Injury of the developing cerebellum: a brief review of the effects of endotoxin and asphyxial challenges in the late gestation sheep fetus.

The vulnerability of the fetal and newborn brain to events in utero or at birth that cause damage arising from perturbations of cerebral blood flow and metabolism, such as the accumulation of free radicals and excitatory transmitters to neurotoxic levels, has received considerable attention over the last few decades. Attention has usually been on the damage to cerebral structures, particularly, periventricular white matter. The rapid growth of the cerebellum in the latter half of fetal life in species with long gestations, such as the human and sheep, suggests that this may be a particularly important time for the development of cerebellar structure and function. In this short review, we summarize data from recent studies with fetal sheep showing that the developing cerebellum is particularly sensitive to infectious processes, chronic hypoxia and asphyxia. The data demonstrates that the cerebellum should be further studied in insults of this nature as it responds differently to the remainder of the brain. Damage to this region of the brain has implications not only for the development of motor control and posture, but also for higher cognitive processes and the subsequent development of complex behaviours, such as learning, memory and attention.

Behavioural effects of near-term acute fetal hypoxia in a small precocial animal, the spiny mouse (Acomys cahirinus).

We have previously developed a model of near-term intra-uterine hypoxia producing significant neonatal mortality (37%) in a small laboratory animal - the spiny mouse - which has precocial offspring at birth. The aim of the present study was to determine if this insult resulted in the appearance of behavioural abnormalities in those offspring which survived the hypoxic delivery. Behavioural tests assessed gait (using footprint patterns), motor coordination and balance on an accelerating rotarod, and spontaneous locomotion and exploration in an open field. We found that the near-term acute hypoxic episode produced a mild neurological deficit in the early postnatal period. In comparison to vaginally delivered controls, hypoxia pups were able to remain on the accelerating rotarod for significantly shorter durations on postnatal days 1-2, and in the open field they travelled significantly shorter distances, jumped less, and spent a greater percentage of time stationary on postnatal days 5 and 15. No changes were observed in gait. Unlike some rodent models of cerebral hypoxia-ischaemia, macroscopic examination of the brain on postnatal day 5 showed no gross cystic lesions, oedema or infarct. Future studies should be directed at identifying hypoxia-induced alterations in the function of specific brain regions, and assessing if maternal administration of neuroprotective agents can prevent against hypoxia-induced neurological deficits and brain damage that occur at birth.

Neuropathology and functional deficits in a model of birth asphyxia in the precocial spiny mouse (Acomys cahirinus).

Birth asphyxia can result in sensory impairment, learning and memory deficits without gross brain injury and severe motor deficits. We developed a model of birth asphyxia resulting in mild neurological injury and cognitive impairment using a long-gestation species with precocial fetal development. Spiny mice (Acomys cahirinus) underwent caesarean-section delivery or 7.5 min of asphyxia at 37 days gestational age (term is 39 days). Brain histology was examined at 1 and 7 days of age, and behaviour was evaluated to 28 days of age. Asphyxiated offspring showed significant impairment in non-spatial memory and learning tasks, accompanied by central nervous system inflammation and increased apoptotic cell death but without the presence of large necrotic or cystic lesions.

Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomys cahirinus).

Birth asphyxia is associated with disturbed development of the neonatal brain. In this study, we determined if low-dose melatonin (0.1 mg/kg/day), administered to the mother over 7 days at the end of pregnancy, could protect against the effects of birth asphyxia in a precocial species - the spiny mouse (Acomys cahirinus). At 37 days of gestation (term is 38-39 days), pups were subjected to birth asphyxia (7.5 min uterine ischemia) and compared to Cesarean section-delivered controls. At 24 h of age, birth asphyxia had increased markers of CNS inflammation (microglia, macrophage infiltration) and apoptosis (activated caspase-3, fractin) in cortical gray matter, which were reduced to control levels by prior maternal melatonin treatment. Melatonin may be an effective prophylactic agent for use in late pregnancy to protect against hypoxic-ischemic brain injury at birth.

Microglial activation, macrophage infiltration, and evidence of cell death in the fetal brain after uteroplacental administration of lipopolysaccharide in sheep in late gestation.

OBJECTIVE: The purpose of this study was to determine whether uteroplacental delivery of endotoxin produces fetal systemic and central nervous system reactions that are suggestive of inflammation. STUDY DESIGN: Lipopolysaccharide (30 or 60 microg) was administered into the uterine artery of late gestation (135 +/- 0.3 days) pregnant sheep. Fetal blood was assayed to determine changes in levels of quinolinic acid, which is a metabolite of tryptophan that is produced by monocytes (macrophages, microglia). Fetal brains were collected after 72 hours and examined for the presence of activated microglia and parenchymal macrophages. RESULTS: The brains of treated fetuses showed microglial activation and macrophage infiltration, which varied between brain region and lipopolysaccharide dose. Cell death that had been determined by cresyl violet/acid fuchsin staining was observed in the external capsule. There was significant increase of quinolinic acid in the fetal circulation, but no lipopolysaccharide was detected. CONCLUSION: Uteroplacental inflammation results in significant microglial activation and macrophage infiltration without direct fetal exposure to endotoxin, which suggests that placental responses contribute to perinatal brain damage that is associated with infection during pregnancy.

Uteroplacental inflammation results in blood brain barrier breakdown, increased activated caspase 3 and lipid peroxidation in the late gestation ovine fetal cerebellum.

Maternal infection is associated with perinatal brain damage, but effects on the cerebellum are not known in detail. In this study, we examined the effects of placental inflammation induced by administering lipopolysaccharide into the uterine artery of pregnant sheep at 134-136 days gestation. The fetal brain was collected 72 h later and compared to brains collected from age-matched untreated fetuses. Placental lipopolysaccharide treatment had substantial effects on the fetal cerebellum, including increasing the number of cells undergoing apoptosis, widespread lipid peroxidation, and extravasation of plasma albumin, suggesting compromise of the cerebellar blood-brain barrier. These effects may account for some of the learning and motor deficits that emerge in neonates from pregnancies compromised by infection.

Sex differences in the pituitary-adrenal response following acute antidepressant treatment in sheep.

RATIONALE: Depression is more prevalent in women than in men, and therapeutic responses may also differ between the sexes. In addition, abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is more common in depressed women. OBJECTIVES: To further examine these phenomena, the present study was designed to investigate whether sex differences exist in the HPA axis responses of male and female sheep following acute antidepressant administration. METHODS: Two commonly prescribed antidepressants, imipramine (a tricyclic antidepressant, TCA; 2.0 and 5.0 mg/kg) and sertraline (a selective serotonin reuptake inhibitor, SSRI; 0.5, 2.0 and 5.0 mg/kg) were administered to gonadectomized male and female sheep via acute subcutaneous injection. Treatment order was randomized. Jugular blood was sampled for the measurement of prolactin, adrenocorticotropin (ACTH), and cortisol by radioimmunoassay. RESULTS: Treatment with sertraline resulted in a comparable increase in prolactin secretion in male and female sheep. However, sertraline stimulated ACTH and cortisol secretion in females but not in males, a sexually dimorphic effect that was independent of circulating sex steroids. Treatment with imipramine had no effect on prolactin, ACTH or cortisol levels in male or female sheep. CONCLUSIONS: These data suggest that the HPA axes of females are more sensitive to the stimulatory effects of serotonin following acute treatment with the SSRI, sertraline.