Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation – Relevance to psychiatric and neurodevelopmental illness, and implications for treatment

Abstract

Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.