Wright, E. C. | Search bioRxiv

bioRxiv2021

Environmental enrichment delays the development of stereotypic behavior and reduces variability in behavioral experiments using California mice (Peromyscus californicus).

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse (Peromyscus californicus) has unique physiological and behavioral traits and has emerged as a powerful model for studying sex differences in the biology of psychiatric disease, which is particularly relevant considering the new NIH guidelines that require the inclusion of sex as a biological variable. Despite its growing role in preclinical research, there is a lack of studies assessing species-specific housing needs, which presents a challenge for research facilities seeking to ensure good welfare and obtaining high-quality experimental data. Indeed, captive California mice present a high prevalence of stereotypic backflipping behavior, a common consequence of suboptimal housing and a potential source of experimental outcome variability. Using three different cage systems, the present studies show that increasing housing space as well as social and environmental complexity can delay the development of stereotypic behavior in male and female California mice. Critically, this reduction in stereotypy is accompanied by increased effect sizes of stress in an established model for social anxiety. These results suggest that increased cage size and enrichment could enhance welfare in California mice while simultaneously increasing the quality of behavioral experiments.

animal behavior and cognition↗

bioRxiv2020

Pubertal androgens reduce the effects of social stress on anxiety-related behaviors in California mice

Anxiety disorders are more common in women than men, and this difference arises during puberty. Increased secretion of gonadal hormones during puberty influences brain structure and function, but the extent to which hormones modulate anxiety-related brain circuits is unclear. The slow developing California mouse (Peromyscus californicus) is an ideal species for studying the effects of hormones on brain function during adolescence. In adults social defeat stress reduces social approach and increases vigilance in females but not males. Here we show this sex difference is absent in juvenile mice, and that prepubertal castration sensitizes adult males to social defeat. Since adult castration has no effect on stress sensitivity, our data show that gonadal hormones act during puberty to program behavioral responses to stress later in life. In adults, calcium imaging in the medioventral bed nucleus of the stria terminalis shows that threatening social contexts increase calcium transients. Furthermore, prepubertal castration generalizes these responses to less threatening social contexts. Prepubertal treatment with the non-aromatizable androgen dihydrotestosterone acts in males and females to reduce sensitivity to social defeat in adults. Together, these data indicate activation of androgen receptors during puberty are critical for programing behavioral responses to stress in adulthood, highlighting a possible mechanism contributing to sex differences in anxiety. Significance StatementPuberty is a key period when sex differences in anxiety emerges. Gonadal hormone release increases during this time but it is largely unknown how they impact brain circuits and behavior. We show that androgens play a key role in programming behavioral responses to social defeat stress. The bed nucleus of the stria terminalis responds to social threats and these responses are more generalized in males without gonadal hormone exposure during puberty. Our findings highlight the importance of pubertal androgens in determining adult behavioral responses to social stress.

developmental biology↗