Using Pregnant Sheep to Model Developmental Brain Damage

Heuij, Lotte G. van den; Wassink, Guido; Gunn, Alistair J.

doi:10.1007/978-1-4939-3014-2_16

Cited by 13 publications

(10 citation statements)

References 78 publications

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“…The chronically instrumented fetal sheep is the primary experimental model for studying fetal physiology and behaviour, where the fetus can be studied growing and developing in utero over long periods without the confounding effects of anaesthesia (van den Heuij et al . ). The authors note the caveat that the precocial development of the fetal sheep brain is such that the brain may be considered equivalent to the human brain at around 125–130 days GA (term in the sheep is 145–150 days) (Barlow, ; McIntosh et al .…”

Section: Introductionmentioning

confidence: 97%

Waking up too early – the consequences of preterm birth on sleep development

Bennet

Walker

Horne

2018

The Journal of Physiology

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Good quality sleep of sufficient duration is vital for optimal physiological function and our health. Sleep deprivation is associated with impaired neurocognitive function and emotional control, and increases the risk for cardiometabolic diseases, obesity and cancer. Sleep develops during fetal life with the emergence of a recognisable pattern of sleep states in the preterm fetus associated with the development, maturation and connectivity within neural networks in the brain. Despite the physiological importance of sleep, surprisingly little is known about how sleep develops in individuals born preterm. Globally, an estimated 15 million babies are born preterm (<37 weeks gestation) each year, and these babies are at significant risk of neural injury and impaired brain development. This review discusses how sleep develops during fetal and neonatal life, how preterm birth impacts on sleep development to adulthood, and the factors which may contribute to impaired brain and sleep development, leading to altered neurocognitive, behavioural and motor capabilities in the infant and child. Going forward, the challenge is to identify specific risk factors for impaired sleep development in preterm babies to allow for the design of interventions that will improve the quality and quantity of sleep throughout life.

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Section: Introductionmentioning

confidence: 97%

Waking up too early – the consequences of preterm birth on sleep development

Bennet

Walker

Horne

2018

The Journal of Physiology

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“…Our physiological understanding of the preterm fetal responses to hypoxia has largely been informed by use of the chronically instrumented fetal sheep model (Gunn & Bennet, ; Giussani, ; van den Heuij et al . ). This powerful paradigm allows the fetus to be studied chronically, in utero , in an integrative physiological manner, without the confounding effects of anaesthesia.…”

Section: Introductionmentioning

confidence: 97%

“…This approach has had significant utility in permitting the investigation of the role of peripheral and central chemoreflexes in modulating the fetal responses to hypoxia, while umbilical cord occlusion (UCO) and uterine artery occlusion have been used to model more severe systemic asphyxial insults (Jensen & Berger, ; Gunn & Bennet, ; van den Heuij et al . ). In our laboratory, we have established acute asphyxia paradigms, using UCO, for sheep fetuses at 0.8, 0.7 and 0.6 gestation, which are near terminal in nature (15, 25 and 30 min, respectively), and designed to model clinical patterns of brain injury to allow examination of mechanisms mediating injury, and to permit the study of the fetal physiological adaptations to asphyxia.…”

Section: Introductionmentioning

confidence: 97%

Sex, drugs and rock and roll: tales from preterm fetal life

Bennet

2017

The Journal of Physiology

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Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes.

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“…In humans and sheep, the majority of nervous system development occurs prenatally (33). In the early-and late-preterm infant, the axonal pathways are developing and especially vulnerable to injury (34).…”

Section: Discussionmentioning

confidence: 99%

The influence of anesthetics on substantia nigra tyrosine hydroxylase expression and tau phosphorylation in the hypoxic–ischemic near-term lamb

et al. 2018

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BackgroundGeneral anesthetics could protect key neurotransmitter systems, such as the dopaminergic system, from hypoxic-ischemic encephalopathy (HIE) by limiting excessive glutamatergic neurotransmission. However, anesthetics may adversely affect inflammation and tau phosphorylation.MethodsA near-term sheep model of HIE by umbilical cord occlusion (UCO) under anesthesia was used. The effect of propofol and isoflurane on the dopaminergic neurotransmitter phenotype in the substantia nigra (SN) was studied using tyrosine hydroxylase immunohistochemistry. The overall microglial response and tau phosphorylation were also measured in the SN, surrounding the midbrain gray matter structures and the hippocampal white matter.ResultsThe isoflurane-treated UCO group had fewer tyrosine hydroxylase-expressing neurons in the SN at 8 h after the insult than the propofol-treated UCO or sham-operated groups (P<0.05). The microglial response was unchanged in the SN region. In the thalamus and the hippocampal stratum moleculare layer, the propofol-treated UCO group had a lower microglial response than the corresponding sham-operated group. Both UCO and the use of anesthetics additively increased tau phosphorylation in the SN region, thalamus, and hippocampus.ConclusionThe choice of anesthetics is important for an emergency C-section. Propofol could potentially protect the dopaminergic neurotransmitter phenotype within the SN at the cost of a widespread increase in tau phosphorylation.

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Using Pregnant Sheep to Model Developmental Brain Damage

Cited by 13 publications

References 78 publications

Waking up too early – the consequences of preterm birth on sleep development

Waking up too early – the consequences of preterm birth on sleep development

Sex, drugs and rock and roll: tales from preterm fetal life

The influence of anesthetics on substantia nigra tyrosine hydroxylase expression and tau phosphorylation in the hypoxic–ischemic near-term lamb

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