The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Ablation of glucocorticoid receptor in the hindbrain of the mouse provides a novel model to investigate stress disorders (#184)

Anne-Louise Gannon 1 2 , Laura O'Hara 2 3 , J Ian Mason 2 , Rod T Mitchell 2 , Diane Rebourcet 1 2 , Sarah Smith 2 , Adriana Traveres 4 , Hanne Frederikson 5 , Anne Jorgensen 5 , Laura Milne 2 , Lee B Smith 1 2
  1. The University of Newcastle, Callaghan, NSW, Australia
  2. CRH, The University of Edinburgh, Edinburgh, Scotland
  3. Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland
  4. Edinburgh Preclinical Imaging, The University of Edinburgh, Edinburgh, Scotland
  5. Department of Growth and Reproduction, University of Copenhagen, Copenhagen, Denmark

According to the World Health Organization, mood disorders will be the second leading cause of disability by the year 2020(1), so the need for appropriate models to understand these disorders is ever pressing. The hypothalamic-pituitary-adrenal (HPA) axis is part of the body’s neuroendocrine system which regulates responses to internal and external stressors. Hyper-stimulation of the HPA axis results in sustained elevated levels of glucocorticoids which has been shown to impair neuronal function and can ultimately result in mental, neurological and substance use conditions (2, 3). Studies investigating the role of GR in the brain has primarily focused on the forebrain, however, glucocorticoid receptor (GR) is also expressed in the hindbrain (4) and has recently become a region of interest for the development of anxiety and HPA-axis dysregulation, yet, its exact role has not been clearly defined.

To determine the role of glucocorticoid signalling in the hindbrain we have developed a novel mouse model that specifically ablates hindbrain GR to ascertain its role in behaviour, HPA-axis regulation and adrenal function. Our study highlights that ablation of GR in the hindbrain results in a stressed phenotype in mice, characterised by excessive barbering and obsessive compulsive digging with lack of cage exploration. These mice also develop kyphosis, elevated circulating corticosterone and severe adrenal cortex disruption, highlighting that functional hindbrain GR is required for normal HPA-axis regulation, adrenal cortex function and behaviour.

Together, this data demonstrates a role for hindbrain GR signalling in regulating stress-related behavior and identifies a novel mouse model that recapitulates what is observed in patients, allowing further investigation into the pathways impacting stress and anxiety. Furthermore, it builds on previous literature that describes a relationship between stress and the dysregulation of the HPA axis leading to adrenal cortex damage.

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