Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission

The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Alpha2-adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system; however, the individual roles of the three highly homologous alpha2-adrenergic-receptor subtypes (alpha2A, alpha2B, alpha2C) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three alpha2-adrenergic-receptor subtypes were disrupted. Here we show that both the alpha2A- and alpha2C-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. Alpha2A-adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the alpha2C-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both alpha2A- and alpha2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.     

Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.     

Molecular cloning and expression of brain-derived neurotrophic factor

During the development of the vertebrate nervous system, many neurons depend for survival on interactions with their target cells. Specific proteins are thought to be released by the target cells and to play an essential role in these interactions. So far, only one such protein, nerve growth factor, has been fully characterized. This has been possible because of the extraordinarily (and unexplained) large quantities of this protein in some adult tissues that are of no relevance to the developing nervous system. Whereas the dependency of many neurons on their target cells for normal development, and the restricted neuronal specificity of nerve growth factor have long suggested the existence of other such proteins, their low abundance has rendered their characterization difficult. Here we report the full primary structure of brain-derived neurotrophic factor. This very rare protein is known to promote the survival of neuronal populations that are all located either in the central nervous system or directly connected with it. The messenger RNA for brain-derived neurotrophic factor was found predominantly in the central nervous system, and the sequence of the protein indicates that it is structurally related to nerve growth factor. These results establish that these two neurotrophic factors are related both functionally and structurally.     

Multiple forms of synaptic plasticity triggered by selective suppression of activity in individual neurons

The rules by which neuronal activity causes long-term modification of synapses in the central nervous system are not fully understood. Whereas competitive or correlation-based rules result in local modification of synapses, homeostatic modifications allow neuron-wide changes in synaptic strength, promoting stability. Experimental investigations of these rules at central nervous system synapses have relied generally on manipulating activity in populations of neurons. Here, we investigated the effect of suppressing excitability in single neurons within a network of active hippocampal neurons by overexpressing an inward-rectifier potassium channel. Reducing activity in a neuron before synapse formation leads to a reduction in functional synaptic inputs to that neuron; no such reduction was observed when activity of all neurons was uniformly suppressed. In contrast, suppressing activity in a single neuron after synapses are established results in a homeostatic increase in synaptic input, which restores the activity of the neuron to control levels. Our results highlight the differences between global and selective suppression of activity, as well as those between early and late manipulation of activity.     

Progenitor cell maintenance requires numb and numblike during mouse neurogenesis

Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.     

En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS.

During development, neurons extend axons to their targets, then become dependent for their survival on trophic substances secreted by their target cells. Competition for limiting amounts of these substances is thought to account for much of the extensive naturally-occurring cell death that is seen throughout the nervous system. Here we show that spinal commissural neurons, a group of long projection neurons in the central nervous system (CNS), are also dependent for their survival on trophic support from one of their intermediate targets, the floor plate of the spinal cord. This dependence occurs during a several-day-long period when their axons extend along the floor plate, following which they develop additional trophic requirements. A dependence of neurons on trophic support derived en passant from their intermediate axonal targets provides a mechanism for rapidly eliminating misprojecting neurons, which may help to prevent the formation of aberrant neuronal circuits during the development of the nervous system.     

A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics

Catecholaminergic systems in discrete regions of the brain are thought to be important in affective psychoses, learning and memory, reinforcement and sleep-wake cycle regulation. Tyrosine hydroxylase (TH) is the first enzyme in the pathway of catecholamine synthesis. Its importance is reflected in the diversity of the mechanisms that have been described which control its activity; TH levels vary both during development and as a function of the activity of the nervous system. Recently, we deduced the complete amino-acid sequence of rat TH from a complementary DNA clone encoding a functional enzyme. Here we demonstrate that, in man, TH molecules are encoded by at least three distinct messenger RNAs. The expression of these mRNAs varies in different parts of the nervous system. The sequence differences observed are confined to the 5' termini of the messengers and involve alternative splicing events. This variation has clear functional consequences for each putative form of the enzyme and could represent a novel means of regulating catecholamine levels in normal and pathological neurons.     

Astroglia induce neurogenesis from adult neural stem cells

During an investigation of the mechanisms through which the local environment controls the fate specification of adult neural stem cells, we discovered that adult astrocytes from hippocampus are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate. This role in fate specification was unexpected because, during development, neurons are generated before most of the astrocytes. Our findings, together with recent reports that astrocytes regulate synapse formation and synaptic transmission, reinforce the emerging view that astrocytes have an active regulatory role--rather than merely supportive roles traditionally assigned to them--in the mature central nervous system.     

