Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment
File(s)
Published version
Author(s)
Gillies, GE
McArthur, S
Pienaar, I
Siddiqi, S
Type
Journal Article
Abstract
The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers’ drinking water on gestational days 16–19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bias.
Date Issued
2015-05-06
Date Acceptance
2015-04-20
Citation
Brain Structure & Function, 2015, 221 (5), pp.2459-2475
ISSN
1863-2661
Publisher
Springer Verlag (Germany)
Start Page
2459
End Page
2475
Journal / Book Title
Brain Structure & Function
Volume
221
Issue
5
License URL
Sponsor
Wellcome Trust
Grant Number
086871/Z/08/Z
Subjects
Antenatal GC treatment
Astrocytes
Dopaminergic neurons
Midbrain
Neurobiological programming
Sex dimorphisms
Neurology & Neurosurgery
1116 Medical Physiology
1109 Neurosciences
1702 Cognitive Science
Publication Status
Published