A simple rule for axon outgrowth and synaptic competition generates realistic connection lengths and filling fractions

Neural connectivity at the cellular and mesoscopic level appears very specific and is presumed to arise from highly specific developmental mechanisms. However, there are general shared features of connectivity in systems as different as the networks formed by individual neurons in Caenorhabditis elegans or in rat visual cortex and the mesoscopic circuitry of cortical areas in the mouse, macaque, and human brain. In all these systems, connection length distributions have very similar shapes, with an initial large peak and a long flat tail representing the admixture of long-distance connections to mostly short-distance connections. Furthermore, not all potentially possible synapses are formed, and only a fraction of axons (called filling fraction) establish synapses with spatially neighboring neurons. We explored what aspects of these connectivity patterns can be explained simply by random axonal outgrowth. We found that random axonal growth away from the soma can already reproduce the known distance distribution of connections. We also observed that experimentally observed filling fractions can be generated by competition for available space at the target neurons--a model markedly different from previous explanations. These findings may serve as a baseline model for the development of connectivity that can be further refined by more specific mechanisms.Comment: 31 pages (incl. supplementary information); Cerebral Cortex Advance Access published online on May 12, 200

Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes

Aims/hypothesis: Diabetic retinopathy is a progressive neuro-degenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analysed its influence on retinal neurodegeneration, using an antioxidant, lutein. Methods: C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-month-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-month-diabetic mice. In the retinal sections of 4-month-diabetic mice, histological changes, cleaved caspase-3 and TUNEL staining were analysed. Results: Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin reduction, and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-month-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell number, together with increase in cleaved caspase-3- and TUNEL-positive cells, were avoided in the retina of lutein-fed mice. Conclusions/interpretation: The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by constant intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes

Adenosine induces growth-cone turning of sensory neurons

The formation of appropriate connections between neurons and their specific targets is an essential step during development and repair of the nervous system. Growth cones are located at the leading edges of the growing neurites and respond to environmental cues in order to be guided to their final targets. Directional information can be coded by concentration gradients of substrate-bound or diffusible-guidance molecules. Here we show that concentration gradients of adenosine stimulate growth cones of sensory neurons (dorsal root ganglia) from chicken embryos to turn towards the adenosine source. This response is mediated by adenosine receptors. The subsequent signal transduction process involves cAMP. It may be speculated that the in vivo function of this response is concerned with the formation or the repair and regeneration of the peripheral nervous system

Competition at silent synapses in reinnervated skeletal muscle

Synaptic connections are made and broken in an activity-dependent manner in diverse regions of the nervous system. However, whether activity is strictly necessary for synapse elimination has not been resolved directly. Here we report that synaptic terminals occupying motor endplates made electrically silent by tetrodotoxin and alpha-bungarotoxin block were frequently displaced by regenerating axons that were also both inactive and synaptically ineffective. Thus, neither evoked nor spontaneous activation of acetylcholine receptors is required for competitive reoccupation of neuromuscular synaptic sites by regenerating motor axons

Control of synaptic vesicle endocytosis by an extracellular signalling molecule

Signalling cascades control multiple aspects of presynaptic function. Synaptic vesicle endocytosis was assumed to be exempt from modulation, due to its essential role maintaining synaptic vesicle supply and thus neurotransmission. Here we show that brain-derived neurotrophic factor arrests the rephosphorylation of the endocytosis enzyme dynamin I via an inhibition of glycogen synthase kinase 3. This event results in a selective inhibition of activity-dependent bulk endocytosis during high-intensity firing. Furthermore, the continued presence of brain-derived neurotrophic factor alleviates the rundown of neurotransmission during high activity. Thus, synaptic strength can be modulated by extracellular signalling molecules via a direct inhibition of a synaptic vesicle endocytosis mode

Een nederzetting uit de Late-Bronstijd/Vroege-IJzertijd op het bedrijventerrein Wijnbergen (fase 3), gemeente Doetinchem : een archeologische opgraving

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