishes a classification of kinds of approach, identification of the main representatives, their contributions, and respective limitations. However, he does not show how the desired integration could be accomplished. Besides summarising De Sousa's efficient analytical work, I make critical (...) comments and briefly report my contribution for the integration project. (shrink)

The sophisticated function of the central nervous system (CNS) is largely supported by proper interactions between neural cells and blood vessels. Accumulating evidence has demonstrated that neurons and glial cells support the formation of blood vessels, which in turn, act as migratory scaffolds for these cell types. Neural progenitors are also involved in the regulation of blood vessel formation. This mutual interaction between neural cells and blood vessels is elegantly controlled by several chemokines, growth factors, extracellular matrix, and adhesion molecules (...) such as integrins. Recent research has revealed that newly migrating cell types along blood vessels repel other preexisting migrating cell types, causing them to detach from the blood vessels. In this review, we discuss vascular formation and cell migration, particularly during development. Moreover, we discuss how the crosstalk between blood vessels and neurons and glial cells could be related to neurodevelopmental disorders. (shrink)

What are the functional units of the brain? If the function of the brain is to process information-carrying signals, then the functional units will be the senders and receivers of those signals. Neurons have been the default candidate, with action potentials as the signals. But there are alternatives: synapses fit the action potential picture more cleanly, and glial activities (e.g., in astrocytes) might also be characterized as signaling. Are synapses or nonneuronal cells better candidates to play the role of functional (...) units? Will informational signaling still be the best model for brain function if we move beyond the neuron doctrine? (shrink)

Neither the pathogenesis nor the aetiology of Down's syndrome (DS) are clearly understood. Numerous studies have examined whether clinical features of DS are a consequence of specific chromosome 21 segments being triplicated. There is no evidence, however, that individual loci are responsible, or that the oxidative damage in DS could be solely explained by a gene dosage effect. Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative stress (...) result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology. BioEssays 24:681–684, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

As a direct consequence of the sophisticated arrangement of its intrinsic neurons, the gastrointestinal tract is unique among peripheral organs, in its ability to mediate its own reflexes. Neurons of the enteric nervous system are intimately associated with enteric glial cells. These supporting cells do not resemble Schwann cells, the glial cell found in all other parts of the peripheral nervous system, but share many similarities with astrocytes of the central nervous system. Ablation of enteric glial cells in adult transgenic (...) mice has demonstrated that these cells are essential to maintain the integrity of the small intestine. Acute loss of enteric glial cells induces massive pathological changes with similarities to necrotizing enterocolitis (NEC) and early Crohn's disease. These human conditions share some mechanistic similarities. Identification of enteric glial cell dysfunction/loss as sufficient to induce necrotic/inflammatory bowel disease may be important to understand the pathogenesis of both NEC and Crohn's disease. BioEssays 24:130–140, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Central nervous system (CNS)Abbreviations: CNS=central nervous system; PNS=peripheral nervous system; MS=multiple sclerosis; MBP=myelin basic protein; MHC=major histocompatibility complex; EAE=experimental allergic encephalomyelitis; O‐2A=oligodendrocyte‐type 2 astrocyte; GC=galactocerebroside; GFAP=glial fibrillary acidic protein; FGF=fibroblast growth factor; IGF1=insulin‐like growth factor. regeneration is a subject of great interest, particularly in diseases causing a dramatic loss of neurons. However, some CNS diseases do not affect neurons but damage other cells, such as the myelin‐forming cells — called oligodendrocytes — which are also crucial to the harmonious function (...) of the nervous system. Diseases in which oligodendrocytes and myelin are attacked can cause devastating neurological dysfunction which is sometimes followed by recovery and myelin repair or remyelination. The question of the regeneration potential of oligodendrocytes in experimental and human demyelinating diseases such as multiple sclerosis has been debated for a long time. Present evidence suggests that oligodendrocyte precursor cells persist in the adult CNS and that oligodendrocyte regeneration can occur but may be limited by ongoing disease processes. Here we will briefly review recent advances which have broadened our understanding of the cellular and molecular events of CNS remyelination. (shrink)

Anamniote animals, such as fish and amphibians, are able to regenerate damaged CNS nerves following injury, but regeneration in the mammalian CNS tracts, such as the optic nerve, does not occur. However, severed adult mammalian retinal axons can regenerate into peripheral nerve segments grafted into the brain and this finding has emphasized the importance of the environment in explaining regenerative failure in the adult mammalian CNS. Following lesions, regenerating axons encounter the glial cells, oligodendrocytes and astro‐cytes, and their derivatives, respectively (...) myelin and the astrocytic scar. Experiments to investigate the influence of these components on axon growth in culture have revealed cell‐surface and extracellular matrix molecules that inhibit axon extension and growth cone motility. Structural and functional characterization of these ligands and their receptors is underway, and may solve the interesting neurobiological conundrum posed by the failure of mammalian CNS regeneration. Simultaneously, this might allow new possibilities for treatment of the severe clinical disabilities resulting from injury to the brain and spinal cord. (shrink)

