Autonomic development in preterm infants is associated with morbidity of prematurity.

BACKGROUND: Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU. METHODS: We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed. RESULTS: The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics. CONCLUSIONS: Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age. IMPACT: Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

Autonomic nervous system maturation in the premature extrauterine milieu.

BACKGROUND: In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation. METHODS: We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) < 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks). RESULTS: One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities. CONCLUSION: Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA. IMPACT: Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.

Development of the Autonomic Nervous System: Clinical Implications.

Investigations of the cellular and molecular mechanisms that mediate the development of the autonomic nervous system have identified critical genes and signaling pathways that, when disrupted, cause disorders of the autonomic nervous system. This review summarizes our current understanding of how the autonomic nervous system emerges from the organized spatial and temporal patterning of precursor cell migration, proliferation, communication, and differentiation, and discusses potential clinical implications for developmental disorders of the autonomic nervous system, including familial dysautonomia, Hirschsprung disease, Rett syndrome, and congenital central hypoventilation syndrome.

Neurovisceral regulatory circuits of affective resilience in youth: Principal outline of a dynamic model of neurovisceral integration in development.

The Neurovisceral Integration Model (NIM) is one of the most influential psychophysiological models addressing the interplay between the autonomic (ANS) and central nervous system (CNS). In their groundbreaking conceptual work, integrating autonomic, attentional, and affective systems into a functional and structural network, Thayer & Lane laid the foundation for empirical research in the past two decades. The present paper provides a principal outline aiming to reflect and further elaborate on the model from a dynamic developmental perspective. The central question at hand is, how does neurovisceral integration develop (early in life)? By reviewing the existing evidence, it is illustrated that key components of the model, both, on a physiological and psychological level, undergo extensive change early in the course of life. This sensitive period of human development seems key for our understanding of the integrated action of the ANS and CNS in emotion across the lifespan. Early life events may interfere with the fine-tuned interplay of this shared neural circuitry resulting in long-term dysfunction and psychiatric illness. In the absence of longitudinal data covering the entire co-development of the ANS and CNS from early childhood to adolescence into early adulthood, it is suggested, that vagal activity and its normative increase in adolescence is a key premise for normative brain development on a structural and functional level, subsequent psychological functioning and adaptive regulation. Implications from this dynamic perspective and suggestions for future research in the field of developmental psychophysiology are discussed.

Maternal, fetal and neonatal heart rate and heart rate variability in Holstein cattle / Frequência cardíaca e variabilidade da frequência cardíaca materna, fetal e neonatal em bovinos da raça Holstein

The aim of this study was to describe the normal values for maternal, fetal and neonatal heart rate (HR) and heart rate variability (HRV) indexes in the time domain (standard deviation of beat-to-beat interval - SDNN; root mean square of successive beat-to-beat differences - RMSSD) and the frequency domain (low frequency - LF; high frequency - HF; relationship between low and high frequency - LF/HF) in 23 Holstein cows, 23 fetuses and 18 neonates during the perinatal period. HR and HRV were calculated by fetomaternal electrocardiography (ECG). Fetomaternal measurements were taken six times prepartum (between days 234 and 279 of pregnancy) and measurements were taken in neonates six times after calving (after birth and five times weekly). HR, time and frequency domain were analyzed. No significant changes in maternal, fetal beat-to-beat interval (RR interval) or HR were found. In maternal variables, SDNN decreased significantly from 38.08±2.6ms (day 14 before calving) to 23.7±2.5ms (day 1 after calving) (p<0.05), but the RMSSD did not change significantly. HR and RR interval of calf differed statistically from the day before delivery (163±7.5bpm; 381±24.2ms) to the day after calving (131±5bpm; 472±16.2ms). Time variables (SDNN and RMSSD) and the frequency-domain variables (LF and HF) were significantly different (p<0.05) between fetal and neonatal stages. Reductions in the values of SDNN and RMSSD can reflect a sympathetic dominance. After calving, the increase in HF and decrease in LF variables can indicate activation of the vagal nerve followed by heart and respiratory modulation.(AU)

