Neuropathology of the near-term and midgestation ovine fetal brain after sustained in utero hypoxemia

Background Glutamate has been implicated in the pathophysiology of neuronal injury associated with cerebral hypoxia-ischemia. A model using chronic in utero microdialysis was developed to sample the extracellular space of the fetal brain. Using this model, we tested the hypothesis that glutamate efflux from the parasagittal parietal cortex of near-term fetuses would increase during maternal hemorrhage. Methods Twelve near-term fetal sheep were instrumented with vascular catheters, and a microdialysis probe(s) was implanted into the parasagittal parietal cortex. After a 3-day recovery period, the animals were subjected to maternal hemorrhage until either the fetal pH was < 7.00 or the fetus died. The extracellular glutamate concentration in the collected dialysate was determined by high pressure liquid chromatography (HPLC). Results Maternal hemorrhage resulted in an 80-90% decrease in uterine blood flow, a decrease fetal po2, and a mixed metabolic and respiratory fetal acidosis. There were two groups of fetuses, survivors (n = 5) and nonsurvivors (n = 7). The nonsurvivor group showed a large increase (10-30-fold) in peak glutamate release (P = 0.0015). Survivors demonstrated a small (threefold) increase that was not statistically significant (P = 0.065), unless one animal with very low probe recovery was excluded (P = 0.0048). Conclusions Extracellular glutamate release from the fetal brain can occur during maternal hemorrhage with fetal acidemia. The pathophysiologic role (if any) of glutamate release in the survivors remains to be elucidated. Our results are consistent with the hypothesis that in utero release of glutamate occurs during periods of fetal asphyxia. This experimental preparation of chronic fetal brain microdialysis can be used to monitor the brain extracellular concentration of any dialyzable substance in response to stress, including maternal hemorrhage.

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Umbilical cord occlusions in near-term ovine fetus induce increased beat-to-beat heart rate variability correlating to decreases in neuroinflammation: a case for the afferent cholinergic anti-inflammatory pathway?

10.1101/013169 ◽

2015 ◽

Author(s):

Martin G Frasch ◽

Mark Szynkaruk ◽

Andrew P Prout ◽

Karen Nygard ◽

Ruud Veldhuizen ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Vagus Nerve ◽

Fetal Brain ◽

In Utero ◽

Inflammatory Pathway ◽

Anti Inflammatory ◽

Near Term ◽

Ovine Fetal

Neuroinflammation in utero may contribute to brain injury resulting in life long neurological disabilities. The pivotal role of the efferent cholinergic anti-inflammatory pathway (CAP) in controlling inflammation has been described in adults, but its importance in the fetus is unknown. Moreover, it is unknown whether CAP may also exert anti-inflammatory effects on the brain via CAP's afferent component of the vagus nerve. Based on multiple clinical studies in adults and our own work in fetal autonomic nervous system, we gauged the degree of CAP activity in vivo using heart rate variability measures reflecting fluctuations in vagus nerve activity. Measuring microglial activation in the ovine fetal brain near-term, we show in vivo that afferent fetal CAP may translate increased vagal cholinergic signaling into suppression of cerebral inflammation in response to near-term hypoxic acidemia as might occur during labour. Our findings suggest a new control mechanism of fetal neuroinflammation via the vagus nerve, providing novel possibilities for its non-invasive monitoring in utero and for targeted treatment.

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Neuropathology of the near-term and midgestation ovine fetal brain after sustained in utero hypoxemia

American Journal of Obstetrics and Gynecology ◽

10.1016/s0002-9378(13)90484-1 ◽

1994 ◽

Vol 170 (5) ◽

pp. 1425-1432 ◽

Cited By ~ 13

Author(s):

Donald H. Penning ◽

Marjorie R. Grafe ◽

Robert Hammond ◽

Yoshio Matsuda ◽

John Patrick ◽

...

Keyword(s):

Fetal Brain ◽

In Utero ◽

Near Term ◽

Ovine Fetal

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Effects of in utero endotoxemia on the ovine fetal brain A model for schizophrenia

Frontiers in Bioscience ◽

10.2741/e588 ◽

2012 ◽

Vol E4 (8) ◽

pp. 2745-2753 ◽

Cited By ~ 4

Author(s):

Boris W Kramer

Keyword(s):

Fetal Brain ◽

In Utero ◽

Ovine Fetal

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Heat production of fetal sheep brain in utero

Journal of Applied Physiology ◽

10.1152/jappl.1977.43.4.747 ◽

1977 ◽

Vol 43 (4) ◽

pp. 747-749 ◽

Cited By ~ 3

Author(s):

R. M. Abrams ◽

J. F. Clapp ◽

M. Notelovitz ◽

T. Tyler ◽

S. Cassin

Keyword(s):

Specific Heat ◽

Heat Production ◽

Brain Temperature ◽

Main Pulmonary Artery ◽

Fetal Brain ◽

In Utero ◽

Total Occlusion ◽

Fetal Sheep ◽

Sheep Brain ◽

Near Term

Thermojunctions were implanted in the brains of 10 near term fetal sheep in utero under halothane anesthesia. Brief total occlusion of fetal brachiocephalic artery was followed immediately by an increase in brain temperature (mean +/- SE) of 0.130 +/- 0.014 degrees C-min-1. Occlusion of main pulmonary artery and ascending aorta, simultaneously, led to a brain temperature increase of 0.144 +/- 0.018 degrees C-min-1. Specific heat of three fetal brains was determined to be 0.898 +/- 0.014 cal-g-1. degrees C-1 or 3.76 +/- 0.059 J-g-1. Rate of fetal brain heat production, computed as the product of the higher rate of temperature change and brain specific heat, was 0.129 +/- 0.014 cal-g-1-min-1 or 9.00 +/- 0.98 mW-g-1.

