Current ideas about the roles of rapid eye movement and non-rapid eye movement sleep in brain development.

Understanding the links between sleep and brain development is important, as rapid eye movement (REM) sleep and non-REM (NREM) sleep seem to contribute to different aspects of brain maturation. If children have sleep problems, REM sleep and NREM sleep are likely to have different consequences for their developing brain, depending on their age. We highlight important discoveries from human and animal research on the role sleep plays in brain development. A hypothetical model is presented to explain the dynamic relationship of REM sleep and NREM sleep with different processes of brain maturation, with implications for current neonatal care and future research.

[Oxytocin as a neuroprotective strategy in neonates: concept and preclinical evidence]. / Oxytocine et neuroprotection en période néonatale : évidences conceptuelles et précliniques.

OBJECTIVE: Prematurity and intra-uterine growth retardation are responsible for brain damage associated with various neurocognitive and behavioral disorders in more than 9 million children each year. Most pharmacological strategies aimed at preventing perinatal brain injury have not demonstrated substantial clinical benefits so far. In contrast, enrichment of the newborn's environment appears to have positive effects on brain structure and function, influences newborn hormonal responses, and has lasting neurobehavioral consequences during infancy and adulthood. Oxytocin (OT), a neuropeptide released by the hypothalamus, may represent the hormonal basis for these long-term effects. METHOD: This review of the literature summarizes the knowledge concerning the effect of OT in the newborn and the preclinical data supporting its neuroprotective effect. RESULTS: OT plays a role during the perinatal period, in parent-child attachment and in social behavior. Furthermore, preclinical studies strongly suggest that endogenous and synthetic OT is capable of regulating the inflammatory response of the central nervous system in response to situations of prematurity or more generally insults to the developing brain. The long-term effect of synthetic OT administration during labor is also discussed. CONCLUSION: All the conceptual and experimental data converge to indicate that OT would be a promising candidate for neonatal neuroprotection, in particular through the regulation of neuroinflammation.

[Oxytocin: a new target for neuroprotection?] / Ocytocine : une nouvelle cible de neuroprotection ?

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante-/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders affecting more than 9 million children each year. Most pharmacological candidates to prevent perinatal brain damage have failed to demonstrate substantial benefits. In contrast, environment enrichment based on developmental care, skin-to-skin contact and vocal/music exposure appear to exert positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the neonatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. In particular, excessive cortisol release in response to perinatal stress associated with prematurity or IUGR is recognized to induce brain-programming effects and neuroinflammation, a key predictor of subsequent neurological impairments. These deleterious effects are known to be balanced by oxytocin (OT), a neuropeptide released by the hypothalamus, which plays a role during the perinatal period and in social behavior. In addition, preclinical studies suggest that OT is able to regulate the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with developing white matter damage, we recently reported that carbetocin, a brain permeable OT receptor (OTR) agonist, induced a significant reduction of activated microglia, the primary immune cells of the brain. Moreover, this reduced microglia reactivity was associated with long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the mechanisms linking endogenous OT and central inflammation response to injury have not yet been established. Further studies are needed to assess the protective role of OT in the developing brain through modulation of microglial activation, a key feature of brain injury observed in infants born preterm or growth-restricted. They are expected to have several impacts in the near future not only for improving knowledge of microglial cell physiology and reactivity during brain development, but also to design clinical trials testing interventions associated with endogenous OT release as a relevant strategy to alleviate neuroinflammation in neonates.