O objetivo deste estudo foi descrever os valores normais para os índices de frequência cardíaca (FC) materna, fetal e neonatal e de variabilidade da frequência cardíaca (VFC) no domínio do tempo (desvio padrão do intervalo batimento a batimento, SDNN; raiz quadrada média de sucessivas diferenças de batimento a batimento, RMSSD) e do domínio da frequência (baixa frequência, LF; alta frequência, HF; relação entre baixa e alta frequência, LF/HF) em 23 vacas Holandesas, 23 fetos e 18 neonatos durante o período perinatal. A FC e a VFC foram calculadas por eletrocardiografia materno-fetal. As medidas materno-fetais foram realizadas seis vezes antes do parto (entre os dias 234 e 279 de gestação) as medidas neonatais foram realizadas seis vezes após o parto (um dia após nascimento e semanalmente, durante cinco semanas). FC, e variáveis no domínio do tempo e de frequência foram analisadas. Não foram encontradas alterações significativas na FC e no intervalo de batimento para batimento (intervalo RR) materno e fetal. Nas variáveis maternas, o SDNN diminuiu significativamente de 38,08±2,6ms (dia 14 antes do parto) para 23,7±2,5ms (dia 1 após o parto) (p<0,05), mas o RMSSD não alterou significativamente. A FC e o intervalo e RR do bezerro diferiram estatisticamente a partir de um dia antes do parto (163±7,5bpm, 381±24,2ms) até o dia seguinte ao parto (131±5bpm, 472±16,2ms). As variáveis de tempo (SDNN e RMSSD) e as variáveis de domínio de frequência (LF e HF) foram significativamente diferentes (p<0,05) entre os momentos fetal e neonatal. As reduções nos valores de SDNN e RMSSD podem refletir domínio simpático. Após o parto, o aumento da HF e a diminuição das variáveis LF podem indicar a ativação do nervo vagal seguido de modulação cardíaca e respiratória.(AU)

Developmental trajectories of autonomic functioning in autism from birth to early childhood.

Deficits in social engagement emerge in autism during the infant and toddler period and may be related to emotion regulation and stress response systems. This study examined patterns of growth in autonomic functioning related to autism diagnosis and addresses the hypothesis that there are differences in autonomic functioning related to autism in infancy. Heart rate (HR) and respiratory sinus arrhythmia (RSA) were measured at 8 time points from 1 to 72 months of age in infants later diagnosed with autism (n = 12) and a non-autistic comparison group (n = 106). Multilevel models were used to describe the developmental course of HR and RSA and to test the effect of autism diagnosis on growth trajectories. Both groups showed an expected age-related decrease in HR and increase in RSA. Groups did not differ in the rate of decrease of HR over time. However, infants with autism demonstrated a smaller linear increase in RSA, indicating slower growth in RSA over time in comparison to controls. These results suggest that differences in physiological regulation may develop with age in autism. The slowed RSA growth in autism was most evident after 18 months of age, at a time when behavioral symptoms become prominent. This is consistent with the view that RSA is a marker of functional status in autism rather than a cause of social deficits in autism.

Autonomic nervous system development and its impact on neuropsychiatric outcome.

The central autonomic nervous system (ANS) is essential for maintaining cardiovascular and respiratory homeostasis in the newborn and has a critical role in supporting higher cortical functions. At birth, the central ANS is maturing and is vulnerable to adverse environmental and physiologic influences. Critical connections are formed early in development between the ANS and limbic system to integrate psychological and body responses. The Polyvagal Theory, developed by Stephen Porges, describes how modulation of the autonomic vagal impulse controls social responses and that a broad range of neuropsychiatric disorders may be due to impaired vagal balance, with either deficient vagal tone or excessive vagal reactivity. Under additional circumstances of prematurity, growth restriction, and environmental stress in the fetus and newborn, the immature ANS may undergo "dysmaturation". Maternal stress and health as well as the intrauterine environment are also quite important and have been implicated in causing ANS changes in the infant and neuropsychiatric diseases in children. This review will cover the aspects of ANS development and maturation that have been associated with neuropsychiatric disorders in children.

