Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury

Oxytocin receptor antagonists for inhibiting preterm labour (Review)

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Stillbirths: recall to action in high-income countries.

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.Mater Research Institute – The University of Queensland provided infrastructure and funding for the research team to enable this work to be undertaken. The Canadian Research Chair in Psychosocial Family Health provided funding for revision of the translation of the French web-based survey of care providers.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S0140-6736(15)01020-

Characteristics of a global classification system for perinatal deaths: a Delphi consensus study.

BACKGROUND: Despite the global burden of perinatal deaths, there is currently no single, globally-acceptable classification system for perinatal deaths. Instead, multiple, disparate systems are in use world-wide. This inconsistency hinders accurate estimates of causes of death and impedes effective prevention strategies. The World Health Organisation (WHO) is developing a globally-acceptable classification approach for perinatal deaths. To inform this work, we sought to establish a consensus on the important characteristics of such a system. METHODS: A group of international experts in the classification of perinatal deaths were identified and invited to join an expert panel to develop a list of important characteristics of a quality global classification system for perinatal death. A Delphi consensus methodology was used to reach agreement. Three rounds of consultation were undertaken using a purpose built on-line survey. Round one sought suggested characteristics for subsequent scoring and selection in rounds two and three. RESULTS: The panel of experts agreed on a total of 17 important characteristics for a globally-acceptable perinatal death classification system. Of these, 10 relate to the structural design of the system and 7 relate to the functional aspects and use of the system. CONCLUSION: This study serves as formative work towards the development of a globally-acceptable approach for the classification of the causes of perinatal deaths. The list of functional and structural characteristics identified should be taken into consideration when designing and developing such a system.This project was initially undertaken as part of the Harmonized Reproductive Health Registries project through the Norwegian Institute of Public Health in Partnership with the Mater Medical Research Institute, Brisbane, Australia, and in collaboration with the Department of Reproductive Health and Research, WHO.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by BioMed Central

Evidence that the serotonin transporter does not shift into the cytosol of remaining neurons after neonatal brain injury

Following neonatal hypoxia-ischemia (HI) serotonin (5-hydroxytryptamine, 5-HT) levels are decreased in the brain. The regulation of brain 5-HT is dependent on the serotonin transporter (SERT) localised at the neuronal pre-synaptic cell membrane. However SERT can also traffic away from the cell membrane into the cytosol and, after injury, may contribute to the cell's inability to maintain 5-HT levels. Whether this occurs after neonatal HI brain injury is not known. In addition, there is contradictory evidence that glial cells may also contribute to the clearance of 5-HT in the brain. Using a postnatal day 3 (P3) HI rat pup model (right carotid ligation + 30 min 6% O-2), we found, in both control and P3 HI animals, that SERT is retained on the cell membrane and is not internalised in the cytosol. In addition, SERT was only detected on neurons. We found no evidence of SERT co-localisation on microglia or astrocytes. We conclude that neuronal SERT is the primary regulator of synaptic 5-HT availability in the intact and P3 HI-injured neonatal brain. Furthermore, since concomitant reductions in 5-HT, SERT and serotonergic neurons occur after neonatal HI, it is plausible that the decrease in brain 5-HT is a consequence of SEAT being lost as neurons degenerate as opposed to remaining neurons internalising SERT or clearance by glial cells. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved

Disruption to the 5-HT7 Receptor Following Hypoxia-Ischemia in the Immature Rodent Brain

