Gravity sensing in the central nervous system

For human based space research it is of high importance to understand the influence of gravity on the properties of the central nervous system (CNS). Untill now it is not much known about how neuronal tissue can sense gravity. The aim of this study was to find out weather and how the CNS, as a complex system, can percept and react to changes in gravity. Neuronal tissue and especially the CNS fulfils all the requirements for excitable media. Consequently, self-organisation, pattern formation and propagating excitation waves as typical events of excitable media have been observed in such tissue. The Spreading Depression (SD), an excitation depression wave is the most obvious and best described of these phenomena in the CNS. In our experiments we showed that the properties of the SD and therefore the CNS in its properties as an excitable medium reacts very sensitive to changes in gravity.     

How does the brain control its own activity? A new function for the basal ganglia

It has long been a problem in neuroscience to known how the brain controls its own activity, how it is able to control the level of CNS excitability and how it is able to select and act on some information as opposed to some other information. In this paper I propose a new theory in which the basal ganglia play a role in selecting information ("selective attention") and in controlling the general level of excitability of the CNS ("state control"), the two processes being to some extent interdependent. The basal ganglia achieve these functions by actions on the thalamic-frontal cortical axis and on the brainstem mesencephalic reticular formation.     

The incredible elastic brain: how neural stem cells expand our minds

Brain development was thought to be largely hardwired and accomplished by birth, and the brain was thought to have essentially no regenerative capacity. The remarkable discovery of adult neurogenesis and neural stem cells (NSCs) existing in the mature CNS changed that, allowing us to think optimistically about CNS repair. These discoveries helped to generate a robust field of neural progenitor cell biology, with relevance to CNS development, pathogenesis, the search for novel neurological therapies, as well as our understanding of how the brain works.     

Role of uncertainty in sensorimotor control

Neural signals are corrupted by noise and this places limits on information processing. We review the processes involved in goal-directed movements and how neural noise and uncertainty determine aspects of our behaviour. First, noise in sensory signals limits perception. We show that, when localizing our hand, the central nervous system (CNS) integrates visual and proprioceptive information, each with different noise properties, in a way that minimizes the uncertainty in the overall estimate. Second, noise in motor commands leads to inaccurate movements. We review an optimal-control framework, known as 'task optimization in the presence of signal-dependent noise', which assumes that movements are planned so as to minimize the deleterious consequences of noise and thereby minimize inaccuracy. Third, during movement, sensory and motor signals have to be integrated to allow estimation of the body's state. Models are presented that show how these signals are optimally combined. Finally, we review how the CNS deals with noise at the neural and network levels. In all of these processes, the CNS carries out the tasks in such a way that the detrimental effects of noise are minimized. This shows that it is important to consider effects at the neural level in order to understand performance at the behavioural level.     

Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination

A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration.     

Isolation of mononuclear cells from the central nervous system of rats with EAE

Whether studying an autoimmune disease directed to the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE, 1), or the immune response to an infection of the CNS, such as poliomyelitis, Lyme neuroborreliosis, or neurosyphilis, it is often necessary to isolate the CNS-infiltrating immune cells.In this video-protocol we demonstrate how to isolate mononuclear cells (MNCs) from the CNS of a rat with EAE. The first step of this procedure requires a cardiac perfusion of the rodent with a saline solution to ensure that no blood remains in the blood vessels irrigating the CNS. Any blood contamination will artificially increase the number of apparent CNS-infiltrating MNCs and may alter the apparent composition of the immune infiltrate. We then demonstrate how to remove the brain and spinal cord of the rat for subsequent dilaceration to prepare a single-cell suspension. This suspension is separated on a two-layer Percoll gradient to isolate the MNCs. After washing, these cells are then ready to undergo any required procedure. Mononuclear cells isolated using this procedure are viable and can be used for electrophysiology, flow cytometry (FACS), or biochemistry. If the technique is performed under sterile conditions (using sterile instruments in a tissue culture hood) the cells can also be grown in tissue culture medium. A given cell population can be further purified using either magnetic separation procedures or a FACS.     

