Alteration in anxiety with relation to the volume of the locus ceruleus in progranulin-deficient mice.

The mammalian brain exhibits sex differences with respect to structure and function. In our previous report, we found that progranulin (PGRN)-deficient (pgrn(-/-)) mice displayed an alteration in male-type behaviors, including reduced frequency of ejaculation and elevated levels of aggression and anxiety. The aim of the present study was to elucidate the role of PGRN in sex differences in anxiety. In the elevated plus maze, wild-type (pgrn(+/+)) female mice spent more time in the closed arms than the pgrn(+/+) males, suggesting that the level of anxiety was higher in females than males. On the other hand, no sex difference was observed in the pgrn(-/-) mice, and their anxiety levels were almost the same as those of the pgrn(+/+) females. To elucidate the effect of testosterone on male anxiety, male mice were castrated at 5 weeks of age and silastic tubes filled with either testosterone or cholesterol were then implanted into them for one week. These treatments did not affect anxiety in the open field in either genotypes, although the pgrn(-/-) males exhibited higher anxiety than pgrn(+/+) males. Next, we measured the volume of the paraventricular nucleus (PVN) and the locus ceruleus (LC), as these are anxiety/stress-related nuclei that are known to have sex differences in their structures. In the pgrn(+/+) mice, there was a tendency for the volume of the LC to be larger in males than females. In addition, the pgrn(-/-) mice had a larger volume of LC than the pgrn(+/+) mice, although no sexual differences were observed. The number of cells in the LC was also larger in the pgrn(-/-) than in the pgrn(+/+) mice. No significant differences in the volumes of the PVN were observed between genotypes or sexes. These results suggest that PGRN plays a role in organization of the LC, which eventually modulates anxiety in novel environments.