The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

Abstract

Central dopaminergic (DA) systems appear to be particularly vulnerable to disruption by exposure to stressors in early life, but the underlying mechanisms are poorly understood. As endogenous glucocorticoids (GCs) are implicated in other aspects of neurobiological programming, this study aimed to characterize the effects of perinatal GC exposure on the cytoarchitecture of DA populations in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). Dexamethasone was administered non-invasively to rat pups via the mothers' drinking water during embryonic days 16-19 or postnatal days 1-7, with a total oral intake circa 0.075 or 0.15 mg/ kg/day, respectively; controls received normal drinking water. Analysis of tyrosine hydroxylase-immunoreactive cell counts and regional volumes in adult offspring identified notable sex differences in the shape and volume of the SNc and VTA, as well as the topographical organization and size of the DA populations. Perinatal GC treatments increased the DA population size and altered the shape of the SNc and VTA as well as the organization of the DA neurons by expanding and/or shifting them in a caudal direction. This response was sexually dimorphic and included a feminization or demasculinization of the three-dimensional cytoarchitecture in males, and subtle differences that were dependent on the window of exposure. These findings demonstrate that inappropriate perinatal exposure to GCs have enduring effects on the organization of midbrain DA systems that are critically important for normal brain function throughout life.

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…Moreover, we have reported a notable sex differences in their topographical distribution, indicating a structural basis for sex differences in connectivity and DA transmission (Fig. 4, A and B) (McArthur et al, 2007a). Despite differences in neuronal number, there are no sex differences in striatal DA content and basal extracellular DA levels in the caudate putamen, which is thought to be due to sex differences in neuron dynamics (DA reuptake, release, terminal density, etc.)…”

“…However, the last decade has seen an exponential increase in evidence for structural, cellular, and molecular sex differences in the brain that can be described as true dimorphisms, defined as the occurrence of two forms in the same species. These include regions of human and animal brains that are important for cognition, memory, and affect, such as the hippocampus, amygdala, and cortex (Kelly et al, 1999;BaronCohen et al, 2005;McCarthy and Konkle, 2005;Cahill, 2006;Cosgrove et al, 2007;Wilson and Davies, 2007), and for regions controlling sensorimotor and reward systems (Becker, 1999;Dewing et al, 2006;Cantuti-Castelvetri et al, 2007;McArthur et al, 2007a). Indeed, post mortem studies, as well as evidence from new technologies for in vivo imaging, are adding rapidly to the view that sex differences in the human brain may be the norm rather than the exception (Madeira and Lieberman, 1995;Allen et al, 2003;Kruijver et al, 2003;Luders et al, 2004;Mechelli et al, 2005;Cosgrove et al, 2007;Ishunina and Swaab, 2008;Swaab, 2008).…”

“…It was soon recognized that an overt difference in nuclear size was not the only salient feature to differ in male and female brains; subsequently, many more subtle dimorphisms in neuronal phenotype, fiber density, neurochemistry, and cytoarchitecture have been discovered (Kelly et al, 1999;Cahill, 2006;McArthur et al, 2006McArthur et al, , 2007aCosgrove et al, 2007;Wilson and Davies, 2007). Most importantly, sexually dimorphic responses to estrogen, which are a key focus of this review, were first characterized in the hypothalamic circuitry regulating reproductive hormonal and behavior patterns.…”

Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems?

“…In rats, a range of adverse effects has been observed upon prenatal GC treatment: low birth weight and hypertension (16), decreased size of the hippocampus and affected short-term memory (9) and alterations in structural brain development as well as in different neurotransmitter systems (17)(18)(19). Behavioural inhibition has also been observed in rats exposed to DEX during the entire gestational period or during late gestation (20).…”

Existe-t-il des différences entre les hommes et les femmes en ce qui concerne les problèmes de toxicomanie ?

“…Le nombre de neurones dopaminergiques a été signalé comme étant sexuellement dimorphique chez plusieurs espèces. Par exemple, chez les rats, les mâles possèdent plus de neurones dopaminergiques à substance noire (SN) et les femelles ont plus de neurones dopaminergiques dans l'aire tegmentale ventrale (VTA) (Murray et al, 2003 ;McArthur et al, 2007), alors que chez les primates non humains, on rapporte que les femelles possèdent plus de neurones dans le SN que les mâles (Leranth et al, 2000). Les diffé-rences dans le nombre de neurones dopaminergiques dépendent de plusieurs facteurs comme les chromosomes sexuels, la présence du gêne SRY et les hormones gonadiques (Milsted et al, 2004 ;Johnson et al, 2010).…”