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Brain Sci. 2017, 7(1), 5; doi:10.3390/brainsci7010005

Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations

1
Division of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
2
Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK
3
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK
4
Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK
5
Department of Psychiatry, University of Cambridge, Cambridge CB2 2QQ, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Yu Ping Tang
Received: 27 October 2016 / Revised: 14 December 2016 / Accepted: 16 December 2016 / Published: 30 December 2016
(This article belongs to the Special Issue Sex Differences in Brain Development)
View Full-Text   |   Download PDF [3807 KB, uploaded 30 December 2016]   |  

Abstract

Glucocorticoid hormones (GCs) released from the fetal/maternal glands during late gestation are required for normal development of mammalian organs and tissues. Accordingly, synthetic glucocorticoids have proven to be invaluable in perinatal medicine where they are widely used to accelerate fetal lung maturation when there is risk of pre-term birth and to promote infant survival. However, clinical and pre-clinical studies have demonstrated that inappropriate exposure of the developing brain to elevated levels of GCs, either as a result of clinical over-use or after stress-induced activation of the fetal/maternal adrenal cortex, is linked with significant effects on brain structure, neurological function and behaviour in later life. In order to understand the underlying neural processes, particular interest has focused on the midbrain dopaminergic systems, which are critical regulators of normal adaptive behaviours, cognitive and sensorimotor functions. Specifically, using a rodent model of GC exposure in late gestation (approximating human brain development at late second/early third trimester), we demonstrated enduring effects on the shape and volume of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (origins of the mesocorticolimbic and nigrostriatal dopaminergic pathways) on the topographical organisation and size of the dopaminergic neuronal populations and astrocytes within these nuclei and on target innervation density and neurochemical markers of dopaminergic transmission (receptors, transporters, basal and amphetamine-stimulated dopamine release at striatal and prefrontal cortical sites) that impact on the adult brain. The effects of antenatal GC treatment (AGT) were both profound and sexually-dimorphic, not only in terms of quantitative change but also qualitatively, with several parameters affected in the opposite direction in males and females. Although such substantial neurobiological changes might presage marked behavioural effects, in utero GC exposure had only a modest or no effect, depending on sex, on a range of conditioned and unconditioned behaviours known to depend on midbrain dopaminergic transmission. Collectively, these findings suggest that apparent behavioural normality in certain tests, but not others, arises from AGT-induced adaptations or compensatory mechanisms within the midbrain dopaminergic systems, which preserve some, but not all functions. Furthermore, the capacities for molecular adaptations to early environmental challenge are different, even opponent, in males and females, which may account for their differential resilience or failure to perform adequately in behavioural tests. Behavioural “normality” is thus achieved by the midbrain dopaminergic network operating outside its normal limits (in a state of allostasis), rendering it at greater risk to malfunction when challenged in later life. Sex-specific neurobiological programming of midbrain dopaminergic systems may, therefore, have psychopathological relevance for the sex bias commonly found in brain disorders associated with these systems, and which have a neurodevelopmental component, including schizophrenia, ADHD (attention/deficit hyperactivity disorders), autism, depression and substance abuse. View Full-Text
Keywords: dopaminergic neurones; astrocytes; midbrain; ventral tegmental area; substantia nigra pars compacta; antenatal glucocorticoid treatment; developmental programming; sex dimorphisms dopaminergic neurones; astrocytes; midbrain; ventral tegmental area; substantia nigra pars compacta; antenatal glucocorticoid treatment; developmental programming; sex dimorphisms
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MDPI and ACS Style

Gillies, G.E.; Virdee, K.; Pienaar, I.; Al-Zaid, F.; Dalley, J.W. Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations. Brain Sci. 2017, 7, 5.

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