The myeloid cells of the central nervous system parenchyma

A microglial cell is both a glial cell of the central nervous system and a mononuclear phagocyte, which belongs to the haematopoietic system and is involved in inflammatory and immune responses. As such, microglia face a challenging task. The neurons of the central nervous system cannot divide and be replenished, and therefore need to be protected against pathogens, which is a key role of the immune system, but without collateral damage. In addition, after physical injury, neural cells need restorative support, which is provided by inflammatory responses. Excessive or chronic inflammatory responses can, however, be harmful. How microglia balance these demands, and how their behaviour can be modified to ameliorate disorders of the central nervous system, is becoming clear.     

Susceptibility to murine lymphocytic choriomeningitis maps to class I MHC genes--a model for MHC/disease associations

Susceptibility to some human diseases is linked, albeit weakly, to major transplantation antigens (HLA) encoded by the major histocompatibility gene complex (MHC). Here we have studied MHC/disease association in inbred strains of mice after intracerebral (i.c.) injection of lymphocytic choriomeningitis virus (LCMV). This route of infection leads to a lymphocytic choriomeningitis (LCM) which is not the result of direct cytopathic effects of the virus but is caused by the induced T-cell immune response: immunocompetent mice die whereas T-cell-deficient mice survive. By using two plaque variants of LCMV strain UBC (refs 7,8), we found that susceptibility to LCM was dependent on the LCMV strain used ('aggressive' versus 'docile' UBC-LCMV) and on the various genes of the host mouse strains. In addition, susceptibility to LCM caused by docile UBC-LCMV was clearly linked to the murine major histocompatibility locus H-2D: in MHC-congeneic C57BL/10 mice, susceptibility correlated with early onset and high activity of measurable LCMV-specific cytotoxic T cells in meninges and spleens and could be mapped to H-2D. This model shows that a severe immunopathologically mediated clinical disease in mice can be regulated directly by MHC genes of class I type and supports the notion that many MHC/disease associations directly reflect MHC-restricted and MHC-regulated T-cell reactivity.     

T cells become licensed in the lung to enter the central nervous system

The blood–brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.     

Regenerating the damaged central nervous system

It is self-evident that the adult mammalian brain and spinal cord do not regenerate after injury, but recent discoveries have forced a reconsideration of this accepted principle. Advances in our understanding of how the brain develops have provided a rough blueprint for how we may bring about regeneration in the damaged brain. Studies in developmental neurobiology, intracellular signalling and neuroimmunology are bringing the regeneration field closer to success. Notwithstanding these advances, clear and indisputable evidence for adult functional regeneration remains to be shown.     

中枢神经系统内的胰岛素及其受体

众所周知,胰岛素是一个小分子的蛋白质类激素,其主要作用是维持外周的血糖平衡,而对于中枢神经系统内胰岛素的研究则相对较少。大脑中非胰岛素依赖性葡萄糖的摄取,是大家认为脑是胰岛素不敏感器官的主要原因。然而,最近的研究结果显示,大脑的提取物中有高浓度的胰岛素;外周分泌的胰岛素,可以经过特异的转运系统穿过血脑屏障进入中枢神经系统。与大脑中胰岛素的来源、定位和功能的研究相比,中枢神经系统中胰岛素受体的表达也得到了相当高的关注。将从中枢神经系统尤其是脑内的胰岛素及其受体,中枢神经系统内胰岛素的功能,包括繁殖、食物摄入与体重控制、糖代谢调节和记忆等方面进行简要的综述。     

Visual processing in the leech central nervous system

In animals with complex visual systems spatial contrast is enhanced by mutual inhibition between retinal neurones monitoring different fields. By analogy, if animals like leeches and some caterpillars, that have several simple (non-image-forming) eyes aimed in different directions, are capable of rudimentary form detection, one might predict mutual antagonism between eyes monitoring different fields. In support of this prediction, I report here a paired interneurone in the central nervous system (CNS) of the leech which is stimulated by eyes on one side of the animal and inhibited by eyes on the other. There are striking parallels between these neurones and other integrating neurones, in particular those processing bilateral auditory input in crickets, suggesting that the visual system of the leech may be representative of a general class of sensory processing systems.     

A physiological role for GABAB receptors in the central nervous system

The role of GABA in synaptic transmission in the mammalian central nervous system is more firmly established than for any other neurotransmitter. With virtually every neuron studied, the synaptic action of GABA is mediated by bicuculline-sensitive GABAA receptors which selectively increase chloride conductance. However, it has been shown that GABA has a presynaptic inhibitory action on transmitter release that is insensiive to bicuculline and is selectively mimicked by baclofen. The receptors involved in this action are referred to as GABAB receptors, to distinguish them from the classic bicuculline-sensitive GABAA receptors. In hippocampal pyramidal cells an additional postsynaptic action of GABA and baclofen has been reported that is also insensitive to GABAA antagonists, and may be mediated by GABAB receptors on the postsynaptic neuron. This action of GABA and baclofen involves an increase in potassium conductance. Synaptic activation of pathways converging on hippocampal pyramidal cells results in a slow inhibitory postsynaptic potential which involves an increase in potassium conductance, and it has been suggested that GABAB receptors might be responsible for this synaptic potential. However, to establish convincingly that GABAB receptors are physiologically important in the central nervous system, a selective GABAB antagonist is required. Here we provide this missing evidence. Using the hippocampal slice preparation, we now report that the phosphonic acid derivative of baclofen, phaclofen, is a remarkably selective antagonist of both the postsynaptic action of baclofen and the bicuculline-resistant action of GABA, and that it selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells.     

ATP receptor-mediated synaptic currents in the central nervous system.

Until now, the only well documented, fast excitatory neurotransmitter in the brain has been glutamate. Although there is evidence for adenosine 5'-triphosphate (ATP) acting as a transmitter in the peripheral nervous system, suggestions for such a role in the central nervous system have so far not been supported by any direct evidence. Here we report the recording of evoked and miniature synaptic currents in the rat medial habenula. The fast rise time of the currents showed that they were mediated by a ligand-activated ion channel rather than a second messenger system, thus limiting the known transmitter candidates. Evidence was found for the presence on the cells of glutamate, gamma-aminobutyric acid, acetylcholine and ATP receptors, but not for 5-hydroxytryptamine (5HT3) or glycine receptors. The evoked currents were unaffected by blockers of glutamate, gamma-aminobutyric acid or acetylcholine receptors but were blocked by the ATP receptor-blocker, suramin and the desensitizing ATP receptor-agonist alpha,beta-methylene-ATP. Our evidence identifies for the first time synaptic currents in the brain, mediated directly by ATP receptors.     

Sensory neurones recognise defined pathways in Drosophila central nervous system

An analysis of the central projection of various sensory neurones in the homoeotic mutant bithorax postbithorax, and in flies where an adult nerve had been experimentally misrouted, reveals that neurones are able to develop a normal projection even if they enter the central nervous system at an unusual place.