The Critical Role of the Central Autonomic Nervous System in Fetal-Neonatal Transition.

The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions.

Developmental milestones of the autonomic nervous system revealed via longitudinal monitoring of fetal heart rate variability.

BACKGROUND: Fetal heart rate variability (fHRV) of normal-to-normal (NN) beat intervals provides high-temporal resolution access to assess the functioning of the autonomic nervous system (ANS). AIM: To determine critical periods of fetal autonomic maturation. The developmental pace is hypothesized to change with gestational age (GA). STUDY DESIGN: Prospective longitudinal observational study. SUBJECTS: 60 healthy singleton fetuses were followed up by fetal magnetocardiographic heart rate monitoring 4-11 times (median 6) during the second half of gestation. OUTCOME MEASURE: FHRV parameters, accounting for differential aspects of the ANS, were studied applying linear mixed models over four predefined pregnancy segments of interest (SoI: <27; 27+0-31+0; 31+1-35+0; >35+1 weeks GA). Periods of fetal active sleep and quiescence were accounted for separately. RESULTS: Skewness of the NN interval distribution VLF/LF band power ratio and complexity describe a saturation function throughout the period of interest. A decreasing LF/HF ratio and an increase in pNN5 indicate a concurrent shift in sympathovagal balance. Fluctuation amplitude and parameters of short-term variability (RMSSD, HF band) mark a second acceleration towards term. In contrast, fetal quiescence is characterized by sequential, but low-margin transformations; ascending overall variability followed by an increase of complexity and superseded by fluctuation amplitude. CONCLUSIONS: An increase in sympathetic activation, connected with by a higher ability of parasympathetic modulation and baseline stabilization, is reached during the transition from the late 2nd into the early 3rd trimester. Pattern characteristics indicating fetal well-being saturate at 35 weeks GA. Pronounced fetal breathing efforts near-term mirror in fHRV as respiratory sinus arrhythmia.

Effect of excessive infant crying on resting BP, HRV and cardiac autonomic control in childhood.

OBJECTIVE: Early life stress has been shown to influence the developing autonomic nervous system. Stressors in infancy may program the autonomic nervous system resting state set point, affecting cardiovascular function in later life. Excessive crying may be an indicator of increased stress arousal in infancy. We hypothesized that excessive infant crying is related to altered cardiac autonomic nervous system activity and increased blood pressure at age 5-6 years. METHODS: In the Amsterdam Born Children and their Development study, excessive crying, maternal burden of infant care and maternal aggressive behavior in the 13th week after birth (range 11-16 weeks) were reported using questionnaires. Blood pressure, heart rate, heart rate variability and indicators of cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia) were measured at age 5-6 years during rest. Inclusion criteria were singleton birth, term-born, and no reported congenital or cardiovascular problems (N = 2153 included). RESULTS: Excessive crying (2.8%) was not associated with resting heart rate, heart rate variability, pre-ejection period, respiratory sinus arrhythmia nor with blood pressure at age 5-6 years. CONCLUSIONS: Excessive infant crying as an indicator of increased stress arousal does not seem to be related to resting activity of the autonomic nervous system or blood pressure at age 5-6. Potential associations may become visible under stressed conditions.

Neonatal autonomic function after pregnancy complications and early cardiovascular development.