Motor learning through the combination of primitives

In this paper we discuss a new perspective on how the central nervous system (CNS) represents and solves some of the most fundamental computational problems of motor control. In particular, we consider the task of transforming a planned limb movement into an adequate set of motor commands. To carry out this task the CNS must solve a complex inverse dynamic problem. This problem involves the transformation from a desired motion to the forces that are needed to drive the limb. The inverse dynamic problem is a hard computational challenge because of the need to coordinate multiple limb segments and because of the continuous changes in the mechanical properties of the limbs and of the environment with which they come in contact. A number of studies of motor learning have provided support for the idea that the CNS creates, updates and exploits internal representations of limb dynamics in order to deal with the complexity of inverse dynamics. Here we discuss how such internal representations are likely to be built by combining the modular primitives in the spinal cord as well as other building blocks found in higher brain structures. Experimental studies on spinalized frogs and rats have led to the conclusion that the premotor circuits within the spinal cord are organized into a set of discrete modules. Each module, when activated, induces a specific force field and the simultaneous activation of multiple modules leads to the vectorial combination of the corresponding fields. We regard these force fields as computational primitives that are used by the CNS for generating a rich grammar of motor behaviours.     

Connecting cytokines and brain: a review of current issues

Cytokines have been a multi-disciplinary research focus for over 2 decades. To date, there have been more than 15,000 articles published concerning the relationship between cytokines and the central nervous system (CNS). Over half of these articles have been published in the last 5 years. From such vast number of studies, two major topics emerge as the critical issues: 1) how do cytokines modulate the functions of the CNS? 2) what is the role of cytokines in the pathogenesis of neurological diseases? Thus far, it has been clearly established that cytokines can alter the functions of the CNS in specific manners, invoking CNS-controlled autonomic, neuroendocrine, and behavioral responses. Induced expression of cytokines has also been found in the CNS during brain injury and infection, contributing to the immunological processes at this "immunologically privileged" site. Furthermore, increasing evidence points to the potential involvement of cytokines in the induction and modulation of an array of neurological diseases ranging from Alzheimer's disease to chronic fatigue syndrome. Despite such progress, however, substantial obstacles remain for both the basic understanding and the potential clinical exploitation of how cytokines interact with CNS. In this review, we will attempt to synopsize the current theories and evidence regarding the answers to the above-mentioned critical questions. These issues will be reviewed not only in isolation, as most of the original reports focused on only one of the questions, but also in parallel such that inter-issue insights may be gained.     

Glial epigenetics in neuroinflammation and neurodegeneration

Epigenetic regulation shapes the differentiation and response to stimuli of all tissues and cells beyond what genetics would dictate. Epigenetic regulation acts through covalent modifications of DNA and histones while leaving the nucleotide code intact. However, these chromatin modifications are known to be vital components of the regulation of cell fate and response. With regards to the central nervous system (CNS), little is known about how epigenetic regulation shapes the function of neural cell types. The focus of research so far has been on epigenetic regulation of neuronal function and the role of epigenetics in tumorigenesis. However, the glial cell compartment, which makes up 90 % of all CNS cells, has so far received scant attention as to how epigenetics shape their differentiation and function. Here, we highlight current knowledge about epigenetic changes in glial cells occurring during CNS injury, neuroinflammatory conditions and neurodegenerative disease. This review offers an overview of the current understanding of epigenetic regulation in glial cells in CNS disease.     

