Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring.
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.
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
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Short
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
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KA
Fennell
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
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VM
Perreau
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
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Fox
Department of Anatomy and Developmental Biology, The Development and Stem Cell Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
M K
MK
O'Bryan
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
J H
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Kim
Cognitive Neuroepigenetics Group, Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.
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Bredy
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
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Pang
Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
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Hannan
D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D003345:Corticosterone / Q000494:pharmacology*; D003863:Depression / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D018812:Paternal Exposure; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D011247:Pregnancy; D058727:RNA, Small Untranslated / Q000235:genetics*; D012737:Sex Factors; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C513121:IGF2 protein, mouse; D035683:MicroRNAs; D058727:RNA, Small Untranslated; D007335:Insulin-Like Growth Factor II; D003345:Corticosterone