Neuroanatomy of cerebellum and olfactory bulb in a substrain of C57BL/6J inbred mice carrying a spontaneous mutation
Introduction
Hippocampal neuroanatomy in mice varies according to genetic background [1], [24]. Especially, the sizes of the hippocampal intra- and infrapyramidal mossy fibre (IIPMF) terminal fields differ between inbred strains and about 35–50% of the phenotypical variation between individuals can be ascribed to heredity [3], [25]. These variations have aroused considerable interest, as they have been found to correlate with several types of behavior: two-way avoidance performance in a shuttle box [16], learning in radial maze [5], [6] and Morris navigation tasks [2], [20], habituation [4] and exploration in an open field [7], and intermale (offensive) aggression [10], [22].
Some years ago, the Nmg substrain of C57BL/6J inbred mice maintained in the laboratory of Dr. J.H.F. van Abeelen (Nijmegen, The Netherlands) underwent a spontaneous change in open-field behavior, with concomitant changes in hippocampal neuroanatomy [8]. As expected, this substrain, having much reduced IIPMF sizes, also showed reduced spatial learning capabilities [12] and increased aggression [23]. As the Nmg substrain was still histocompatible with the original C57BL/6J substrain [8], these changes were most probably due to a spontaneous mutation in one single gene, a hypothesis confirmed by a Mendelian cross-breeding study [13]. However, up until now, only the hippocampal neuroarchitecture of these mutants has been studied, so that the possibility exists that other brain structures are also modified. To test whether the effects of the mutation are hippocampus-specific, we examined the neuroanatomy of the accessory olfactory bulbs and cerebellum. These structures were selected because, as the hippocampus, they are laminated, increasing the probability that they may show modifications. Moreover, the granular layer of the accessory olfactory bulb is innervated by terminals from the central amygdala that are nearly as rich in zinc as the IIPMF [18]. Although it has not yet been possible to determine the cause of the IIPMF differences between both substrains, we postulated that structures sharing some crucial features with the hippocampal formation might have a larger probability to show pleiotropic effects of the mutation than others.
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Animals
Subjects were 14 male mice from each of the sublines C57BL/6JNmg and C57BL/6J//Kun (abbreviated N and K, respectively). N was procured from The Jackson Laboratory, Bar Harbor, ME, USA in 1965 (at which time it had reached the 85th generation of inbreeding), maintained in Nijmegen for 66 generations, and then transferred to our laboratory in Paris, France in 1990. K was relocated in 1977 from The Jackson Laboratory to the Oxfordshire Laboratory Animal Colonies, Bicester, England (Ola) and after
Results
The results from the Lipp test are presented in Fig. 1. The time needed to cross the bar decreased significantly over trials [F(4,84)=4.48, P<.01] in a comparable way for both strains, as neither the Strain factor nor the Strain×Trials interaction were significant. A similar result was obtained for the number of left hind-paw slips [Trials F(4,84)=4.26, P<.01]. However, for the number of right hind-paw slips, both the Trials [F(4,84=4.00, P<.01] and the Strain [F(1,21)=5.36, P<.05] factors were
Discussion
In the present experiment, we compared a mutated substrain of C57BL/6J animals with wild-type animals concerning their motor function, cerebellar neuroanatomy, and size of the accessory granular layer. The results obtained for body and brain weight replicated those reported before [12]. N mice are generally somewhat smaller than K animals. This may simply be due to the generally somewhat higher activity levels of N mice [8], as there are no apparent strain differences in health status, for
Acknowledgements
We thank the late Dr. J.H.F. van Abeelen (Nijmegen, The Netherlands) for generously providing us with breeding pairs of his two substrains. This study was supported by the Centre National de la Recherche Scientifique (UPR 9074), Ministry for Research and Technology, Région Centre, University of Orléans, and Préfecture de la Région Centre. FRE 2134 is affiliated with INSERM.
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Quiet mutations in inbred strains of mice
2007, Trends in Molecular MedicineCitation Excerpt :They noticed an unexpected drop in frequency of vertical rearing (i.e. standing up on hindlimbs) in their mice and when they measured this behaviour in a second substrain, C57BL/6J/Kun, this difference was robust. Subsequent studies of both substrains has led them to postulate that a single spontaneous mutation (as yet unknown) has caused this behavioural variation in C57BL/6J/Nmg and probably acts specifically on the hippocampal intra- and infra-pyramidal mossy fibres of the brain [12,13]. One important aspect of this research was the direct comparison between the substrains – because, as Connolly et al. point out (in an unrelated project to study behavioural and electrophysiological variation between two DBA/2 substrains), differences in phenotype might also be caused by environmental factors, including different pup-rearing environments, and this needs to be investigated before concluding that a genetic change is responsible [14].