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Damaged axons do not regenerate after axotomy in the adult mammalian central nervous system (CNS). This may be due to local inhibitory factors at the site of injury, such as overexpression of chondroitin sulfate (CS) proteoglycans (CSPG), and the presence of myelin-associated inhibitors (MAI). To overcome CSPG- or myelin-induced inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For example, NEP1-40 is a synthetic peptide that promotes axonal regeneration by blocking Nogo-66/NgR interaction and chondroitinase ABC (ChABC), which degrades CS, thereby also promoting axon regrowth. Here, we examined whether the combination of these complementary strategies facilitates regeneration of the lesioned entorhino-hippocampal pathway (EHP) in slice cultures. In this model, overexpressed CSPG and MAI impaired axon regrowth, which mimics regeneration failure in vivo. Both CS cleavage with ChABC and NEP1-40 strongly facilitated the regrowth of entorhinal axons after axotomy, permitting the re-establishment of synaptic contacts with target cells. However, the combined treatment did not improve the regeneration induced by ChABC alone, and the delayed treatment of ChABC, but not NEP1-40, had a less pronounced effect on axonal regrowth compared with acute treatment. These results provide insight into the development of new assays and strategies to enhance axon regeneration in injured cortical connections.

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Severed adult CNS axons can extend over long distances when a permissive 'milieu', such as grafted Schwann cells or ensheathing cells, is provided. Moreover, functional blocking of endogenous inhibitory factors, such as Nogo-A or proteoglycans, enhances the regeneration of axotomized neurons. Here we examine whether guidance cues available during the development of axonal pathways could also potentiate the regeneration of lesioned adult circuits. The Cajal-Retzius cells in the hippocampus are transient pioneer neurons that guide entorhino-hippocampal afferents to their target layers. By using an in vitro model of axotomy of the entorhino-hippocampal pathway we show that Cajal-Retzius cells triggered the regeneration of the axotomized entorhino-hippocampal pathway. Furthermore, the regrowth induced by Cajal-Retzius cells was robust and its pattern was indistinguishable from that of the unlesioned entorhino-hippocampal pathway. Thus, regenerating axons regrew in a layer-specific fashion towards the appropriate target layers, making synaptic contacts with target pyramidal neurons. Interestingly, the ability of lesioned entorhinal axons to regrow was maintained for at least 9 days after axotomy. These results show that the growth-promoting cells controlling the development of neural circuits will be a relevant approach to promoting the regeneration of lesioned adult CNS pathways.

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Consider the density of the solution Xt; x of a stochastic heat equation with small noise at a xed t 2 0; T , x 2 0; 1 . In the paper we study the asymptotics of this density as the noise is vanishing. A kind of Taylor expansion in powers of the noise parameter is obtained. The coe cients and the residue of the expansion are explicitly calculated. In order to obtain this result some type of exponential estimates of tail probabilities of the di erence between the approximating process and the limit one is proved. Also a suitable local integration by parts formula is developped.

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