Linking maternal stress during gestation to resilience vs. susceptibility in the offspring: a preclinical imaging study

This project will be embedded within an on-going EU HORIZON funded study ("HappyMums"), which seeks to improve our understanding about biological causes of depression during pregnancy, how it impacts the offspring, and the efficacy of interventions. The study encompasses both clinical research as well as 'reverse-translation' into animal models.

Whilst clinical and epidemiological research in humans, also used in this project, offers valuable information regarding maternal wellbeing during pregnancy and neurodevelopmental outcomes in the offspring, this is limited in its ability to uncover causal pathogenic mechanisms. The proof of causality can instead be better achieved using animal models, which are able to model both stress during gestation and the ensuing depressive-like symptoms that occur before and continue during pregnancy.

The primary goal of this project is to identify neuroimaging biomarkers associated with risk and resilience (as measured by behaviour) in mouse dams and their offspring exposed to different prenatal stressors in utero. The secondary goal is to identify the impact of one therapeutic intervention on these biomarkers.

To achieve these goals we propose the following specific aims: Year 1 - Aim (1) Identify brain biomarkers associated with depressive-like behaviour in pregnant dams

Year 2 - Aim (2) Characterise brain development in the offspring in relation to behavioural outcome (susceptibility vs resilience) Year 3 - Aim (3) Measure impacts of therapeutic intervention in the most relevant model, on these biomarkers.

To address the specific aims of this project, we will use up to three different and complimentary animal models, distinguished by the time window of induction of depressive-like symptoms in dams. These are: 1. Unpredictable maternal separation combined with unpredictable maternal stress (MSUS) model [Boscardin C et al.

Environ Epigenet. 2022]; 2. Chronic social isolation rearing (CSIR) model [Scarborough J et al. Molecular Psychiatry, 2021) and 3.

Prenatal and/or postnatal stress (PNS and PNS/LBN) model [Creutzberg KC et al. Translational. Psychiatry 2023] adapted to mice.

For each aim, the group sizes are informed by the measured effect sizes using published behavioural data for each model.