Perinatal nutrition interacts with genetic background to alter behavior in a parent‐of‐origin‐dependent manner in adult Collaborative Cross mice

Abstract

Previous studies in animal models and humans have shown that exposure to nutritional deficiencies in the perinatal period increases the risk of psychiatric disease. Less well understood is how such effects are modulated by the combination of genetic background and parent-of-origin (PO). To explore this, we exposed female mice from 20 Collaborative Cross (CC) strains to protein deficient, vitamin D deficient, methyl donor enriched or standard diet during the perinatal period. These CC females were then crossed to a male from a different CC strain to produce reciprocal F1 hybrid females comprising 10 distinct genetic backgrounds. The adult F1 females were then tested in the open field, light/dark, stress-induced hyperthermia, forced swim and restraint stress assays. Our experimental design allowed us to estimate effects of genetic background, perinatal diet, PO and their interactions on behavior. Genetic background significantly affected all assessed phenotypes. Perinatal diet exposure interacted with genetic background to affect body weight, basal body temperature, anxiety-like behavior and stress response. In 8 of 9 genetic backgrounds, PO effects were observed on multiple phenotypes. Additionally, we identified a small number of diet-by-PO effects on body weight, stress response, anxiety- and depressive-like behavior. Our data show that rodent behaviors that model psychiatric disorders are affected by genetic background, PO and perinatal diet, as well as interactions among these factors.

A diallel of the mouse Collaborative Cross founders reveals strong strain-specific maternal effects on litter size

“…The Collaborative Cross (CC) and its eight founder strains are an important resource for studying complex traits, establishing mouse models for human disease, and understanding the mouse Diversity Outbred (DO), which originated from the CC (Ferris et al 2013;Chesler 2014;Rogala et al 2014;Rasmussen et al 2014;Gralinski et al 2015Gralinski et al , 2017Schoenrock et al 2017;Maurizio et al 2018). The CC resource and its founder strains can also be used to study reproductive ability, which is especially interesting because this population has an established record both of breeding successes and of failures.…”

Collaborative Cross Mouse Populations as a Resource for the Study of Epilepsy

“…In addition, whole genome sequences have been established for each individual CC strain, and other genomic tools have been developed to enable the identification of genetic variants from mapping studies 9,10 . The CC has been used to model complex traits such as behavior [11][12][13][14] , cancer 15 , and infectious disease susceptibility [16][17][18][19][20][21][22][23] . In order for us to take advantage of the immense genetic diversity available in the CC to study epilepsy, we needed a seizure induction protocol amenable to high throughput analysis.…”

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

“…By mating different CC strains, we can generate recombinant inbred inter-crosses (CC-RIX) (Z ou et al . 2005; S choenrock et al . 2018).…”

“…The genetic diversity of CC-RIX enables the study of parent-of-origin effects and their phenotypic characterization has demonstrated that there are strong strain effects in some measures (C rowley et al . 2015; S choenrock et al . 2018).…”