BACKGROUND: Heart rate variability (HRV) has emerged as a predictor of later cardiac risk. This study tested whether pregnancy complications that may have long-term offspring cardiac sequelae are associated with differences in HRV at birth, and whether these HRV differences identify abnormal cardiovascular development in the postnatal period. METHODS: Ninety-eight sleeping neonates had 5-min electrocardiogram recordings at birth. Standard time and frequency domain parameters were calculated and related to cardiovascular measures at birth and 3 months of age. RESULTS: Increasing prematurity, but not maternal hypertension or growth restriction, was associated with decreased HRV at birth, as demonstrated by a lower root mean square of the difference between adjacent NN intervals (rMSSD) and low (LF) and high-frequency power (HF), with decreasing gestational age (p < 0.001, p = 0.009 and p = 0.007, respectively). We also demonstrated a relative imbalance between sympathetic and parasympathetic tone, compared to the term infants. However, differences in autonomic function did not predict cardiovascular measures at either time point. CONCLUSIONS: Altered cardiac autonomic function at birth relates to prematurity rather than other pregnancy complications and does not predict cardiovascular developmental patterns during the first 3 months post birth. Long-term studies will be needed to understand the relevance to cardiovascular risk.

Universal characteristics of evolution and development are inherent in fetal autonomic brain maturation.

Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61-0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies.

Modulation of heart rate and heart rate variability by n-3 long chain polyunsaturated fatty acids: Speculation on mechanism(s).

Heart rate (HR) and heart rate variability (HRV) are valuable markers of health. Although the underlying mechanism(s) are controversial, it is well documented that n-3 long chain polyunsaturated fatty acid (LCPUFA) intake improves HR and HRV in various populations. Autonomic modulation and/or alterations in cardiac electrophysiology are commonly cited as potential mechanisms responsible for these effects. This article reviews existing evidence for each and explores a separate mechanism which has not received much attention but has scientific merit. Based on presented evidence, it is proposed that n-3 LCPUFAs affect HR and HRV directly by autonomic modulation and indirectly by altering circulating factors, both dependently and independently of the autonomic nervous system. The evidence for changes in cardiac electrophysiology as the mechanism by which n-3 LCPUFAs affect HR and HRV needs strengthening.

Developmental changes in autonomic responses are associated with future reward/punishment expectations: A study of sympathetic skin responses in the Markov decision task.

OBJECTIVE: Autonomic nervous system activity is recognized as a major component of emotional responses. Future reward/punishment expectations depend upon the process of decision making in the frontal lobe, which is considered to play an important role in executive function. The aim of this study was to investigate the relationship between autonomic responses and decision making during reinforcement tasks using sympathetic skin responses (SSR). METHODS: Nine adult and 9 juvenile (mean age, 10.2years) volunteers were enrolled in this study. SSRs were measured during the Markov decision task (MDT), which is a reinforcement task. In this task, subjects must endure a small immediate loss to ultimately get a large reward. The subjects had to undergo three sets of tests and their scores in these tests were assessed and evaluated. RESULTS: All adults showed gradually increasing scores for the MDT from the first to third set. As the trial progressed from the first to second set in adults, SSR appearance ratios remarkably increased for both punishment and reward expectations. In comparison with adults, children showed decreasing scores from the first to second set. There were no significant inter-target differences in the SSR appearance ratio in the first and second set in children. In the third set, the SSR appearance ratio for reward expectations was higher than that in the neutral condition. CONCLUSIONS: In reinforcement tasks, such as MDT, autonomic responses play an important role in decision making. We assume that SSRs are elicited during efficient decision making tasks associated with future reward/punishment expectations, which demonstrates the importance of autonomic function. In contrast, in children around the age of 10years, the autonomic system does not react as an organized response specific to reward/punishment expectations. This suggests the immaturity of the future reward/punishment expectations process in children.

The role of the autonomic nervous system in control of cardiac and air-breathing responses to sustained aerobic exercise in the African sharptooth catfish Clarias gariepinus.