Dissecting planarian central nervous system regeneration by the expression of neural-specific genes

The planarian central nervous system (CNS) can be used as a model for studying neural regeneration in higher organisms. Despite its simple structure, recent studies have shown that the planarian CNS can be divided into several molecular and functional domains defined by the expression of different neural genes. Remarkably, a whole animal, including the molecularly complex CNS, can regenerate from a small piece of the planarian body. In this study, a collection of neural markers has been used to characterize at the molecular level how the planarian CNS is rebuilt. Planarian CNS is composed of an anterior brain and a pair of ventral nerve cords that are distinct and overlapping structures in the head region. During regeneration, 12 neural markers have been classified as early, mid-regeneration and late expression genes depending on when they are upregulated in the regenerative blastema. Interestingly, the results from this study show that the comparison of the expression patterns of different neural genes supports the view that at day one of regeneration, the new brain appears within the blastema, whereas the pre-existing ventral nerve cords remain in the old tissues. Three stages in planarian CNS regeneration are suggested.     

Evidence for differential and redundant function of the Sox genes Dichaete and SoxN during CNS development in Drosophila

Group B Sox-domain proteins encompass a class of conserved DNA-binding proteins expressed from the earliest stages of metazoan CNS development. In all higher organisms studied to date, related Group B Sox proteins are co-expressed in the developing CNS; in vertebrates there are three (Sox1, Sox2 and Sox3) and in Drosophila there are two (SoxNeuro and Dichaete). It has been suggested there may be a degree of functional redundancy in Sox function during CNS development. We describe the CNS phenotype of a null mutation in the Drosophila SoxNeuro gene and provide the first direct evidence for both redundant and differential Sox function during CNS development in DROSOPHILA: In the lateral neuroectoderm, where SoxNeuro is uniquely expressed, SoxNeuro mutants show a loss or reduction of achaete expression as well as a loss of many correctly specified lateral neuroblasts. By contrast, in the medial neuroectoderm, where the expression of SoxNeuro and Dichaete overlaps, the phenotypes of both single mutants are mild. In accordance with an at least partially redundant function in that region, SoxNeuro/Dichaete double mutant embryos show a severe neural hypoplasia throughout the central nervous system, as well as a dramatic loss of achaete expressing proneural clusters and medially derived neuroblasts. However, the finding that Dichaete and SoxN exhibit opposite effects on achaete expression within the intermediate neuroectoderm demonstrates that each protein also has region-specific unique functions during early CNS development in the Drosophila embryo.     

Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by ‘infecting’ neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS.     

The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1

Lipoprotein metabolism in the central nervous system (CNS) is based on high-density lipoprotein-like particles that use apoE as their predominant apolipoprotein rather than apoA-I. Although apoA-I is not expressed in astrocytes and microglia, which produce CNS apoE, apoA-I is reported to be expressed in porcine brain capillary endothelial cells and also crosses the blood-brain barrier (BBB). These mechanisms allow apoA-I to reach concentrations in cerebrospinal fluid (CSF) that are approximately 0.5% of its plasma levels. Recently, apoA-I has been shown to enhance cognitive function and reduce cerebrovascular amyloid deposition in Alzheimer's Disease (AD) mice, raising questions about the regulation and function of apoA-I in the CNS. Peripheral apoA-I metabolism is highly influenced by ABCA1, but less is known about how ABCA1 regulates CNS apoA-I. We report that ABCA1 deficiency leads to greater retention of apoA-I in the CNS than in the periphery. Additionally, treatment of symptomatic AD mice with GW3965, an LXR agonist that stimulates ABCA1 expression, increases apoA-I more dramatically in the CNS compared to the periphery. Furthermore, GW3965-mediated up-regulation of CNS apoA-I is independent of ABCA1. Our results suggest that apoA-I may be regulated by distinct mechanisms on either side of the BBB and that apoA-I may serve to integrate peripheral and CNS lipid metabolism. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).     

CNS regeneration: a morphogen's tale

Tissue regeneration will soon become an avenue for repair of damaged or diseased tissues as stem cell niches have been found in almost every organ of the vertebrate body including the CNS. In addition, different animals display an array of regenerative capabilities that are currently being researched to dissect the molecular mechanisms involved. This review concentrates on the different ways in which CNS tissues such as brain, spinal cord and retina can regenerate or display neurogenic potential and how these abilities are modulated by morphogens.     

