Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model

Tremblay, Sophie; Pai, Alex; Richter, Lindsay L; Vafaei, Rod; Potluri, Praneetha; Ellegood, Jacob; Lerch, Jason P.; Goldowitz, Daniel

doi:10.1016/j.bbi.2017.07.013

Cited by 11 publications

(7 citation statements)

References 126 publications

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“…C57BL/6J and ICR (CD1) mice used in this study were obtained from the Goldowitz Laboratory mouse inbred and outbred colonies, respectively. A non-nursing ICR female mouse was added to the litter to prevent rejection of pups from nursing C57BL/6J dam and improve survival rate of treated mouse pups (Tremblay et al, 2017a). Postnatal day 0 (P0) was defined as the day of birth.…”

Section: Methodsmentioning

confidence: 99%

“…A platform was located in an arbitrarily defined quadrant of the maze and 2 cm below the surface of the water so that mice could not see the platform when swimming. Mice were trained for 3 days to assess learning (2 tests/day- in AM and PM for 3 days) and two probe trials in the absence of the platform were used to test short (on fourth day) and long-term (7 days post-training) memory (Tremblay et al, 2017a). Between each session, mice were resting in a heated standard cage with paper towel and water gel for a 10 min inter-trial period.…”

Section: Methodsmentioning

confidence: 99%

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Adverse Behavioral Changes in Adult Mice Following Neonatal Repeated Exposure to Pain and Sucrose

et al. 2019

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Sucrose is recommended for the treatment of pain during minor procedures in preterm infants in the neonatal intensive care unit (NICU) and is currently used worldwide as the standard of care. We recently reported that adult mice repetitively exposed to sucrose compared to water during the first week of life, irrespective of exposure to an intervention, had significantly smaller brain volumes in large white matter, cortical and subcortical structures (e.g., hippocampus, striatum, fimbria). These structures are important for stress regulation and memory formation. Here, we report the effects of repeated neonatal exposure to pain and sucrose on adult behavior in mice. Neonatal C57BL/6J mice (N = 160, 47% male) were randomly assigned to one of two treatments (sucrose, water) and one of three interventions (needle-prick, tactile, handling). Pups received 10 interventions daily from postnatal day 1 (P1) to P6. A single dose of 24% sucrose or water was given orally 2 min before each intervention. At adulthood (P60-85) mice underwent behavioral testing to assess spatial memory, anxiety, motor function, pain sensitivity, and sugar preference. We found that mice that had received sucrose and handling only, had poorer short-term memory in adulthood compared to water/handling controls (p < 0.05). When exposed to pain, mice treated with repetitive sucrose or water did not differ on memory performance (p = 0.1). A sugar preference test showed that adult mice that received sucrose before an intervention as pups consumed less sugar solution compared to controls or those that received water before pain (p < 0.05). There were no significant group differences in anxiety, motor, or pain sensitivity. In a mouse model that closely mimics NICU care, we show for the first time that memory in adulthood was poorer for mice exposed to pain during the first week of life, irrespective of sucrose treatment, suggesting that sucrose does not protect memory performance when administered for pain. In the absence of pain, early repetitive sucrose exposure induced poorer short-term memory, highlighting the importance of accurate pain assessment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Adverse Behavioral Changes in Adult Mice Following Neonatal Repeated Exposure to Pain and Sucrose

et al. 2019

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“…Mechanisms of reduced cerebellar size due to preterm birth generally include subarachnoid hemorrhage or hypoxia. Cerebellar volume has shown to be reduced in a neonatal mouse model of cerebellar hemorrhage [27]. In infants born preterm, blood over the cerebellum due to subarachnoid hemorrhage, accompanied by hemosiderin deposition, has been shown to result in reduced cerebellar volume [28,29] and potentially direct effects on Purkinje cells in preterm newborns, as discussed by Volpe [7].…”

Section: Discussionmentioning

confidence: 99%

Preterm Birth Impedes Structural and Functional Development of Cerebellar Purkinje Cells in the Developing Baboon Cerebellum

Barron¹,

Kim²

2020

Brain Sciences

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Human cerebellar development occurs late in gestation and is hindered by preterm birth. The fetal development of Purkinje cells, the primary output cells of the cerebellar cortex, is crucial for the structure and function of the cerebellum. However, morphological and electrophysiological features in Purkinje cells at different gestational ages, and the effects of neonatal intensive care unit (NICU) experience on cerebellar development are unexplored. Utilizing the non-human primate baboon cerebellum, we investigated Purkinje cell development during the last trimester of pregnancy and the effect of NICU experience following premature birth on developmental features of Purkinje cells. Immunostaining and whole-cell patch clamp recordings of Purkinje cells in the baboon cerebellum at different gestational ages revealed that molecular layer width, driven by Purkinje dendrite extension, drastically increased and refinement of action potential waveform properties occurred throughout the last trimester of pregnancy. Preterm birth followed by NICU experience for 2 weeks impeded development of Purkinje cells, including action potential waveform properties, synaptic input, and dendrite extension compared with age-matched controls. In addition, these alterations impact Purkinje cell output, reducing the spontaneous firing frequency in deep cerebellar nucleus (DCN) neurons. Taken together, the primate cerebellum undergoes developmental refinements during late gestation, and NICU experience following extreme preterm birth influences morphological and physiological features in the cerebellum that can lead to functional deficits.

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“…The association of infection with decreased cerebral NAA/Cho ratio has been previously described 38 . Animal models of systemic inflammation have been shown to lead to microstructural cerebellar injury 39 . In this cohort, we observed an independent association of systemic infection and NEC with several metabolic alterations in the developing cerebellum in the early postnatal period.…”

Section: Discussionmentioning

confidence: 99%

Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury

Basu

Pradhan

Kapse

et al. 2019

Sci Rep

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Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy (1H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality 1H-MRS at median 33.0 (IQR 31.6–35.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0–29.0) weeks. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value < 0.0001) and negative correlation of Cho/Cr ratio (R −0.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value < 0.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.

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Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model

Cited by 11 publications

References 126 publications

Adverse Behavioral Changes in Adult Mice Following Neonatal Repeated Exposure to Pain and Sucrose

Adverse Behavioral Changes in Adult Mice Following Neonatal Repeated Exposure to Pain and Sucrose

Preterm Birth Impedes Structural and Functional Development of Cerebellar Purkinje Cells in the Developing Baboon Cerebellum

Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury

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