Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

Andre L M Reis; Jillian M Hammond; Igor Stevanovski; Jonathon C Arnold; Iain S McGregor; Ira W Deveson; Anand Gururajan

doi:10.1016/j.isci.2022.104861

Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

iScience. 2022 Aug 2;25(9):104861. doi: 10.1016/j.isci.2022.104861. eCollection 2022 Sep 16.

Authors

Andre L M Reis^{1

2}, Jillian M Hammond^{1

2}, Igor Stevanovski^{1

2}, Jonathon C Arnold^{3

4

5}, Iain S McGregor^{4

5

6}, Ira W Deveson^{1

2

7}, Anand Gururajan⁴

Affiliations

¹ Genomics Pillar, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
² Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, Australia.
³ Faculty of Medicine and Health, Sydney Pharmacy School, Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2050, Australia.
⁴ Brain & Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
⁵ The Lambert Initiative for Cannabinoid Therapeutics, Australia.
⁶ School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW 2050, Australia.
⁷ School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2010, Australia.

Abstract

Our understanding of the molecular pathology of posttraumatic stress disorder (PTSD) is evolving due to advances in sequencing technologies. With the recent emergence of Oxford Nanopore direct RNA-seq (dRNA-seq), it is now also possible to interrogate diverse RNA modifications, collectively known as the "epitranscriptome.". Here, we present our analyses of the male and female mouse amygdala transcriptome and epitranscriptome, obtained using parallel Illumina RNA-seq and Oxford Nanopore dRNA-seq, associated with the acquisition of PTSD-like fear induced by Pavlovian cued-fear conditioning. We report significant sex-specific differences in the amygdala transcriptional response during fear acquisition and a range of shared and dimorphic epitranscriptomic signatures. Differential RNA modifications are enriched among mRNA transcripts associated with neurotransmitter regulation and mitochondrial function, many of which have been previously implicated in PTSD. Very few differentially modified transcripts are also differentially expressed, suggesting an influential, expression-independent role for epitranscriptional regulation in PTSD-like fear acquisition.

Keywords: Behavioral neuroscience; Molecular biology; Molecular mechanism of behavior; Omics; Transcriptomics.