Title: Ocytocine  : une nouvelle cible de neuroprotection ? Abstract: Chaque année, dans le monde, 30 millions de nouveau-nés naissent après un retard de croissance intra-utérin (RCIU) et 15 millions naissent prématurément. Ces deux conditions sont les principales causes de stress anté-/périnatal et de lésions cérébrales responsables de troubles neurocognitifs et comportementaux chez plus de 9 millions d'enfants chaque année. La plupart des stratégies pharmacologiques visant à prévenir les lésions cérébrales périnatales n'ont pas réussi à démontrer des bénéfices cliniques substantiels. En revanche, l'enrichissement de l'environnement basé sur les soins de développement, le contact peau à peau et l'exposition vocale/musicale semblent avoir des effets positifs sur la structure et la fonctionnalité du cerveau. Toutefois, les mécanismes qui sous-tendent ces effets restent inconnus. De nombreuses évidences montrent qu'un environnement défavorable pendant la grossesse et la période néonatale peut influencer les réponses hormonales du nouveau-né et avoir des conséquences neurocomportementales durables pendant la petite enfance et à l'âge adulte. L'ocytocine (OT), un neuropeptide libéré par l'hypothalamus, joue un rôle pendant la période périnatale dans l'attachement parents-enfant et dans le comportement social. En outre, des études précliniques suggèrent que l'OT est capable de réguler la réponse inflammatoire centrale aux lésions dans le cerveau adulte. Ces données font de l'OT un candidat prometteur pour la neuroprotection néonatale par la régulation de la neuro-inflammation.

Oxytocin neurons mediate the effect of social isolation via the VTA circuits.

Social interaction during adolescence strongly influences brain function and behavior, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidence has shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that 1 week of social isolation during adolescence in male mice increased social interaction at the expense of social habituation and social novelty preference. Behavioral changes were accompanied by the acute hyperexcitability of putative dopamine (pDA) neurons in the ventral tegmental area and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto pDA neurons that project to the prefrontal cortex. Social isolation-dependent behavioral deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus of the hypothalamus. These results demonstrate that social isolation in male mice has acute and long-lasting effects on social interaction and suggest that homeostatic adaptations mediate these effects within the reward circuit.

The Role of Oxytocin in Abnormal Brain Development: Effect on Glial Cells and Neuroinflammation.

The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm.

The value of cardiorespiratory parameters for sleep state classification in preterm infants: A systematic review.

Cardiorespiratory activity is highly associated with infants' sleep duration and quality. We performed a systematic literature search of PubMed and EMBASE databases to investigate if and how cardiorespiratory parameters can be used for sleep state classification in preterm infants and in what way maturation influences this relation. All retrieved citations were screened against predetermined inclusion and exclusion criteria. Only studies of preterm infants (<37 wk postmenstrual age during sleep state classification) admitted to a neonatal ward and of whom at least one sleep state and one cardiorespiratory parameter was measured, were included. Two researchers independently reviewed the included studies on methodological quality. Of the 1097 initially retrieved studies, 23 were included for analysis. Heart rate and respiration frequency are strongly correlated with active sleep and quiet sleep. In quiet sleep, as compared to active sleep, respiratory frequency is more stable, and the heart rate is lower and less variable. This association, however, differed across preterm birth subtypes (i.e., extremely, very or late preterm), indicating that maturation - in the form of both gestational and postnatal age - influences the cardiorespiratory characteristics of preterm sleep states. The knowledge gained from this review can help improve behavioral sleep classification and automated sleep classification algorithms for preterm infants.

Impact of Fetal Growth Restriction on the Neonatal Microglial Proteome in the Rat.

Microglial activation is a key modulator of brain vulnerability in response to intra-uterine growth restriction (IUGR). However, the consequences of IUGR on microglial development and the microglial proteome are still unknown. We used a model of IUGR induced by a gestational low-protein diet (LPD) in rats. Microglia, isolated from control and growth-restricted animals at P1 and P4, showed significant changes in the proteome between the two groups. The expression of protein sets associated with fetal growth, inflammation, and the immune response were significantly enriched in LPD microglia at P1 and P4. Interestingly, upregulation of protein sets associated with the oxidative stress response and reactive oxygen species production was observed at P4 but not P1. During development, inflammation-associated proteins were upregulated between P1 and P4 in both control and LPD microglia. By contrast, proteins associated with DNA repair and senescence pathways were upregulated in only LPD microglia. Similarly, protein sets involved in protein retrograde transport were significantly downregulated in only LPD microglia. Overall, these data demonstrate significant and multiple effects of LPD-induced IUGR on the developmental program of microglial cells, leading to an abnormal proteome within the first postnatal days.