Steroid profiling in male wobbler mouse, a model of Amyotrophic Lateral Sclerosis

The Wobbler mouse is an animal model for human motoneuron diseases, especially amyotrophic lateral sclerosis (ALS), used in the investigation of both pathology and therapeutic treatment. ALS is a fatal neurodegenerative disease, characterized by the selective and progressive death of motoneurons, leading to progressive paralysis. Previous limited studies have reported steroidal hormone dysregulation in Wobbler mouse and in ALS patients, suggesting endocrine dysfunctions which may be involved in the pathogenesis of the disease. In this study, we established a steroid profiling in brain, spinal cord, plasma, adrenal glands, and testes in 2-month-old male Wobbler mice and their littermates by gas chromatography coupled to mass spectrometry. Our results show in Wobbler mice the following: 1) a marked up-regulation of corticosterone levels in adrenal glands, plasma, spinal cord regions (cervical, thoracic, lumbar) and brain; 2) a strong decrease in T levels in the testis, plasma, spinal cord, and brain; and 3) increased levels of progesterone and especially of its reduced metabolites 5α-dihydroprogesterone, allopregnanolone, and 20α-dihydroprogesterone in the brain, spinal cord, and adrenal glands. Furthermore, Wobbler mice showed a hypothalamic-pituitary-gonadal hypoactivity. Interestingly, plasma concentrations of corticosterone and T correlate well with their respective levels in cervical spinal cord in both control and Wobbler mice. T down-regulation is probably the consequence of adrenal hyperactivity, and the up-regulation of progesterone and its reduced metabolites may correspond to an endogenous protective mechanism in response to motoneuron degeneration. Our findings suggest that increased levels of corticosterone and decreased levels of T in plasma could be a signature of motoneuron degeneration.Fil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Liere, Philippe. Inserm; Francia. Université Paris Saclay; FranciaFil: Pianos, Antoine. Inserm; Francia. Université Paris Saclay; FranciaFil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Aprahamian, Fanny. Inserm; Francia. Université Paris Saclay; FranciaFil: Cambourg, Annie. Inserm; Francia. Université Paris Saclay; FranciaFil: Di Giorgio, Noelia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Schumacher, Michael. Inserm; Francia. Université Paris Saclay; Francia. Universite Paris Sud; FranciaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guennoun, Rachida. Université Paris Saclay; Francia. Inserm; Francia. Universite Paris Sud; Franci

Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival

A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora+/sg, heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora+/sg), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora+/sg Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora+/sg cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora+/sg their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency

Progesterone receptors: a key for neuroprotection in experimental stroke

Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.Fil: Liu, Ailing. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Margaill, Isabelle. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia. University Paris Descartes; FranciaFil: Zhang, Shaodong. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Coqueran, Bérard. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: Delespierre, Brigitte. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Liere, Philippe. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Marchand Leroux, Catherine. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: O’Malley, Bert W.. Baylor College of Medicine;Fil: Lydon, John P.. Baylor College of Medicine;Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sitruk Ware, Regine. The Rockefeller University; Estados UnidosFil: Mattern, Claudia. MetP Pharma AG; SuizaFil: Plotkine, Michel. Universite de Paris V; FranciaFil: Schumacher, Michael. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Guennoun, Rachida. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Franci

Nestorone® as a Novel Progestin for Nonoral Contraception:Structure-Activity Relationships and Brain Metabolism Studies

Nestorone® (NES) is a highly potent non-androgenic progestin being developed for contraception. NES is a synthetic progestin that may possess neuroprotective and myelin regenerative potential as an added health benefits. In receptor transactivation experiments, NES displayed greater potency than progesterone to transactivate the human progesterone receptor (hPR). This was confirmed by docking experiments which revealed that NES adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone and forms additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD supporting its higher potency than progesterone. The analogue 13-ethyl NES also establishes similar contacts as NES with Met909, leading to comparable potency as NES. In contrast, NES is not stabilized within the human androgen receptor (hAR)-LBD leading to negligible AR transactivation. Since progesterone acts in the brain by both PR-binding and indirectly via the metabolite allopregnanolone binding to GABA_A receptor (GABA_A_R), we investigated if NES is metabolized to 3α, 5α-tetrahydronestorone (3α, 5α-THNES) in the brain and if this metabolite could interact with GABA_A_R. In female mice, low concentrations of reduced NES metabolites were identified by Gas Chromatography-Mass Spectrometry in both plasma and brain. However, electrophysiological studies showed that 3α, 5α-THNES exhibited only limited activity to enhance GABAAR-evoked responses with WSS-1 cells and did not modulate synaptic GABA_A_Rs of mouse cortical neurons. Thus the inability of reduced metabolite of NES (3α, 5α-THNES) to activate GABA_A_R suggests that the neuroprotective and myelin regenerative effects of NES are mediated via PR binding and not via its interaction with the GABA_A_R

Emulation of X-ray light-field cameras

X-ray plenoptic cameras acquire multi-view X-ray transmission images in a single exposure (light-field). Their development is challenging: designs have appeared only recently, and they are still affected by important limitations. Concurrently, the lack of available real X-ray light-field data hinders dedicated algorithmic development. Here, we present a physical emulation setup for rapidly exploring the parameter space of both existing and conceptual camera designs. This will assist and accelerate the design of X-ray plenoptic imaging solutions, and provide a tool for generating unlimited real X-ray plenoptic data. We also demonstrate that X-ray light-fields allow for reconstructing sharp spatial structures in three-dimensions (3D) from single-shot data

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies

Progesterone and fetal-neonatal neuroprotection

International audienceThe role of progesterone goes beyond the maintenance of pregnancy. The hormone, indeed, protects the developing fetal brain and influences its maturation. Metabolomes analyzed by mass spectrometric methods have revealed the great diversity of steroids in maternal plasma and fetal fluids, but their developmental significance remains to be investigated. Progesterone and its metabolites reach highest levels during the third trimester, when the brain growth spurt occurs: its volume triples, synaptogenesis is particularly active, and axons start to be myelinated. This developmental stage coincides with a period of great vulnerability. Studies in sheep have shown that progesterone and its metabolite allopregnanolone protect the vulnerable fetal brain. Work in rats and mice have demonstrated that progesterone plays an important role in myelin formation. These experimental studies are discussed in relation to preterm birth. Influences of progesterone on very early stages of neural development at the beginning of pregnancy are yet to be explored

Revisiting medial preoptic area plasticity induced in male mice by sexual experience

Abstract Sexual experience in male rodents, induced by a first exposure to a receptive female, improves efficiency of following copulations. In mice, the mechanisms supporting this improvement are poorly understood. We characterized molecular modifications of the mouse hypothalamic medial preoptic area (mPOA), the main integrative structure for male sexual behaviour, after a single mating event. This paradigm induced long-lasting behavioural improvements and mPOA morphological changes, evidenced by dendritic spine maturation and an increase in the acetylated and tri-methylated forms of histone H3. Ejaculation affected testosterone, progesterone and corticosterone levels in both naive and experienced mice, but sexual experience did not modify basal plasma or hypothalamic levels of steroids. In contrast to studies carried out in rats, no changes were observed, either in the nitrergic system, or in sex steroid receptor levels. However, levels of glutamate- and calcium-associated proteins, including PSD-95, calbindin and the GluN1 subunit of the NMDA receptor, were increased in sexually experienced male mice. The Iba-1 microglial marker was up-regulated in these animals suggesting multicellular interactions induced within the mPOA by sexual experience. In conclusion, plasticity mechanisms induced by sexual experience differ between rat and mouse, even if in both cases they converge to potentiation of the mPOA network