Genetic ablation reveals that the roof plate is essential for dorsal interneuron specification

During neural development in vertebrates, a spatially ordered array of neurons is generated in response to inductive signals derived from localized organizing centres. One organizing centre that has been proposed to have a role in the control of neural patterning is the roof plate. To define the contribution of signals derived from the roof plate to the specification of neuronal cell types in the dorsal neural tube, we devised a genetic strategy to ablate the roof plate selectively in mouse embryos. Embryos without a roof plate lack all the interneuron subtypes that are normally generated in the dorsal third of the neural tube. Using a genetically based lineage analysis and in vitro assays, we show that the loss of these neurons results from the elimination of non-autonomous signals provided by the roof plate. These results reveal that the roof plate is essential for specifying multiple classes of neurons in the mammalian central nervous system.     

Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

Cutting the axons of the cholinergic neurons that project to the hippocampal formation results in death of most of these cells. Previous studies have shown that administration of nerve growth factor before or at the same time as the lesion will prevent this cell death. Here we demonstrate that basic fibroblast growth factor (FGF) administered into the brain reduces the death of cholinergic neurons in the medial septum and diagonal band of Broca after transection of their axons, in both young adult and aged rats. Moreover, FGF can partially protect against death of cholinergic neurons even when administered two days after axonal transection. These results indicate a possible function for FGF in the normal support of basal forebrain cholinergic neurons, but its range of activity could be wider, for FGF also supports noncholinergic neurons in vitro, it is localized in many of the central nervous system neurons, and it is found in relatively high concentrations in the brain.     

Programmed cell death in developing human fetal CNS

The spatial and temporal distributions of programmed cell death (PCD) in developing central nervous system (CNS) of human fetuses ranging from 12 to 39 weeks of gestation were investigated using techniques of flow cytometry and terminal transferase-mediated nick end labeling (TUNEL). The results showed that PCD did occur in every representative brain region of all fetuses examined in different stages. It was found that there were two peaks of PCD appearing at the 12th and 39th weeks respectively, which suggested that the first peak of apoptosis may be involved in the selective elimination of neurons overproduced during the early development and the second may play an important role in establishing the correct neuronal circuitry.     

对软式排球与全民健身运动的探讨

本文拟从软式排球的特性、场地器材及规则、技术特点和锻炼价值等方面探讨了其对全民健身运动的积极影响。软式排球场地器材设备简单,运动量可大可小,适合不同年龄、性别、不同训练程度的人活动。经常参加软式排球活动可改善人体中枢神经系统和内脏器官功能,提高速度、弹跳力、耐力、灵敏性等身体素质和运动能力,有利于促进身体生长发育,强身健体。是一项适合全民开展的健身运动。     

Developmental genetics of vertebrate glial-cell specification

Oligodendrocytes and astrocytes are macroglial cells of the vertebrate central nervous system. These cells have diverse roles in the maintenance of neurological function. In the embryo, the genetic mechanisms that underlie the specification of macroglial precursors in vivo appear strikingly similar to those that regulate the development of the diverse neuron types. The switch from producing neuronal to glial subtype-specific precursors can be modelled as an interplay between region-restricted components and temporal regulators that determine neurogenic or gliogenic phases of development, contributing to glial diversity. Gaining insight into the developmental genetics of macroglia has great potential to improve our understanding of a variety of neurological disorders in humans.     

Regulation of the G1-S transition in postembryonic neuronal precursors by axon ingrowth.

In the newly cellularized Drosophila embryo, progress through the cell cycle is regulated at the G2-M transition. We have examined cell-cycle regulation later in Drosophila development, in a group of postembryonic neuronal precursors. The S-phase precursor cells, which generate photoreceptor target neurons (lamina neurons) in the central nervous system, are not present in the absence of photoreceptor innervation. Here we report that axons selectively approach G1-phase precursors. Without axon ingrowth, lamina precursors do not enter their final S phase and by several criteria, arrest in the preceding G1 phase. These findings provide evidence that at this stage in development the control of cell division can occur at the G1-S transition.     

