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

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

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory

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

Applications of positron emission tomography in animal models of neurological and neuropsychiatric disorders

Positron emission tomography (PET) provides dynamic images of the biodistribution of radioactive tracers in the brain. Through application of the principles of compartmental analysis, tracer uptake can be quantified in terms of specific physiological processes such as cerebral blood flow, cerebral metabolic rate, and the availability of receptors in brain. Whereas early PET studies in animal models of brain diseases were hampered by the limited spatial resolution of PET instruments, dedicated small-animal instruments now provide molecular images of rodent brain with resolution approaching 1 mm, the theoretic limit of the method. Major applications of PET for brain research have consisted of studies of animal models of neurological disorders, notably Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD), stroke, epilepsy and traumatic brain injury; these studies have particularly benefited from selective neurochemical lesion models (PD), and also transgenic rodent models (AD, HD). Due to their complex and uncertain pathophysiologies, corresponding models of neuropsychiatric disorders have proven more difficult to establish. Historically, there has been an emphasis on PET studies of dopamine transmission, as assessed with a range of tracers targeting dopamine synthesis, plasma membrane transporters, and receptor binding sites. However, notable recent breakthroughs in molecular imaging include the development of greatly improved tracers for subtypes of serotonin, cannabinoid, and metabotropic glutamate receptors, as well as noradrenaline transporters, amyloid-β and neuroinflammatory changes. This article reviews the considerable recent progress in preclinical PET and discusses applications relevant to a number of neurological and neuropsychiatric disorders in humans

Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein

The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5–6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments o

Phenotypic variation of autosomal-dominant corticobasal degeneration

Neurodegenerative tauopathies may be inherited as autosomal-dominant disorders with variable clinicopathological phenotypes, and causative mutations in the microtubule-associated protein tau (MAPT) gene are not regularly seen. Herein, we describe a patient with clinically typical and autopsy-proven corticobasal degeneration (CBD). Her mother was diagnosed to have Parkinson's disease, but autopsy showed CBD pathology as in the index patient. The sister of the index patient had the clinical symptoms of primary progressive aphasia (PPA), but no pathology was available to date. Molecular analysis did not reveal any mutation in the MAPT or progranulin (GRN) genes. Our findings illustrate that CBD, progressive supranuclear palsy and PPA may be overlapping diseases with a common pathological basis rather than distinct entities. Clinical presentation and course might be determined by additional, yet unknown, genetic modifying factors