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In utero hypoxia altered Ang II-induced contraction via PKCβ in fetal cerebral arteries

Journal of Endocrinology ◽

10.1530/joe-19-0370 ◽

2020 ◽

Vol 244 (1) ◽

pp. 213-222

Author(s):

Hongyu Su ◽

Xueyi Chen ◽

Yueming Zhang ◽

Linglu Qi ◽

Yun He ◽

...

Keyword(s):

Protein Expression ◽

Cerebral Circulation ◽

Cerebral Arteries ◽

Fetal Brain ◽

Calcium Transient ◽

In Utero ◽

Protective Effects ◽

Ang Ii ◽

Voltage Dependent ◽

Near Term

Cerebral circulation is important in fetal brain development, and angiotensin II (Ang II) plays vital roles in regulation of adult cerebral circulation. However, functions of Ang II in fetal cerebral vasculature and influences of in utero hypoxia on Ang II-mediated fetal cerebral vascular responses are largely unknown. This study investigated the effects and mechanisms of in utero hypoxia on fetal middle cerebral arteries (MCA) via Ang II. Near-term ovine fetuses were exposed to in utero hypoxia, and fetal MCA responses to Ang II were tested for vascular tension, calcium transient, and molecular analysis. Ang II caused significant dose-dependent contraction in control fetal MCA. Ang II-induced MCA constriction was decreased significantly in hypoxic fetuses. Neither losartan (AT1R antagonist, 10−5 mol/L) nor PD123,319 (AT2R antagonist, 10−5 mol/L) altered Ang II-mediated contraction in fetal MCA. Phenylephrine-mediated constriction was also significantly weaker in hypoxic fetuses. Bay K8644 caused similar contractions between the two groups. Protein expression of L-type voltage-dependent calcium channels was unchanged. There were no differences in caffeine-mediated vascular tension or calcium transients. Contraction induced by PDBu (PKC agonist) was obviously weaker in hypoxic MCA. Protein expression of PKCβ was reduced in the hypoxic compared with the control, along with no differences in phosphorylation levels. The results showed that fetal MCA was functionally responsive to Ang II near term. Intrauterine hypoxia reduced the vascular agonist-mediated contraction in fetal MCA, probably via decreasing PKCβ and its phosphorylation, which might play protective effects on fetal cerebral circulation against transient hypoxia.

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Development of ingestive behavior

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.4.r879 ◽

1998 ◽

Vol 274 (4) ◽

pp. R879-R893 ◽

Cited By ~ 22

Author(s):

Michael G. Ross ◽

Mark J. M. Nijland

Keyword(s):

Amniotic Fluid ◽

Functional System ◽

In Utero ◽

Ingestive Behavior ◽

Salt Appetite ◽

Fetal Life ◽

Ovine Fetus ◽

Near Term ◽

Ovine Fetal ◽

In Utero Development

Swallowing represents a primary physiological function that provides for the ingestion of food and fluid. In precocial species, swallowing activity likely develops in utero to provide for a functional system during the neonatal period. The chronically instrumented ovine fetal preparation has provided the opportunity for recent advances in understanding the regulation of in utero swallowing activity. The near-term ovine fetus swallows fluid volumes (100–300 ml/kg) that are markedly greater, per body weight, than that of the adult (40–60 ml/kg). Spontaneous in utero swallowing and ingestive behavior contribute importantly to the regulation of amniotic fluid volume and composition, the acquisition and potential recirculation of solutes from the fetal environment, and the maturation of the fetal gastrointestinal tract. Fetal swallowing activity is influenced by fetal maturation, neurobehavioral state alterations, and the volume of amniotic fluid. Furthermore, intact dipsogenic mechanisms (osmolality, angiotensin II) have been demonstrated in the near-term ovine fetus. It remains unknown to what degree, if any, fetal swallowing may be influenced by nutrient appetite, salt appetite, or taste. Nevertheless, the development of dipsogenic and additional regulatory mechanisms for ingestive behavior occurs during fetal life and may be susceptible to changes in the pregnancy environment. This review describes what is currently known regarding the in utero development of ingestive behavior and the importance of this activity for fetal and perhaps ultimately adult fluid homeostasis.

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Thyroid hormones in fetal growth and prepartum maturation

Journal of Endocrinology ◽

10.1530/joe-14-0025 ◽

2014 ◽

Vol 221 (3) ◽

pp. R87-R103 ◽

Cited By ~ 172

Author(s):

A J Forhead ◽

A L Fowden

Keyword(s):

Growth Factors ◽

Thyroid Hormones ◽

Fetal Growth ◽

Growth And Development ◽

Fetal Brain ◽

Normal Growth ◽

In Utero ◽

Somatic Tissues ◽

Near Term ◽

Maternal Thyroid

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailabilityin uterodepends on development of the fetal hypothalamic–pituitary–thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4and T3concentrations are also affected by gestational age, nutritional and endocrine conditionsin utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating theprepartummaturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4and T3bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

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