静态直流电场作用下神经元放电动力学分析

无创式直流电刺激中枢神经系统是现在用来减轻多种神经疾病症状的有效方法.为了探究静态直流电场对神经活动的作用机制,利用二维最小模型研究了其在静态直流电场作用下的动力学行为.通过分岔和相平面分析,发现3类神经元兴奋性对相同刺激的不同响应是由不同的峰放电起始动力过程造成的.从起始动力学的角度得到了静态直流电场对神经活动的影响,研究结果可以为无创式直流脑调制技术的应用和发展提供一定的理论指导.     

Transmitter-evoked local calcium release stabilizes developing dendrites

In the central nervous system, dendritic arborizations of neurons undergo dynamic structural remodelling during development. Processes are elaborated, maintained or eliminated to attain the adult pattern of synaptic connections. Although neuronal activity influences this remodelling, it is not known how activity exerts its effects. Here we show that neurotransmission-evoked calcium (Ca(2+)) release from intracellular stores stabilizes dendrites during the period of synapse formation. Using a ballistic labelling method to load cells with Ca(2+) indicator dyes, we simultaneously monitored dendritic activity and structure in the intact retina. Two distinct patterns of spontaneous Ca(2+) increases occurred in developing retinal ganglion cells--global increases throughout the arborization, and local 'flashes' of activity restricted to small dendritic segments. Blockade of local, but not global, activity caused rapid retraction of dendrites. This retraction was prevented locally by focal uncaging of caged Ca(2+) that triggered Ca(2+) release from internal stores. Thus, local Ca(2+) release is a mechanism by which afferent activity can selectively and differentially regulate dendritic structure across the developing arborization.     

Selective dendritic transport of RNA in hippocampal neurons in culture

Typical neurons of the central nervous system (CNS) elaborate tens of thousands of membrane specializations at sites of synaptic contacts on their dendrites. To construct, maintain, and modify these specializations, neurons must produce and deliver the appropriate molecular constituents to particular synaptic sites. Previous studies have revealed that polyribosomes are selectively positioned beneath postsynaptic sites, suggesting that in neurons, as in other cell types, protein synthetic machinery is located at or near the sites where particular proteins are needed. The mechanisms that deliver ribosomes and messenger RNA to their specific destinations in cells are therefore of considerable interest. Here we describe a system for RNA transport in dendrites that could provide a mechanism for the delivery of ribosomes and mRNA to synaptic sites in dendrites. Hippocampal neurons grown in culture incorporate 3H-uridine in the nucleus, then selectively transport the newly synthesized RNA into dendrites at a rate of about 0.5 mm day-1. The transport is inhibited by metabolic poisons, suggesting that it is an active, energy-dependent process. The RNA may be transported in association with the cytoskeleton.     

Intrinsic differences in the growth rate of early nerve fibres related to target distance

Target field innervation in the developing vertebrate nervous system coincides with the onset of important trophic interactions. Two factors that determine the timing of this event are the distance axons have to grow to reach their targets, which are known to vary, and the rate at which they grow. There have been few studies of axonal growth rate at this stage of development and no comparative study of the relationship between growth rate and target distance. Embryonic chick cranial sensory neurons are located in discrete ganglia and the distance axons have to grow to reach their targets is different for each ganglion, ranging from several hundred to several thousand microns. Here, I show that these neurons differ in their in vivo growth rates; neurons with more distant targets growing faster. In vitro, single isolated neurons from each of these populations grow at a similar rate to that observed in vivo, indicating that growth rate is an intrinsically determined property of neurons before they reach their targets.     

Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition

Synaptic activity drives synaptic rearrangement in the vertebrate nervous system; indeed, this appears to be a main way in which experience shapes neural connectivity. One rearrangement that occurs in many parts of the nervous system during early postnatal life is a competitive process called 'synapse elimination'. At the neuromuscular junction, where synapse elimination has been analysed in detail, muscle fibres are initially innervated by multiple axons, then all but one are withdrawn and the 'winner' enlarges. In support of the idea that synapse elimination is activity dependent, it is slowed or speeded when total neuromuscular activity is decreased or increased, respectively. However, most hypotheses about synaptic rearrangement postulate that change depends less on total activity than on the relative activity of the competitors. Intuitively, it seems that the input best able to excite its postsynaptic target would be most likely to win the competition, but some theories and results make other predictions. Here we use a genetic method to selectively inhibit neurotransmission from one of two inputs to a single target cell. We show that more powerful inputs are strongly favoured competitors during synapse elimination.