Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt)... Show moreHuntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD -related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell -type and brain regionspecific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD -related symptoms, with the exception of the anti -epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option. Show less
Non-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic... Show moreNon-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic options are available. In this study, we set out to evaluate the novel glucocorticoid receptor modulator CORT125385, an analogue of the previously studied miricorilant but without mineralocorticoid receptor binding activity. Male and female mice that received high-fat diet and fructose water were treated with either vehicle, CORT125385 or mifepristone. We found that CORT125385 significantly lowered hepatic triglyceride levels in male mice, and hepatic triglyceride and cholesterol levels in female mice. Mifepristone treatment had no effect in male mice, but significantly lowered hepatic triglyceride and cholesterol levels in female mice. In reporter assays in vitro, CORT125385 showed weak partial agonism on the progesterone receptor (PR) at high doses, as well as PR antagonism at a potency 1000-fold lower than mifepristone. In vivo, CORT125385 treatment did not influence PR-responsive gene expression in the oviduct, while mifepristone treatment strongly influenced these genes in the oviduct, thus excluding in vivo PR cross-reactivity of CORT125385 at a therapeutically active dose. We conclude that CORT125385 is a promising glucocorticoid receptor modulator that effectively reduces liver steatosis in male and female mice without affecting other steroid receptors at doses that lower hepatic lipid content. Show less
Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is... Show moreIntroduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females. Show less
"Adaptive dynamics" is the study of evolution driven by rare mutations with small effects. The essential tool is the "invasion fitness", the expected number of offspring for a rare mutant in a... Show more"Adaptive dynamics" is the study of evolution driven by rare mutations with small effects. The essential tool is the "invasion fitness", the expected number of offspring for a rare mutant in a resident community at equilibrium. The first part of this thesis starts by generalising the "canonical equation of adaptive dynamics", a first-order approximation of the speed of change of multidimensional traits under directional selection, so that it holds for general physiologically structured (i.e., arbitrarily complex) population models. Secondly, it proves that near evolutionary singularities and up to second-order terms, such models have the same invasion fitness as the much simpler Lotka-Volterra models (but third-order terms can differ). Thirdly, it combines those results in a recipe for studying analytically the complete dynamics of evolutionary models with limited mutational effects. A prerequisite for models of sympatric speciation to work is the evolution of assortative mating, which has never been validated against alternatives. Therefore the second part compares in a general setting the relative probabilities of the evolution of assortative mate choice to that of dominance interactions, and the conditions favouring each one. This part also shows that allowing for the possibility of sexual dimorphism makes sympatric speciation much less likely. Show less
