Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring.

A K Short,A Fox,J H Kim,K A Fennell,A J Hannan,T W Bredy,V M Perreau,M K O’Bryan,T Y Pang

doi:10.1038/tp.2016.109

Abstract

Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.

Highlights

There is growing preclinical and epidemiological evidence supporting a transgenerational influence of paternal stress on the behavior of offspring in a manner not involving direct parenting interactions
Epidemiological studies of parents suffering from post-traumatic stress disorder (PTSD) have found a correlation with an increased instance of PTSD-like symptoms in the offspring, without the offspring being exposed to the trauma themselves.[1,2,3,4]
There was no effect of CORT treatment on total immobility time during the forced-swim test (t(46) = 0.98, P = 0.3322; Figure 1c)

Summary

INTRODUCTION

There is growing preclinical and epidemiological evidence supporting a transgenerational influence of paternal stress on the behavior of offspring in a manner not involving direct parenting interactions. USV analysis was performed using the Avisoft Sound Analysis and Synthesis Software pro and IV transcripts are associated with anxiety disorders in humans[21,22] and Bdnf exon IV is required for the extinction of conditioned fear in rodents.[23,24] Another gene potentially involved in paternal transgenerational effects is the paternally imprinted insulin-like growth factor II (Avisoft Bioacoustics) using the automatic detection settings, with each call manually confirmed in accordance with previous studies.[32] The number of USV calls made per minute over the 5-min separation period was determined. Total time spent in the light half of the apparatus was mRNA in the F1 offspring These changes are associated with the expressed as a percentage of the test duration.

MATERIALS AND METHODS

RESULTS

DISCUSSION