Metabolic Underpinnings of Susceptibility to Adverse Childood Experiences
Abstract
Adverse childhood experiences (ACE) constitute a major risk factor for neuropsychiatric perturbations in adult life. Here, we propose a role for peripheral lipids and their associated non-coding RNAs in conferring susceptibility versus resilience to the long-term effects of ACE via modulation of microglia in the brain.
Our preliminary investigations demonstrate differential changes in serum lipids and microRNAs in children that exhibit susceptibility versus resilience to ACE. Capitalizing on this preliminary evidence, we aim to investigate the role of lipids and microglia in susceptibility versus resilience in a mouse model of ACE (induced by maternal separation and unpredictable maternal stress; MSUS). MSUS mice will be fed high-fat diet (HFD) followed by transcriptomic and functional analysis of microglia and behavioral phenotyping. The importance of microglia in the susceptibility to ACE will be then assessed by repeating MSUS and HFD paradigms in mice with microglial depletion. The candidate microglial pathways identified will then be verified and targeted specifically in a transgenic mouse model. The results will also be translationally validated via stimulating microglia-containing human brain organoids with serum samples from human ACE cohorts. Finally, pre-clinical investigations in mice will assess the potential of lipid-modifying dietary supplements, as well as targeted microRNA therapeutics, for enhancement of resilience against the long-term effects of ACE.
Keywords
(Epi)genetic approaches
Omics approaches
Gene targeting in the brain
Molecular modelling techniques
Behavioural methodologies
Patient cohorts
Human data analysis
Human pre-clinical studies
Animal studies
In vitro model
Call topic
Resilience in Mental Health
Proposed runtime
n/a - n/a
Project team
Ali Jawaid (Coordinator)
Poland (NCBR)
Rosa Paolicelli
Switzerland (SNSF)
Anthony Hannan
Australia (NHMRC)