Clarias gariepinus is a facultative air-breathing catfish that exhibits changes in heart rate (ƒH) associated with air-breaths (AB). A transient bradycardia prior to the AB is followed by sustained tachycardia during breath-hold. This study evaluated air-breathing and cardiac responses to sustained aerobic exercise in juveniles (total length~20cm), and how exercise influenced variations in fH associated with AB. In particular, it investigated the role of adrenergic and cholinergic control in cardiac responses, and effects of pharmacological abolition of this control on air-breathing responses. Sustained exercise at 15, 30 and 45cms-1 in a swim tunnel caused significant increases in fAB and fH, from approximately 5breathsh-1 and 60heartbeatsmin-1 at the lowest speed, to over 60breathsh-1 and 100beatsmin-1 at the highest, respectively. There was a progressive decline in the degree of variation in fH, around each AB, as fAB increased with exercise intensity. Total autonomic blockade abolished all variation in fH during exercise, and around each AB, but fAB responses were the same as in untreated animals. Cardiac responses were exclusively due to modulation of inhibitory cholinergic tone, which varied from >100% at the lowest speed to <10% at the highest. Cholinergic blockade had no effect on fAB compared to untreated fish. Excitatory ß-adrenergic tone was approximately 20% and did not vary with swimming speed, but its blockade increased fAB at all speeds, compared to untreated animals. This reveals complex effects of autonomic control on air-breathing during exercise in C. gariepinus, which deserve further investigation.

Capturing the biology of disease severity in a PSC-based model of familial dysautonomia.

Familial dysautonomia (FD) is a debilitating disorder that affects derivatives of the neural crest (NC). For unknown reasons, people with FD show marked differences in disease severity despite carrying an identical, homozygous point mutation in IKBKAP, encoding IκB kinase complex-associated protein. Here we present disease-related phenotypes in human pluripotent stem cells (PSCs) that capture FD severity. Cells from individuals with severe but not mild disease show impaired specification of NC derivatives, including autonomic and sensory neurons. In contrast, cells from individuals with severe and mild FD show defects in peripheral neuron survival, indicating that neurodegeneration is the main culprit for cases of mild FD. Although genetic repair of the FD-associated mutation reversed early developmental NC defects, sensory neuron specification was not restored, indicating that other factors may contribute to disease severity. Whole-exome sequencing identified candidate modifier genes for individuals with severe FD. Our study demonstrates that PSC-based modeling is sensitive in recapitulating disease severity, which presents an important step toward personalized medicine.

Measuring Cardiac Autonomic Nervous System (ANS) Activity in Toddlers - Resting and Developmental Challenges.

The autonomic nervous system (ANS) consists of two branches, the parasympathetic and sympathetic nervous systems, and controls the function of internal organs (e.g., heart rate, respiration, digestion) and responds to everyday and adverse experiences (1). ANS measures in children have been found to be related to behavior problems, emotion regulation, and health (2-7). Therefore, understanding the factors that affect ANS development during early childhood is important. Both branches of the ANS affect young children's cardiovascular responses to stimuli and have been measured noninvasively, via external monitoring equipment, using valid and reliable measures of physiological change (8-11). However, there are few studies of very young children with simultaneous measures of the parasympathetic and sympathetic nervous systems, which limits understanding of the integrated functioning of the two systems. In addition, the majority of existing studies of young children report on infants' resting ANS measures or their reactivity to commonly used mother-child interaction paradigms, and less is known about ANS reactivity to other challenging conditions. We present a study design and standardized protocol for a non-invasive and rapid assessment of cardiac autonomic control in 18 month old children. We describe methods for continuous monitoring of the parasympathetic and sympathetic branches of the ANS under resting and challenge conditions during a home or laboratory visit and provide descriptive findings from our sample of 140 ethnically diverse toddlers using validated equipment and scoring software. Results revealed that this protocol can produce a range of physiological responses to both resting and developmentally challenging conditions, as indicated by changes in heart rate and indices of parasympathetic and sympathetic activity. Individuals demonstrated variability in resting levels, responses to challenges, and challenge reactivity, which provides additional evidence that this protocol is useful for the examination of ANS individual differences for toddlers.

Distinct roles of hand2 in developing and adult autonomic neurons.

The bHLH transcription factor Hand2 is essential for the acquisition and maintenance of noradrenergic properties of embryonic sympathetic neurons and controls neuroblast proliferation. Hand2 is also expressed in embryonic and postnatal parasympathetic ganglia and remains expressed in sympathetic neurons up to the adult stage. Here, we address its function in developing parasympathetic and adult sympathetic neurons. We conditionally deleted Hand2 in the parasympathetic sphenopalatine ganglion by crossing a line of floxed Hand2 mice with DbhiCre transgenic mice, taking advantage of the transient Dbh expression in parasympathetic ganglia. Hand2 elimination does not affect Dbh expression and sphenopalatine ganglion size at E12.5 and E16.5, in contrast to sympathetic ganglia. These findings demonstrate different functions for Hand2 in the parasympathetic and sympathetic lineage. Our previous Hand2 knockdown in postmitotic, differentiated chick sympathetic neurons resulted in decreased expression of noradrenergic marker genes but it was unclear whether Hand2 is required for maintaining noradrenergic neuron identity in adult animals. We now show that Hand2 elimination in adult Dbh-expressing sympathetic neurons does not decrease the expression of Th and Dbh, in contrast to the situation during development. However, gene expression profiling of adult sympathetic neurons identified 75 Hand2-dependent target genes. Interestingly, a notable proportion of down-regulated genes (15%) encode for proteins with synaptic and neurotransmission functions. These results demonstrate a change in Hand2 target genes during maturation of sympathetic neurons. Whereas Hand2 controls genes regulating noradrenergic differentiation during development, Hand2 seems to be involved in the regulation of genes controlling neurotransmission in adult sympathetic neurons. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1111-1124, 2016.

Purinergic signalling and development of the autonomic nervous system.

Most early studies of the role of nucleotides in development have evidenced their crucial importance as carriers of energy in all organisms. However, an increasing number of studies are now available to suggest that purines and pyrimidines, acting as extracellular ligands specifically on receptors of the plasma membrane, may play a pivotal role throughout pre- and postnatal development in a wide variety of organisms including amphibians, birds, and mammals. Purinergic receptor expression and functions have been studied in the development of many organs, including the autonomic nervous system (ANS). Nucleotide receptors can induce a multiplicity of cellular signalling pathways via crosstalk with bioactive molecules acting on growth factors and neurotransmitter receptors which are fundamental for the development of a mature and functional ANS. Purines and pyrimidines may influence all the stages of neuronal development, including neural cell proliferation, migration, differentiation and phenotype determination of differentiated cells. Indeed, the normal development of the ANS is disturbed by dysfunction of purinergic signalling in animal models. To establish the primitive and fundamental nature of purinergic neurotransmission in the ontogeny of the ANS, in this review the roles of purines and pyrimidines as signalling molecules during embryological and postnatal development are considered.

The influence of age and weight status on cardiac autonomic control in healthy children: a review.

Heart rate variability (HRV) analyses can provide a non-invasive evaluation of cardiac autonomic activity. How autonomic control normally develops in childhood and how this is affected by obesity remain incompletely understood. In this review we examine the evidence that childhood age and weight status influence autonomic control of the heart as assessed using HRV. Electronic databases (Pubmed, EMBASE and Cochrane Library) were searched for studies examining HRV in healthy children from birth to 18 years who adhered to the Task Force (1996) guidelines. Twenty-four studies met our inclusion criteria. Seven examined childhood age and HRV. A reduction in 24-hour LF:HF was reported from birth to infancy (1 year), while overall HRV (SDNN) showed a marked and progressive increase. From infancy to early-to-late childhood (from 12 months to 15 years) LF:HF ratio was reported to decline further albeit at a slower rate, while RMSSD and SDNN increased. Twenty studies examined the effects of weight status and body composition on HRV. In a majority of studies, obese children exhibited reductions in RMSSD (n = 8/13), pNN50% (n = 7/9) and HF power (n = 14/18), no difference was reported for LF (n = 10/18), while LF:HF ratio was elevated (n = 10/15). HRV changes during childhood are consistent with a marked and progressive increase in cardiac parasympathetic activity relative to sympathetic activity. Obesity disrupts the normal maturation of cardiac autonomic control.