Abstract
The hypothalamic-pituitary-adrenal (HPA) axis regulates responses to internal and external stressors. Many patients diagnosed with conditions such as depression or anxiety also have hyperactivity of the HPA axis. Hyper-stimulation of the HPA axis results in sustained elevated levels of glucocorticoids which impair neuronal function and can ultimately result in a psychiatric disorder. Studies investigating Glucocorticoid Receptor (GR/NR3C1) in the brain have primarily focused on the forebrain, however in recent years, the hindbrain has become a region of interest for research into the development of anxiety and depression, though the role of GR signalling in the hindbrain remains poorly characterised. 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 structure. Our study highlights that ablation of GR in the hindbrain results in excessive barbering, obsessive compulsive digging and lack of cage exploration. These mice also develop kyphosis, elevated circulating corticosterone and severe adrenal cortex disruption. Together, this data demonstrates a role for hindbrain GR signalling in regulating stress-related behaviour and identifies a novel mouse model to allow further investigation into the pathways impacting stress and anxiety.
Highlights
According to the World Health Organization, mood disorders will be the second leading cause of disability by the year 2020, the need for appropriate models to understand these disorders is essential
As the Cre expression is driven by a Cyp11a1 promoter, and Cyp11a1 is widely expressed throughout the adrenal cortex, we interrogated expression of the transgene in the adrenal gland in order to fully understand the sites of targeting that could underpin any observable phenotype
Through use of Cyp11a1+/GC: R26-EYFP mice and double immunofluorescence localisation we are able to rule out this potential confounder since the analysis shows that the Cre does not target glucocorticoid receptor (GR) expressing cell types in the adrenal (Fig. 1B)
Summary
According to the World Health Organization, mood disorders will be the second leading cause of disability by the year 2020, the need for appropriate models to understand these disorders is essential. The detrimental effects of excessive glucocorticoid levels on the hippocampus seems to require GR to be functioning normally, whereas these same excessive glucocorticoid levels in conditions such as depression, may result from impaired negative feedback inhibition on the HPA axis, which is caused by loss of function of GR4 For these reasons, more research is needed into the various regions of the brain expressing GR and their role in depression and anxiety which can be achieved through the development of novel models. We demonstrate that ablation of GR in the hindbrain results in a stress-sensitive phenotype in mice, with excessive barbering, obsessive compulsive digging and lack of cage exploration These mice develop kyphosis, elevated circulating corticosterone and severe adrenal cortex disruption, suggesting that this novel mouse model represents a suitable experimental system with which to investigate mood disorders
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