title: Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment.
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.
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.|Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.|Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Sindhu M
authors.initials: SM
authors.lastname: Siddiqi
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK. g.gillies@imperial.ac.uk.
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gillies
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count; D003907:Dexamethasone / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065842:Pars Compacta / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D012727:Sex Characteristics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D014446:Tyrosine 3-Monooxygenase
keywords: Antenatal GC treatment; Astrocytes; Dopaminergic neurons; Midbrain; Neurobiological programming; Sex dimorphisms