It has become increasingly evident the serotonergic (5-hydroxytryptamine, 5-HT) system is an important central neuronal network disrupted following neonatal hypoxic-ischemic (HI) insults. Serotonin acts via a variety of receptor subtypes that are differentially associated with behavioural and cognitive mechanisms. The 5-HT7 receptor is purported to play a key role in epilepsy, anxiety, learning and memory and neuropsychiatric disorders. Furthermore, the 5-HT7 receptor is highly localized in brain regions damaged following neonatal HI insults. Utilising our well-established neonatal HI model in the postnatal day 3 (P3) rat pup we demonstrated a significant decrease in levels of the 5-HT7 protein in the frontal cortex, thalamus and brainstem one week after insult. We also observed a relative decrease in both the cytosolic and membrane fractions of 5-HT7. The 5-HT7 receptor was detected on neurons throughout the cortex and thalamus, and 5-HT cell bodies in the brainstem. However we found no evidence of 5-HT7 co-localisation on microglia or astrocytes. Moreover, minocycline treatment did not significantly prevent the HI-induced reductions in 5-HT7. In conclusion, neonatal HI injury caused significant disruption to 5-HT7 receptors in the forebrain and brainstem. Yet the use of minocycline to inhibit activated microglia, did not prevent the HI-induced changes in 5-HT7 expression

Differential effects of neonatal hypoxic-ischemic brain injury on brainstem serotonergic raphe nuclei

Serotonergic fibres have a pervasive innervation of hypoxic-ischemic (HI)-affected areas in the neonatal brain and serotonin (5-HT) is pivotal in numerous neurobehaviours that match many HI-induced deficits. However, little is known about how neonatal HI affects the serotonergic system. We therefore examined whether neonatal HI can alter numbers of serotonergic raphe neurons in specific sub-divisions of the midbrain and brainstem since these nuclei are the primary sources of serotonin throughout the central nervous system (CNS). We utilised an established neonatal HI model in the postnatal day 3 (P3) rat pup (right common carotid artery ligation + 30 min 6% O(2)) and determined the effects of P3 HI on 5-HT counts in 5 raphe sub-divisions in the midbrain and brainstem one and six weeks later. After P3 HI, numbers of 5-HT-positive neurons were significantly decreased in the dorsal raphe dorsal, dorsal raphe ventrolateral and dorsal raphe caudal nuclei on P10 but only in the dorsal raphe dorsal and dorsal raphe ventrolateral nuclei on P45. In contrast, P3 HI did not alter counts in the dorsal raphe interfascicular and raphe magnus nuclei. We also discovered that P3 HI significantly reduces brainstem SERT protein expression; the key regulator of 5-HT in the CNS. In conclusion, neonatal HI injury caused significant disruption of the brainstem serotonergic system that can persist for up to six weeks after the insult. The different vulnerabilities of serotonergic populations in specific raphe nuclei suggest that certain raphe nuclei may underpin neurological deficits in HI-affected neonates through to adulthood. (C) 2010 Elsevier B.V. All rights reserved

Inhibition of neuroinflammation prevents injury to the serotonergic network after hypoxia-ischemia in the immature rat brain

The phenotypic identities and characterization of neural networks disrupted after neonatal hypoxia-ischemia (HI) in the preterm brain remain to be elucidated. Interruption of the central serotonergic (5-hydroxytryptamine [5-HT]) system can lead to numerous functional deficits, many of which match those in human preterm neonates exposedto HI. How the central serotonergic network is damaged after HIand mechanisms underlying such injury are not known. We used aPostnatal Day 3 rat model of preterm HI and found parallel reductionsin the 5-HT transporter expression, 5-HT levels and numbers of 5-HT-positive dorsal raphe neurons 1 week after insult. Post-HI administration of minocycline, an inhibitor of activated microglia, attenuated HI-induced damage to the serotonergic network. Minocycline effects seemed to be region specific, that is, where there was microglialactivation and increases in tumor necrosis factor-α and interleukin1β. The concurrent improvement in serotonergic outcomes suggests that inhibition of neuroinflammation prevented damage to theserotonergic neurons rather than affected the regulation of 5-HT orserotonin transporter. These data elucidate the mechanisms of serotonergic network injury in HI, and despite the known adverse effects associated with the use of minocycline in neonates, postinsult administration of minocycline may represent a novel approach to counter neuroinflammation and preserve the integrity of the central serotonergic network in the preterm neonate