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Abstract Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

IntroductionDuring hypothalamic development, the germinative neuroepithelium gives birth to diverse neural cells that regulate numerous physiological functions in adulthood.MethodsHere, we studied the ontogeny of ependymal cells in the mouse mediobasal hypothalamus using the BrdU approach and publicly available single-cell RNAseq datasets.ResultsWe observed that while typical ependymal cells are mainly produced at E13, tanycyte birth depends on time and subtypes and lasts up to P8. Typical ependymocytes and β tanycytes are the first to arise at the top and bottom of the dorsoventral axis around E13, whereas α tanycytes emerge later in development, generating an outside-in dorsoventral gradient along the third ventricle. Additionally, α tanycyte generation displayed a rostral-to-caudal pattern. Finally, tanycytes mature progressively until they reach transcriptional maturity between P4 and P14.DiscussionAltogether, this data shows that ependyma generation differs in time and distribution, highlighting the heterogeneity of the third ventricle.

Abstract Non-traumatic intracranial bleeding (NTIB), comprising subarachnoid hemorrhage (SAH) and intra-cranial bleeding (ICH) is a significant public health concern. Tranexamic acid (TXA) is a promising treatment with benefits yet to be fully demonstrated. We conducted a systematic review and meta-analysis on the impact of TXA on mortality in NTIB. We searched the PubMed, Cochrane Library, Google Scholar and ScienceDirect databases for studies reporting mortality data following the use of TXA in NTIB for comparisons with a control group. We computed random-effect meta-analysis on estimates of risk and sensitivity analyses. We computed meta-regression to examine the putative effects of the severity of NTIB, sociodemographic data (age, sex), and publication date. Among potentially 10,008 articles, we included 15 studies representing a total of 4883 patients: 2455 receiving TXA and 2428 controls; 1110 died (23%) during the follow-up. The meta-analysis demonstrated a potential of 22% decrease in mortality for patients treated by TXA (RR = 0.78, 95%CI 0.58–0.98, p = 0.002). Meta-regression did not demonstrate any influence of the severity of NTIB, age, sex, length of treatment or date of publication. Sensitivity analyses confirmed benefits of TXA on mortality. TXA appears to be a therapeutic option to reduce non-traumatic intracranial bleeding mortality, particularly in patients with SAH.

Objectives: Glucagon secretion to stimulate hepatic glucose production is the first line of defense against hypoglycemia. This response is triggered by so far incompletely characterized central hypoglycemia-sensing mechanisms, which control autonomous nervous activity and hormone secretion. The objective of this study was to identify novel hypothalamic genes controlling insulin-induced glucagon secretion. Methods: To obtain new information on the mechanisms of hypothalamic hypoglycemia sensing, we combined genetic and transcriptomic analysis of glucagon response to insulin-induced hypoglycemia in a panel of BXD recombinant inbred mice. Results: We identified two QTLs on chromosome 8 and chromosome 15. We further investigated the role of Irak4 and Cpne8, both located in the QTL on chromosome 15, in C57BL/6J and DBA/2J mice, the BXD mouse parental strains. We found that the poor glucagon response of DBA/2J mice was associated with higher hypothalamic expression of Irak4, which encodes a kinase acting downstream of the interleukin-1 receptor (Il-1R), and of Il-ß when compared with C57BL/6J mice. We showed that intracerebroventricular administration of an Il-1R antagonist in DBA/2J mice restored insulin-induced glucagon secretion; this was associated with increased c-fos expression in the arcuate and paraventricular nuclei of the hypothalamus and with higher activation of both branches of the autonomous nervous system. Whole body inactivation of Cpne8, which encodes a Ca++-dependent regulator of membrane trafficking and exocytosis, however, had no impact on insulin-induced glucagon secretion. Conclusions: Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion.

