Alteration in Anxiety with Relation to the Volume of the Locus Ceruleus in Progranulin-Deficient Mice

Abstract

Abstract. 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. Key words: Anxiety, Locus ceruleus, Progranulin, Sex-difference, Testosterone (J. Reprod. Dev. 55: [518][519][520][521][522] 2009) he mammalian brain exhibits sex differences with respect to structure and function [1]. Such sex differences in the brain arise from the organizing effect of sex-steroid hormones during the perinatal period, followed by the same hormones activating sexrelated behaviors after puberty. Anxiety-like behavior in novel environments is one of the behaviors characterized by sex differences and is also under the influence of sex-steroid hormones [2].Progranulin (PGRN) is a cystein-rich protein composed of 593 amino acid residues and has an estimated molecular weight of about 68 kDa in the unglycosylated form [3][4][5]. PGRN is expressed in various tissues including neural cells in the hippocampus, cerebral cortex and cerebellum [6][7][8]. Our previous studies have demonstrated that it mediates the organizing effects of sexsteroid hormones in the process of sexual differentiation of the brain [9][10][11][12][13]. PGRN also mediates estrogen-induced adult neurogenesis [14]. Mutations including the null mutation in the PGRN gene have been found in patients with frontotemp...

Dissociable Effects of Sry and Sex Chromosome Complement on Activity, Feeding and Anxiety-Related Behaviours in Mice

“…male and female rodents show different levels and patterns of food consumption [8], activity [9] and anxiety-related behaviours [10]. Whilst there is fairly consistent data regarding the direction of effects for the first two measures (whereby males consume more food and achieve higher bodyweights [11,12], and females are more active [13,14]), the data regarding the direction of anxiety-related behaviours is more uncertain [15,16]. This uncertainty could reflect inter-study heterogeneity related to the strain and species used, differences in experimental protocols, or failure to account for stage of female oestrus [17].…”

Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

“…In the open-field test, wt females generally show higher levels of anxiety than males and Grn loss raises the anxiety level of males significantly to similar levels of females [75]. A follow up-study on the same mice linked increased anxiety in Grn −/− males to an increase in the volume and number of cells in the locus ceruleus [185], a nucleus involved in physiological responses to stress and anxiety. Furthermore, Grn −/− males exhibited enhanced aggressiveness towards females and increased frequency of biting attacks in the resident-intruder test, which was ascribed to alterations in the brain serotonergic system of Grn −/− mice [75].…”

Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mice Suggest a Role for Progranulin in Successful Aging

“…Subsequently, it was suggested that the volumetric difference in the locus ceruleus of progranulin-deficient mice compared with controls was a possible cause of sexually dimorphic anxiety. 20 Given that progranulin deficiency in humans leads to FTLD-U, it was surprising that C-terminal cleavage products of the TDP-43 protein that are characteristic for human FTLD-U were not observed in these progranulin-deficient mice. 21 The objective of the current study was to characterize an aged series (1,7,12, and 23 months) of GRN-deficient ( Ϫ/ϩ and Ϫ/Ϫ ) mice to determine the neuropathological consequences of having partial or complete loss of PGRN function throughout life as a means to understand the biological role of PGRN in the CNS.…”