Research

Research Figure

Animal studies provide critical insights into the aetio-pathogenesis of stress-related psychiatric states. Our approach is to study the effects of chronic social stress (CSS) on neurobehavioural states in mice, at the inter-dependent levels of cell populations, neural circuits and behaviour. We focus on increasing understanding of the aetio-pathogenesis and pharmacological treatment of specific trans-diagnostic psychopathologies, including reduced interest in reward, apathy, aversion hyper-sensitivity and deficient environmental control. In the mouse amygdala, CSS leads to altered resting-state functional connectivity with frontal cortex regions (fMRI), increased levels of inflammatory markers (MRS, LC-MS/MS, immunofluorescence), and altered gene expression (mRNA-Seq). We are currently elucidating the contributions of specific populations of amygdala glutamate projection neurons to (1) regulation of reward and aversion processing, and (2) CSS disruption of reward and aversion processing. This includes use of viral vectors to silence amygdala basal nucleus (BA) glutamate neurons projecting to nucleus accumbens (NAc) and comparison of its effects with CSS effects in terms of: disrupted reward-directed behaviour; BA-NAc neural reactivity to reward and NAc dopamine release using in vivo photometry; BA-NAc glutamate neuron transcriptome and proteome expression. We are also studying effects of CSS on BA glutamate neurons projecting to amygdala central nucleus (CeA) in terms of BA-CeA neural reactivity to aversion and BA-CeA glutamate neuron transcriptome. Another major focus is the contribution of disturbances in the oligodendrocyte lineage and myelination in amygdala-prefrontal cortex circuits to CSS-induced disruption of reward and aversion processing. With regard to aetiological mechanisms, we are particularly interested in involvement of inflammation in mediating CSS effects on the brain, focusing on extracellular vesicles released from immune cells with a cargo of microRNAs. In this research, as well as research aimed at identifying transcriptomic and proteomic markers of the stressed amygdala, we are conducting direct comparisons of CSS mice and depressed humans. Specific major projects are:

  • 2016-2021: Mouse models of apathy and helplessness: increasing circuit and target understanding at sub-regional and cellular levels
  • 2017-2021: Extracellular-vesicle micro-RNAs as informative peripheral biomarkers in immune-inflammation brain pathologies
  • 2018-2022: Chronic social stress reduces reward salience: investigating amygdala reward neurons as a substrate of this effect and a therapeutic target
  • 2019-2022: Translational discovery, verification and validation of a biomarker profile for depression
  • 2016-2022: Mouse models for discovery and validation of pharmacological targets for reward and aversion psychopathologies