Bartonella species represent important causative agents of blood culture-negative infective endocarditis (IE). Their diagnosis represents a challenge for microbiologists and often relies on serological and molecular tools. However, even if the sensitivity of blood culture remains low, it should not be definitely ruled out. Indeed, we report the unusual case of a 22 year-old Guinean homeless man diagnosed with an IE due to Bartonella quintana. Unexpectedly, conventional blood cultures were positive after 13 days of incubation. Subculture was obtained on blood and chocolate agar, after 15 days of incubation in a 5 % CO2 atmosphere. Bacterial identification was obtained up to the species level using molecular tools (16S rRNA gene amplification and sequencing). A literature review of B. quintana blood culture-positive IE was conducted and revealed eighteen similar reported cases on a 25-year period. This case illustrates that, despite low sensitivity, Bartonella IE may be diagnosed thanks to prolonged blood culture.

The bed nucleus of the stria terminalis (BNST) is a telencephalic structure well-connected to hypothalamic regions known to control goal-oriented behaviors such as feeding. In particular, we showed that the dorsomedial division of the anterior BNST innervate neurons of the paraventricular (PVH), dorsomedial (DMH), and arcuate (ARH) hypothalamic nuclei as well as the lateral hypothalamic area (LHA). While the anatomy of these projections has been characterized in mice, their ontogeny has not been studied. In this study, we used the DiI-based tract tracing approach to study the development of BNST projections innervating several hypothalamic areas including the PVH, DMH, ARH, and LHA. These results indicate that projections from the dorsomedial division of the anterior BNST to hypothalamic nuclei are immature at birth and substantially reach the PVH, DMH, and the LHA at P10. In the ARH, only sparse fibers are observed at P10, but their density increased markedly between P12 and P14. Collectively, these findings provide new insight into the ontogeny of hypothalamic circuits, and highlight the importance of considering the developmental context as a direct modulator in their proper formation.

Summary: The paraventricular nucleus of the thalamus (PVT) controls goal-oriented behavior through its connections to the nucleus accumbens (NAc). We previously characterized Glut2aPVT neurons that are activated by hypoglycemia, and which increase sucrose seeking behavior through their glutamatergic projections to the NAc. Here, we identified glucokinase (Gck)-expressing neurons of the PVT (GckaPVT) and generated a mouse line expressing the Cre recombinase from the glucokinase locus (GckCre/+ mice). Ex vivo calcium imaging and whole-cell patch clamp recordings revealed that GckaPVT neurons that project to the NAc were mostly activated by hyperglycemia. Their chemogenetic inhibition or optogenetic stimulation, respectively, enhanced food intake or decreased sucrose-seeking behavior. Collectively, our results describe a neuronal population of Gck-expressing neurons in the PVT, which has opposite glucose sensing properties and control over feeding behavior than the previously characterized Glut2aPVT neurons. This study allows a better understanding of the complex regulation of feeding behavior by the PVT.

The human ingestion of mercury (Hg) from sea food is of big concern worldwide due to adverse health effects, and more specifically if shark consumption constitutes a regular part of the human diet. In this study, the total mercury (THg) concentration in muscle tissue were determined in six sympatric shark species found in a fishing vessel seized in the Galapagos Marine Reserve in 2017. The THg concentrations in shark muscle samples (n = 73) varied from 0.73 mg kg-1 in bigeye thresher sharks (Alopias superciliosus) to 8.29 mg kg-1 in silky sharks (Carcharhinus falciformis). A typical pattern of Hg bioaccumulation was observed for all shark species, with significant correlation between THg concentration and shark size for bigeye thresher sharks, pelagic thresher sharks (Alopias pelagicus) and silky sharks. Regarding human health concerns, the THg mean concentration exceeded the maximum weekly intake fish serving in all the studied species. Mass-Dependent Fractionation (MDF, δ202Hg values) and Mass-Independent Fractionation (MIF, Δ199Hg values) of Hg in whitetip sharks (Carcharhinus longimanus) and silky sharks, ranged from 0.70‰ to 1.08‰, and from 1.97‰ to 2.89‰, respectively. These high values suggest that both species are feeding in the epipelagic zone (i.e. upper 200 m of the water column). While, blue sharks (Prionace glauca), scalloped hammerhead sharks (Shyrna lewini) and thresher sharks were characterized by lower Δ199Hg and δ202Hg values, indicating that these species may focus their foraging behavior on prey of mesopelagic zone (i.e. between 200 and 1000 m depth). In conclusion, the determination of THg concentration provides straight-forward evidence of the human health risks associated with shark consumption, while mercury isotopic compositions constitute a powerful tool to trace the foraging strategies of these marine predators. Capsule: A double approach combining Hg concentrations with stable isotopes ratios allowed to assess ontogeny in common shark species in the area of the Galapagos Marine Reserve and the human health risks concern associated to their consumption.

Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

Despite the consequences of night-shift work, the diet of night-shift workers has not been widely studied. To date, there are no studies related to food intake among emergency healthcare workers (HCWs). We performed a prospective observational study to assess the influence of night work on the diet of emergency HCWs. We monitored 24-h food intake during a day shift and the consecutive night, and during night work and the daytime beforehand. We analyzed 184 emergency HCWs’ food intakes. Emergency HCWs had 14.7% lower (−206 kcal) of their 24-h energy intake during night shifts compared to their day-shift colleagues (1606.7 ± 748.2 vs. 1400.4 ± 708.3 kcal, p = 0.049) and a 16.7% decrease in water consumption (1451.4 ± 496.8 vs. 1208.3 ± 513.9 mL/day, p = 0.010). Compared to day shifts, night-shift had 8.7% lower carbohydrates, 17.6% proteins, and 18.7% lipids. During the night shift the proportion of emergency HCWs who did not drink for 4 h, 8 h and 12 h increased by 20.5%, 17.5%, and 9.1%, respectively. For those who did not eat for 4 h, 8 h and 12 h increased by 46.8%, 27.7%, and 17.7%, respectively. A night shift has a huge negative impact on both the amount and quality of nutrients consumed by emergency healthcare workers.

Summary: Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss. : Prader-Willi syndrome (PWS) is a genetic obesity syndrome. Bochukova et al. report gene expression changes in the hypothalamus of people with PWS that support neurodegeneration and neuroinflammation as key processes involved in this condition. Keywords: hypothalamus, Prader-Willi syndrome, BDNF, Agrp, obesity, SNORD116

The autonomic nervous system plays a critical role in glucose metabolism through both its sympathetic and parasympathetic branches, but the mechanisms that underlie the development of the autonomic innervation of the pancreas remain poorly understood. Here, we report that cholinergic innervation of pancreatic islets develops during mid-gestation under the influence of leptin. Leptin-deficient mice display a greater cholinergic innervation of pancreatic islets beginning in embryonic life, and this increase persists into adulthood. Remarkably, a single intracerebroventricular injection of leptin in embryos caused a permanent reduction in parasympathetic innervation of pancreatic β cells and long-term impairments in glucose homeostasis. These developmental effects of leptin involve a direct inhibitory effect on the outgrowth of preganglionic axons from the hindbrain. These studies reveal an unanticipated regulatory role of leptin on the parasympathetic nervous system during embryonic development and may have important implications for our understanding of the early mechanisms that contribute to diabetes.

Proopiomelanocortin (POMC) neurons are major negative regulators of energy balance. A distinct developmental property of POMC neurons is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the mechanisms underlying the differentiation of Pomc progenitors remain unknown. Here, we show that the loss of the microRNA (miRNA)-processing enzyme Dicer in POMC neurons causes metabolic defects, an age-dependent decline in the number of PomcmRNA-expressing cells, and an increased proportion of Pomc progenitors acquiring a NPY phenotype. miRNome microarray screening further identified miR-103/107 as candidates that may be involved in the maturation of Pomc progenitors. In vitro inhibition of miR-103/107 causes a reduction in the number of Pomc-expressing cells and increases the proportion of Pomc progenitors differentiating into NPY neurons. Moreover, in utero silencing of miR-103/107 causes perturbations in glucose homeostasis. Together, these data suggest a role for prenatal miR-103/107 in the maturation of Pomc progenitors and glucose homeostasis.