Hypersensitivity to sertraline in the absence of hippocampal 5-HT1AR and 5-HTT gene expression changes following paternal corticosterone treatment

Abstract

The male germ line is capable of transmitting a legacy of stress exposure to the next generation of offspring. This transgenerational process manifests by altering offspring affective behaviours, cognition and metabolism. Paternal early life trauma causes hippocampal serotonergic dysregulation in male offspring. We previously showed a transgenerational modification to male offspring anxiety-like behaviours by treatment of adult male breeders with corticosterone (CORT) prior to mating. In the present study, we used offspring from our paternal CORT model and characterised offspring serotonergic function by examining their responses to the 5HT1AR agonist, 8-OH-DPAT, and the selective serotonin reuptake inhibitor, sertraline. We also examined whether post-weaning environmental enrichment, a paradigm well-known to modulate serotonergic signalling in the brain, had the capacity to normalise the anxiety phenotype of male offspring. Finally, we assessed gene expression levels of 5HT1AR and serotonin transporter in the offspring hippocampus to determine whether deficits in gene transcription contributed to the male-only anxiety phenotype. We report that male and female offspring of CORT-treated fathers are hypersensitive to sertraline but have normal hypothermic responses to 8-OH-DPAT. No deficits in htr1a and sert were found in association with paternal CORT treatment, and environmental enrichment did not rescue the anxiety phenotype of male offspring on the elevated-plus maze. These findings indicate that varying forms of paternal stress exert different effects on offspring brain serotonergic function.

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

“…We have provided initial in vitro evidence that mouse epididymal cells are responsive to CORT but that response was not replicated in vivo. Given our previous report that chronic (28 day) paternal CORT treatment is associated with behavioural modifications in offspring 15,16 , this study has now demonstrated that the duration of stress exposure is a crucial determinant of the paternal-derived intergenerational risk for anxiety disorders. This prompts further questions regarding the discrete influences of periodicity, age of exposure, and stress severity on the observable intergenerational effects.…”

“…Novelty-suppressed feeding test (NSFT) was performed as previously described 15 . Briefly, mice were food-deprived for 48 h with a 1 h feeding period after the first 24 h. Mice were weighed on the morning of the NSFT to calculate % body weight loss, with an expected weight loss of at least 15%.…”

“…Our group previously modelled generalised daily stress and chronic elevation of HPA axis activity by supplementing male C57Bl/6J breeders with low-dose CORT for 28 days prior to mating. In the process, we discovered transgenerational alterations to anxiety and depression-related behaviours of adult F1 and F2 offspring 15,16 .…”

A molecular insight into the dissociable regulation of associative learning and motivation by the synaptic protein neuroligin-1

“…Each session was video-recorded, and total mobility time throughout the 5-min session was measured (no time bins excluded). Scoring was obtained using the automated ForcedSwimScan software (CleverSys Inc., VA, USA) under previously optimized settings [ 82 ] eliminating the need for manual observer scoring.…”

Avaliação dos efeitos da exposição ambiental paterna no fenótipo da prole de camundongos >i<Swiss>/i<.

“…Dentre os paradigmas mais utilizados, estão a dieta hiperlipídica , estresse durante a infância (Franklin et al, 2010;Gapp et al, 2014a), tratamento com corticosterona (Short et al, 2016) e enriquecimento ambiental (Yeshurun et al, 2017, Benito et al, 2018. Vários efeitos foram descritos, como aumento de comportamento dirigido (goal-directed) e flexibilidade comportamental, (Gapp et al, 2014b), alterações em comportamento relacionado à ansiedade (Franklin et al, 2010;Short et al, 2016), alteração no eixo HPA (Rodgers et al, 2013) e sensibilidade comportamental a sertralina (Rawat et al, 2018). Foram descritos efeitos tanto intergeracionais quanto transgeracionais.…”