GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Response to change in the number of visual stimuli in zebrafish:A behavioural and molecular study.

Evidence has shown that a variety of vertebrates, including fish, can discriminate collections of visual items on the basis of their numerousness using an evolutionarily conserved system for approximating numerical magnitude (the so-called Approximate Number System, ANS). Here we combine a habituation/dishabituation behavioural task with molecular biology assays to start investigating the neural bases of the ANS in zebrafish. Separate groups of zebrafish underwent a habituation phase with a set of 3 or 9 small red dots, associated with a food reward. The dots changed in size, position and density from trial to trial but maintained their numerousness, and the overall areas of the stimuli was kept constant. During the subsequent dishabituation test, zebrafish faced a change (i) in number (from 3 to 9 or vice versa with the same overall surface), or (ii) in shape (with the same overall surface and number), or (iii) in size (with the same shape and number). A control group of zebrafish was shown the same stimuli as during the habituation. RT-qPCR revealed that the telencephalon and thalamus were characterized by the most consistent modulation of the expression of the immediate early genes c-fos and egr-1 upon change in numerousness; in contrast, the retina and optic tectum responded mainly to changes in stimulus size.

KLB, encoding ß-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with ß-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

[MicroRNAs: new players in the hypothalamic control of fertility]. / Les micro-ARN - Nouveaux acteurs du contrôle hypothalamique de la fertilité.

MicroRNAs are small non-coding RNAs that modulate gene expression post-transcriptionally. Discovered more than 15 years ago, their functions start to be unraveled. Increasing evidence points to an important functional role of microRNAs in brain development. In particular, miRNAs have recently been established to play a vital role in the mechanisms underlying the infantile rise in gonadotropin-releasing hormone (GnRH) production by neurons in the hypothalamus, a phenomenon necessary for the onset of puberty in mammals.

A microRNA switch regulates the rise in hypothalamic GnRH production before puberty.

A sparse population of a few hundred primarily hypothalamic neurons forms the hub of a complex neuroglial network that controls reproduction in mammals by secreting the 'master molecule' gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH expression are essential for puberty and adult fertility. Here we report that a multilayered microRNA-operated switch with built-in feedback governs increased GnRH expression during the infantile-to-juvenile transition and that impairing microRNA synthesis in GnRH neurons leads to hypogonadotropic hypogonadism and infertility in mice. Two essential components of this switch, miR-200 and miR-155, respectively regulate Zeb1, a repressor of Gnrh transcriptional activators and Gnrh itself, and Cebpb, a nitric oxide-mediated repressor of Gnrh that acts both directly and through Zeb1, in GnRH neurons. This alteration in the delicate balance between inductive and repressive signals induces the normal GnRH-fuelled run-up to correct puberty initiation, and interfering with this process disrupts the neuroendocrine control of reproduction.

Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion.

Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS.

Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain.

Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.

Fatal cranial injury in an individual from Messina (Sicily) during the times of the Roman Empire.

Forensic and archaeological examinations of human skeletons can provide us with evidence of violence. In this paper, we present the patterns of two cranial lesions found on an adult male (T173) buried in a grave in the necropolis 'Isolato 96', Messina, Sicily, dating back to the Roman Empire (1st century BC - 1st century AD). The skull reveals two perimortem traumatic lesions, one produced by a sharp object on the right parietal bone and the other one on the left parietal bone, presumably the result of a fall. The interpretation of fracture patterns found in this cranium are an illustration of how forensic approaches can be applied with great benefit to archaeological specimens.

Origin and diet of the prehistoric hunter-gatherers on the mediterranean island of Favignana (Ègadi Islands, Sicily).

Hunter-gatherers living in Europe during the transition from the late Pleistocene to the Holocene intensified food acquisition by broadening the range of resources exploited to include marine taxa. However, little is known on the nature of this dietary change in the Mediterranean Basin. A key area to investigate this issue is the archipelago of the Ègadi Islands, most of which were connected to Sicily until the early Holocene. The site of Grotta d'Oriente, on the present-day island of Favignana, was occupied by hunter-gatherers when Postglacial environmental changes were taking place (14,000-7,500 cal BP). Here we present the results of AMS radiocarbon dating, palaeogenetic and isotopic analyses undertaken on skeletal remains of the humans buried at Grotta d'Oriente. Analyses of the mitochondrial hypervariable first region of individual Oriente B, which belongs to the HV-1 haplogroup, suggest for the first time on genetic grounds that humans living in Sicily during the early Holocene could have originated from groups that migrated from the Italian Peninsula around the Last Glacial Maximum. Carbon and nitrogen isotope analyses show that the Upper Palaeolithic and Mesolithic hunter-gatherers of Favignana consumed almost exclusively protein from terrestrial game and that there was only a slight increase in marine food consumption from the late Pleistocene to the early Holocene. This dietary change was similar in scale to that at sites on mainland Sicily and in the rest of the Mediterranean, suggesting that the hunter-gatherers of Grotta d'Oriente did not modify their subsistence strategies specifically to adapt to the progressive isolation of Favignana. The limited development of technologies for intensively exploiting marine resources was probably a consequence both of Mediterranean oligotrophy and of the small effective population size of these increasingly isolated human groups, which made innovation less likely and prevented transmission of fitness-enhancing adaptations.