The Journal of Mind and Behavior, Winter 2003, Volume 24, Number 1, Pages 91–118, ISSN 0271–0137 This paper focuses on a logical systems flow-down of a set of consciousness requirements, which together with biological quantification of human brain anatomy sets limits on the neurological network in the cerebrum in order to produce the mind. It employs data to validate inferences, or when data do not exist, proposes methods for acquiring valid evidence. Many of these systems requirements will be imposed after (...) some fundamental assumptions are made. These assumptions are not new to theories on consciousness. However, their application as fundamentals may actually represent a new approach. Concurrent with these fundamentals, explicit periods of awareness while conscious are employed. Justification for their use is found in a theoretical process described as cerebral fusion. Additionally, storage of memory elements is postulated within local glia sites, proximal to synaptic nodes, and conductive transport through the astrocytes responsible for recall of data. The model permits variations in neural–glial interface physics and allows forecasts of mind/brain dysfunctions to be inferred. One key result from the model is hypothesized and expanded upon, and may have impact in certain types of dementia, such as Alzheimer’s disease. (shrink)

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain1, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development (4). These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few scientists (...) readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works.Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology(5); it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span(6, 7). Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth(8). There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes(9); but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial.Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in. (shrink)

Retroviral lineage tracing experiments suggest that the cortical ventricular zone is composed of a mixture of precursor cell types. The majority generate a single cell type (neurones, astrocytes or oligodendrocytes) and the remainder generate neurones and a single type of glial cell. Pluripotential precursor cells, that have the ability to generate all three cell types, are not observed. A recent paper, however, reports that when single ventricular zone cells are cultured in isolation, a small percentage of these cells are pluripotential(1). (...) This review will discuss what this knowledge tells us about cortical development. (shrink)

One major success of studying neural cell development in tissue culture has been the discovery of the O‐2A cell. This bipotential cell generates oligodendrocytes or, under certain conditions, a type of astrocyte. This essay considers the evidence that the characteristic properties demonstrated by the O‐2A cells in vitro are an accurate reflection of oligodendrocyte development in vivo.

content" – where big money is involved. The conflict could become a war to the death, and I think we will all be better off if we can find an alternative: a way to pay for premium content without sacrificing our digital freedoms. 26 December, 2006 by Philip Dorrell © 2006 Blog Index Some Previous Articles... Web 2.0? We Haven't Finished Decentralising Yet. Were the Neanderthals Ugly? Zero Divided By Zero: Application to Spherical Coordinates Adding Comments to My Blog The (...) Definition of "Automobile" Are Musical Items Intrinsically Musical? Music is Things that Happen and Things that Don't Happen Is There Musical Syntax Like Language Syntax? Musical Genomics and the Musical Astrocyte Theory How to Get Your Article Onto The Digg Front Page, Twice. (shrink)

Neuronal remodeling is a conserved mechanism that eliminates unwanted neurites and can include the loss of cell bodies. In these processes, a key role for glial cells in events from synaptic pruning to neuron elimination has been clearly identified in the last decades. Signals sent from dying neurons or neurites to be removed are received by appropriate glial cells. After receiving these signals, glial cells infiltrate degenerating sites and then, engulf and clear neuronal debris through phagocytic mechanisms. There are few (...) identified or proposed signals and receptors involved in neuron‐glia crosstalk, which induces the transformation of glial cells to phagocytes during neuronal remodeling in Drosophila. Many of these signaling pathways are conserved in mammals. Here, we particularly emphasize the role of Orion, a recently identified neuronal CX3C chemokine‐like secreted protein, which induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling. Although, chemokine signaling was not described previously in insects we propose that chemokine‐like involvement in neuron/glial cell interaction is an evolutionarily ancient mechanism. (shrink)

Standard semantic information processing models—information in; information processed; information out —lend themselves to standard models of the functioning of the brain in terms, e.g., of threshold-switch neurons connected via classical synapses. That is, in terms of sophisticated descendants of McCulloch and Pitts models. I argue that both the cognition and the brain sides of this framework are incorrect: cognition and thought are not constituted as forms of semantic information processing, and the brain does not function in terms of passive input (...) processing units organized as neural nets. An alternative framework is developed that models cognition and thought not in terms of semantic information processing, and, correspondingly, models brain functional processes also not in terms of semantic information processing. As alternative to such models: I outline a pragmatist oriented, interaction based, model of representation; derive from this model a fundamental framework of constraints on how the brain must function; show that such a framework is in fact found in the brain, and develop the outlines of a broader model of how mental processes can be realized within this alternative framework. Part I of this discussion focuses on some criticisms of standard modeling frameworks for representation and cognition, and outlines an alternative interactivist, pragmatist oriented, model. In part II, the focus is on the fact that the brain does not, in fact, function in accordance with standard passive input processing models—e.g., information processing models. Instead, there are multiple endogenously active processes at multiple spatial and temporal scales across multiple kinds of cells. A micro-functional model that accounts for, and even predicts, these multi-scale phenomena in generating emergent representation and cognition is outlined. That is, I argue that the interactivist model of representation outlined offers constraints on how the brain should function that are in fact empirically found, and, in reverse, that the multifarious details of brain functioning entail the pragmatist representational model—a very strong interrelationship. In the sequel paper, starting with part III, this model is extended to address macro-functioning in the CNS. In part IV, I offer a discussion of an approach to brain functioning that has some similarities with, as well as differences from, the model presented here: sometimes called the predictive brain approach. (shrink)