The many faces of EMMPRIN—Roles in neuroinflammation

The central nervous system (CNS) is a relatively immune-privileged organ, wherein a well-instated barrier system (the blood-brain barrier) prevents the entry of blood cells into the brain with the exception of regular immune surveillance cells. Despite this tight security immune cells are successful in entering the CNS tissue where they result in states of neuroinflammation, tissue damage and cell death. Various components of the blood-brain barrier and infiltrating cells have been examined to better understand how blood cells are able to breach this secure barrier. Proteases, specifically matrix metalloproteinases (MMP), have been found to be the common culprits in most diseases involving neuroinflammation. MMPs secreted by infiltrating cells act specifically upon targets on various components of the blood-brain barrier, compromising this barrier and allowing cell infiltration into the CNS. Extracellular matrix metalloproteinase inducer (EMMPRIN) is an upstream inducer of several MMPs and is suggested to be the master regulator of MMP production in disease states such as cancer metastasis. EMMPRIN in the context of the CNS is still relatively understudied. In this review we will introduce EMMPRIN, discuss its ligands and roles in non-CNS conditions that can help implicate its involvement in CNS disorders, showcase its expression within the CNS in healthy and disease conditions, elucidate its ligands and receptors, and briefly discuss the emerging roles it plays in various diseases of the CNS involving inflammation.     

Neuroendocrinology-based therapy for Alzheimer's disease

The nervous system interacts directly with the endocrine system to control a plethora of central nervous system (CNS) functions. Metabolic and reproductive hormones are known to be important in the maintenance of neuronal health and their fluctuations are important for CNS aspects ranging from sleep and appetite regulation to cognitive function. This review will summarize and critically evaluate how age-related changes in sex and metabolic hormones modulate affect cognitive function and the implications of targeting the neuroendocrinological system as a therapeutic strategy in Alzheimer's disease.     

Neuronal action on the developing blood vessel pattern

The nervous system relies on a highly specialized network of blood vessels for development and neuronal survival. Recent evidence suggests that both the central and peripheral nervous systems (CNS and PNS) employ multiple mechanisms to shape the vascular tree to meet its specific metabolic demands, such as promoting nerve-artery alignment in the PNS or the development the blood brain barrier in the CNS. In this article we discuss how the nervous system directly influences blood vessel patterning resulting in neuro-vascular congruence that is maintained throughout development and in the adult.     

Modeling of microstructural kinematics during simple elongation of central nervous system tissue

Damage to axons and glial cells in the central nervous system (CNS) white matter is a nearly universal feature of traumatic brain injury, yet it is not clear how the tissue mechanical deformations are transferred to the cellular components of the CNS. Defining how cellular deformations relate to the applied tissue deformation field can both highlight cellular populations at risk for mechanical injury, and define the fraction of cells in a specific population that will exhibit damage. In this investigation, microstructurally based models of CNS white matter were developed and tested against measured transformations of the CNS tissue microstructure under simple elongation. Results show that axons in the unstretched optic nerves were significantly wavy or undulated, where the measured axonal path length was greater than the end-to-end distance of the axon. The average undulation parameter--defined as the true axonal length divided by the end-to-end length--was 1.13. In stretched nerves, mean axonal undulations decreased with increasing applied stretch ratio (lambda)--the mean undulation values decreased to 1.06 at lambda = 1.06, 1.04 at lambda = 1.12, and 1.02 at lambda = 1.25. A model describing the gradual coupling, or tethering, of the axons to the surrounding glial cells best fit the experimental data. These modeling efforts indicate the fraction of the axonal and glial populations experiencing deformation increases with applied elongation, consistent with the observation that both axonal and glial cell injury increases at higher levels of white matter injury. Ultimately, these results can be used in conjunction with computational simulations of traumatic brain injury to aid in establishing the relative risk of cellular structures in the CNS white matter to mechanical injury.