Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience

We demonstrated previously that antenatal glucocorticoid treatment (AGT, gestational days 16-19) altered the size and organization of the adult rat midbrain dopaminergic (DA) populations. Here we investigated the consequences of these AGT-induced cytoarchitectural disturbances on indices of DA function in adult rats. We show that in adulthood, enrichment of striatal DA fiber density paralleled AGT-induced increases in the numbers of midbrain DA neurons, which retained normal basal electrophysiological properties. This was co-incident with changes in (i) striatal D2-type receptor levels (increased, both sexes); (ii) D1-type receptor levels (males decreased; females increased); (iii) DA transporter levels (males increased; females decreased) in striatal regions; and (iv) amphetamine-induced mesolimbic DA release (males increased; females decreased). However, despite these profound, sexually dimorphic changes in markers of DA neurotransmission, in-utero glucocorticoid overexposure had a modest or no effect on a range of conditioned and unconditioned appetitive behaviors known to depend on mesolimbic DA activity. These findings provide empirical evidence for enduring AGT-induced adaptive mechanisms within the midbrain DA circuitry, which preserve some, but not all, functions, thereby casting further light on the vulnerability of these systems to environmental perturbations. Furthermore, they demonstrate these effects are achieved by different, often opponent, adaptive mechanisms in males and females, with translational implications for sex biases commonly found in midbrain DA-associated disorders

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

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 bia

Associations between respiratory sinus arrhythmia reactivity and internalizing and externalizing symptoms are emotion specific

Internalizing and externalizing disorders are often, though inconsistently in studies of young children, associated with low baseline levels of respiratory sinus arrhythmia (RSA). RSA is thus considered to reflect the capacity for flexible and regulated affective reactivity and a general propensity for psychopathology. However, studies assessing RSA reactivity to emotional challenges tend to report more consistent associations with internalizing than with externalizing disorders, although it is unclear whether this is a function of the type of emotion challenges used. In the present study, we examined whether baseline RSA was associated with internalizing and/or externalizing severity in a sample of 273 young children (ages 5–6) with elevated symptoms of psychopathology. Following motivation-based models of emotion, we also tested whether RSA reactivity during withdrawal-based (fear, sadness) and approach-based (happiness, anger) emotion inductions was differentially associated with internalizing and externalizing symptoms, respectively. Baseline RSA was not associated with externalizing or internalizing symptom severity. However, RSA reactivity to specific emotional challenges was associated differentially with each symptom domain. As expected, internalizing symptom severity was associated with greater RSA withdrawal (increased arousal) during fearful and sad film segments. Conversely, externalizing symptom severity was related to blunted RSA withdrawal during a happy film segment. The use of theoretically derived stimuli may be important in characterizing the nature of the deficits in emotion processing that differentiate the internalizing and externalizing domains of psychopathology