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known. Recent studies have showed that vagus nerve stimulation (VNS, a
well-established adjunctive treatment for intractable epilepsy and treatment-
resistant depression) can induce neurogenesis and plasticity in the hippocam-
pus ( Biggio et al., 2009 ). In particular, it was demonstrated that acute
VNS induces cell proliferation in the dentate gyrus of the adult rat hippo-
campus and an increase of both the total amount of doublecortin (DCX)
immunoreactivity and the number of DCX-positive neurons in the dentate
gyrus. In contrast, chronic VNS induced an increase of the BDNF expres-
sion, which may serve to promote and maintain new neuronal connections
formed in response to chronic VNS ( Biggio et al., 2009 ). Moreover, it was
shown that acute VNS increased the expression of genes for BDNF and basic
FGF in the rat hippocampus, both of which are important modulators of
hippocampal plasticity and neurogenesis ( Follesa et al., 2007 ). Finally, a
recent study showed that damage to the subdiaphragmatic vagus in adult rats
is followed by microglia activation and long-lasting changes in the dentate
gyrus, leading to alteration of neurogenesis ( Ronchi, Ryu, Fornaro, &
Czaja, 2012 ).
5. HOW TO STUDY PERIPHERAL NERVE REGENERATION?
Essential progress in peripheral nerve regeneration research has been
possible using animal models which may simulate anatomical, physiological,
and behavioral aspects of the regenerative process. The experimental models
available can be divided into three main groups according to (i) the animal
model, (ii) the localization of lesion, and (iii) the type of lesion.
By far, in nerve regeneration studies, the most employed laboratory ani-
mals are rats. The main reason appears to be the larger physical size of rat
nerves compared to mouse nerves, which reduces the complexity of the
microsurgical procedures ( Tos et al., 2008 ), the possibility to have standard-
ized and comparable functional tests and the fact that rats are more resilient
than mice. On the other hand, the availability of genetically modified mouse
colonies will probably increase mouse employment since transgenic models
will allow to elucidate the role of a particular gene or protein in the mech-
anisms of the nerve regeneration process. In addition to these models, var-
ious large animal models have been employed including rabbits, sheep, pigs,
and primates because several authors believe that the translation to clinical
application may benefit from a preclinical study on large animal nerves since
the regeneration process of nerves in large animals is more similar to humans
( Fullarton, Lenihan, Myles, & Glasby, 2000 ).
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