Wired for eating: how is an active feeding circuitry established in the postnatal brain?

International audienceFrom birth, mammals have to find food and maximize caloric intake to ensure growth and survival. Suckling must be initiated quickly after birth and then maintained and controlled until weaning. It is a complex process involving interactions between sensory and motor neuronal pathways. Meanwhile, the control of food intake and energy homeostasis is progressively established via the development of hypothalamic circuits. The development of these circuits is influenced by hormonal and nutritional signals and can be disturbed in a variety of developmental disorders leading to long-term metabolic, behavioral and cognitive dysfunctions. This review summarizes our current knowledge of the neuronal circuits involved in early postnatal feeding processes

Neonatal oxytocin gives the tempo of social and feeding behaviors

The nonapeptide oxytocin (OT) is a master regulator of the social brain in early infancy, adolescence, and adult life. Here, we review the postnatal dynamic development of OT-system as well as early-life OT functions that are essential for shaping social behaviors. We specifically address the role of OT in neonates, focusing on its role in modulating/adapting sensory input and feeding behavior; both processes are involved in the establishing mother-infant bond, a crucial event for structuring all future social interactions. In patients and rodent models of Prader-Willi and Schaaf-Yang syndromes, two neurodevelopmental diseases characterized by autism-related features, sensory impairments, and feeding difficulties in early infancy are linked to an alteration of OT-system. Successful preclinical studies in mice and a phase I/II clinical trial in Prader-Willi babies constitute a proof of concept that OT-treatment in early life not only improves suckling deficit but has also a positive long-term effect on learning and social behavior. We propose that in early postnatal life, OT plays a pivotal role in stimulating and coordinating the maturation of neuronal networks controlling feeding behavior and the first social interactions. Consequently, OT therapy might be considered to improve feeding behavior and, all over the life, social cognition, and learning capabilities

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death

BACKGROUND: The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause. RESULTS: We report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context. Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons. CONCLUSION: Overall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor

ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs

Posttranscriptional, site-specific adenosine to inosine (A-to-I) base conversions, designated as RNA editing, play significant roles in generating diversity of gene expression. However, little is known about how and in which cellular compartments RNA editing is controlled. Interestingly, the two enzymes that catalyze RNA editing, adenosine deaminases that act on RNA (ADAR) 1 and 2, have recently been demonstrated to dynamically associate with the nucleolus. Moreover, we have identified a brain-specific small RNA, termed MBII-52, which was predicted to function as a nucleolar C/D RNA, thereby targeting an A-to-I editing site (C-site) within the 5-HT2C serotonin receptor pre-mRNA for 2′-O-methylation. Through the subcellular targeting of minigenes that contain natural editing sites, we show that ADAR2- but not ADAR1-mediated RNA editing occurs in the nucleolus. We also demonstrate that MBII-52 forms a bona fide small nucleolar ribonucleoprotein particle that specifically decreases the efficiency of RNA editing by ADAR2 at the targeted C-site. Our data are consistent with a model in which C/D small nucleolar RNA might play a role in the regulation of RNA editing

Necdin mediates skeletal muscle regeneration by promoting myoblast survival and differentiation

Regeneration of muscle fibers that are lost during pathological muscle degeneration or after injuries is sustained by the production of new myofibers. An important cell type involved in muscle regeneration is the satellite cell. Necdin is a protein expressed in satellite cell–derived myogenic precursors during perinatal growth. However, its function in myogenesis is not known. We compare transgenic mice that overexpress necdin in skeletal muscle with both wild-type and necdin null mice. After muscle injury the necdin null mice show a considerable defect in muscle healing, whereas mice that overexpress necdin show a substantial increase in myofiber regeneration. We also find that in muscle, necdin increases myogenin expression, accelerates differentiation, and counteracts myoblast apoptosis. Collectively, these data clarify the function and mechanism of necdin in skeletal muscle and show the importance of necdin in muscle regeneration

Necdin Protects Embryonic Motoneurons from Programmed Cell Death

NECDIN belongs to the type II Melanoma Associated Antigen Gene Expression gene family and is located in the Prader-Willi Syndrome (PWS) critical region. Necdin-deficient mice develop symptoms of PWS, including a sensory and motor deficit. However, the mechanisms underlying the motor deficit remain elusive. Here, we show that the genetic ablation of Necdin, whose expression is restricted to post-mitotic neurons in the spinal cord during development, leads to a loss of 31% of specified motoneurons. The increased neuronal loss occurs during the period of naturally-occurring cell death and is not confined to specific pools of motoneurons. To better understand the role of Necdin during the period of programmed cell death of motoneurons we used embryonic spinal cord explants and primary motoneuron cultures from Necdin-deficient mice. Interestingly, while Necdin-deficient motoneurons present the same survival response to neurotrophic factors, we demonstrate that deletion of Necdin leads to an increased susceptibility of motoneurons to neurotrophic factor deprivation. We show that by neutralizing TNFα this increased susceptibility of Necdin-deficient motoneurons to trophic factor deprivation can be reduced to the normal level. We propose that Necdin is implicated through the TNF-receptor 1 pathway in the developmental death of motoneurons

L’ocytocine, dès la naissance, conditionne le comportement alimentaire et social d’un individu

L’ocytocine (OT) est une neurohormone qui, dans le cerveau, régule ce que l’on appelle le « cerveau social » et dont l’étude est principalement conduite chez l’adulte. Au cours du développement postnatal, les mécanismes par lesquels le système OT structure divers comportements sont peu explorés. Nous présentons ici le processus dynamique du développement postnatal du système OT ainsi que ses rôles fonctionnels, en période périnatale, qui sont essentiels pour façonner les comportements sociaux. Nous abordons spécifiquement le rôle de l’OT chez le nouveau-né, qui permet d’intégrer et d’adapter des réponses aux premières stimulations sensorielles et qui stimule aussi l’activité de succion. Ce dialogue sensoriel et la tétée sont impliqués dans les liens mère-enfant et structurent les futures interactions sociales. Chez les rongeurs et chez l’homme, des maladies neuro-développementales avec des troubles du spectre autistique, comme les syndromes de Prader-Willi et de Schaaf-Yang, sont associées à des déficiences sensorielles, alimentaires et comportementales dans la petite enfance. Nous proposons qu’au début de la vie postnatale, l’OT joue un rôle clé dans la maturation des réseaux neuronaux contrôlant le comportement alimentaire et les premières interactions sociales. Une administration d’OT chez le nouveau-né améliore l’intégration sensorielle des facteurs environnementaux et la relation avec la mère ainsi que l’activité de succion comme nous l’avons montré chez des modèles de souris ainsi que chez des bébés atteints du syndrome de Prader-Willi. Des effets à long terme ont aussi été observés sur le comportement social et cognitif. Par conséquent, les difficultés précoces d’alimentation peuvent être un marqueur prédictif précoce des cas de troubles du spectre autistique (TSA) et l’administration exogène d’OT pourrait améliorer le comportement alimentaire et, à plus long terme, les troubles du comportement social

Natural breaking of the maternal silence at the mouse and human imprinted Prader-Willi locus

International audienc

Ontogenesis of Hypothalamic Neurons in Mammals

International audienc

Régulation transcriptionnelle de la région chromosomique 7C murine soumise à l'empreinte génomique parentale

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF