The Journal of physiology
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The Journal of physiology · Dec 2018
The central amygdala to periaqueductal gray pathway comprises intrinsically distinct neurons differentially affected in a model of inflammatory pain.
The central nucleus of the amygdala (CeA) encompasses the main output pathways of the amygdala, a temporal lobe structure essential in affective and cognitive dimensions of pain. A major population of neurons in the CeA send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. CeA-PAG neurons are topographically organized based on their targeted subregion within the PAG. PAG-projecting neurons in the central medial (CeM) and central lateral (CeL) regions of CeA are intrinsically distinct. CeL-PAG neurons are a homogeneous population of intrinsically distinct neurons while CeM-PAG neurons are intrinsically heterogeneous. Membrane properties of distinct CeM-PAG subtypes are altered in the complete Freund's adjuvant model of inflammatory pain. ⋯ A major population of neurons in the central nucleus of amygdala (CeA) send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. While the CeA-PAG pathway has proved to be a component of descending anti-nociceptive circuitry, the functional organization of CeA-PAG neurons remains unclear. We identified CeA-PAG neurons in C57BL/6 mice of both sexes using intracranial injection of a fluorescent retrograde tracer into the PAG. In acute brain slices, we investigated the topographical and intrinsic characteristics of retrogradely labelled CeA-PAG neurons using epifluorescence and whole-cell electrophysiology. We also measured changes to CeA-PAG neurons in the complete Freund's adjuvant (CFA) model of inflammatory pain. Neurons in the central lateral (CeL) and central medial (CeM) amygdala project primarily to different regions of the PAG. CeL-PAG neurons consist of a relatively homogeneous population of intrinsically distinct neurons while CeM-PAG neurons are intrinsically heterogeneous. Membrane properties of distinct CeM-PAG subtypes are altered 1 day after induction of the CFA inflammatory pain model. Collectively, our results provide insight into pain-induced changes to a specific population of CeA neurons that probably play a key role in the integration of noxious input with endogenous analgesia and behavioural coping response.
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The Journal of physiology · Dec 2018
Moderate preterm birth affects right ventricular structure and function and pulmonary artery blood flow in adult sheep.
Preterm birth occurs when the heart muscle is immature and ill-prepared for the changes in heart and lung function at birth. MRI imaging studies show differences in the growth and function of the heart of young adults born preterm, with the effects more pronounced in the right ventricle. The findings of this study, conducted in sheep, showed that following moderate preterm birth the right ventricular wall was thinner in adulthood, with a reduction in the number and size of the heart muscle cells; in addition, there was impaired blood flow in the main artery leading from the right ventricle to the lungs. The findings indicate that being born only a few weeks early adversely affects the cellular structure of the right ventricle and blood flow to the lungs in adulthood. The reduced number of heart muscle cells has the potential to deleteriously affect right ventricular growth potential and function. ⋯ Preterm birth prematurely exposes the immature heart to the haemodynamic transition at birth, which has the potential to induce abnormal cardiac remodelling. Magnetic resonance imaging studies in young adults born preterm have shown abnormalities in the gross structure of the ventricles (particularly the right ventricle; RV), but the cellular basis of these alterations is unknown. The aim of this study, conducted in sheep, was to determine the effect of moderate preterm birth on RV cellular structure and function in early adulthood. Male singleton lambs were delivered moderately preterm (132 ± 1 days; n = 7) or at term (147 ± 1 days; n = 7). At 14.5 months of age, intra-arterial blood pressure and heart rate were measured. Pulmonary artery diameter and peak systolic blood flow were determined using ultrasound imaging, and RV stroke volume and output calculated. Cardiomyocyte number, size, nuclearity and levels of cardiac fibrosis were subsequently assessed in perfusion-fixed hearts using image analysis and stereological methods. Blood pressure (systolic, diastolic and mean), heart rate, levels of myocardial fibrosis and RV stroke volume and output were not different between groups. There was, however, a significant reduction in RV wall thickness in preterm sheep, and this was accompanied by a significant reduction in peak systolic blood flow in the pulmonary artery and in RV cardiomyocyte number. Cellular changes in the RV wall and reduced pulmonary artery blood flow following preterm birth have the potential to adversely affect cardiac and respiratory haemodynamics, especially when the cardiovascular system is physiologically or pathologically challenged.
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The Journal of physiology · Dec 2018
Afferent neural feedback overrides the modulating effects of arousal, hypercapnia and hypoxaemia on neonatal cardiorespiratory control.
Evidence obtained at whole animal, organ-system, and cellular and molecular levels suggests that afferent volume feedback is critical for the establishment of adequate ventilation at birth. As a result of the irreversible nature of the vagal ablation studies performed to date, it was difficult to quantify the roles of afferent volume input, arousal and changes in blood gas tensions on neonatal respiratory control. During reversible perineural vagal block, profound apnoeas and hypoxaemia and hypercarbia were observed, necessitating the termination of perineural blockade. Respiratory depression and apnoeas were independent of sleep state. We demonstrate that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. A change in sleep state and concomitant respiratory depression result from a lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period. ⋯ Afferent volume feedback plays a vital role in neonatal respiratory control. Mechanisms for the profound respiratory depression and life-threatening apnoeas observed in vagally denervated neonatal animals remain unclear. We investigated the roles of sleep states, hypoxic-hypercapnia and afferent volume feedback on respiratory depression using reversible perineural vagal block during the early postnatal period. Seven lambs were instrumented during the first 48 h of life to record/analyse sleep states, diaphragmatic electromyograph, arterial blood gas tensions, systemic arterial blood pressure and rectal temperature. Perineural cuffs were placed around the vagi to attain reversible blockade. Postoperatively, during the awake state, both vagi were blocked using 2% xylocaine for up to 30 min. Compared to baseline values, pHa , P a o 2 and S a o 2 decreased and P ac o 2 increased during perineural blockade (P < 0.05). Four of seven animals exhibited apnoeas of ≥20 s requiring the immediate termination of perineural blockade. Breathing rates decreased from the baseline value of 53 ± 12 to 24 ± 20 breaths min-1 during blockade despite an increased P ac o 2 (P < 0.001). Following blockade, breathing patterns returned to baseline values despite marked hypocapnia ( P ac o 2 33 ± 3 torr; P = 0.03). Respiratory depression and apnoeas were independent of sleep states. The present study provides the much needed physiological evidence indicating that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. Rather, a change in sleep state and concomitant respiratory depression result from a lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period.
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The Journal of physiology · Dec 2018
Altered autonomic control of heart rate variability in the chronically hypoxic fetus.
Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV. In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy. We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans. Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected. ⋯ Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In this study, we present a longitudinal study of the development of autonomic control of FHRV, assessed by indirect indices, time domain and power spectral analysis, in normoxic and chronically hypoxic, chronically catheterised, singleton fetal sheep over the last third of gestation. We used isobaric chambers able to maintain pregnant sheep for prolonged periods in hypoxic conditions (stable fetal femoral arterial P O 2 10-12 mmHg), and a customised wireless data acquisition system to record beat-to-beat variation in the fetal heart rate. We determined in vivo longitudinal changes in overall FHRV and the sympathetic and parasympathetic contribution to FHRV in hypoxic (n = 6) and normoxic (n = 6) ovine fetuses with advancing gestational age. Normoxic fetuses show gestational age-related increases in overall indices of FHRV, and in the sympathetic nervous system contribution to FHRV (P < 0.001). Conversely, gestational age-related increases in overall FHRV were impaired by exposure to chronic hypoxia, and there was evidence of suppression of the sympathetic nervous system control of FHRV after 72 h of exposure to hypoxia (P < 0.001). This demonstrates that exposure to late gestation isolated chronic fetal hypoxia has the potential to alter the development of the autonomic nervous system control of FHRV in sheep. This presents a potential mechanism by which a reduction in indices of FHRV in human fetuses affected by uteroplacental dysfunction can predict fetuses at increased risk.