Selective Losses of Brainstem Catecholamine Neurons After Hypoxia-Ischemia in the Immature Rat Pup

Buller, Kathryn M.; Wixey, Julie A.; Pathipati, Praneeti; Carty, Michelle L.; Colditz, Paul B.; Williams, Christopher E.; Scheepens, Arjan

doi:10.1203/pdr.0b013e3181659774

Cited by 34 publications

(27 citation statements)

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“…Similar results have been found in 3-week-old rats exposed on the 3rd postnatal day to hypoxia/ischemia [20] induced by unilateral ligation of the carotid artery, an animal model of perinatal hypoxia in humans [57,58]. In addition to the loss of TH-IR neurons in LC ispilateral to the ligation, Buller et al [20] have further reported reduction of the cerebral hemisphere size, as well as decreased dopamine-β-hydroxylase immunoreactivity in the forebrain to the ligated hemisphere, indicating long-term alterations of the volume and the noradrenergic innervation of the cortex after perinatal hypoxia/ischemia.…”

Section: Discussionsupporting

confidence: 89%

“…In addition to the loss of TH-IR neurons in LC ispilateral to the ligation, Buller et al [20] have further reported reduction of the cerebral hemisphere size, as well as decreased dopamine-β-hydroxylase immunoreactivity in the forebrain to the ligated hemisphere, indicating long-term alterations of the volume and the noradrenergic innervation of the cortex after perinatal hypoxia/ischemia. The mechanisms leading to this reduction in TH immunoreactivity in LC neurons after perinatal hypoxia are not currently known.…”

Section: Discussionmentioning

confidence: 99%

“…We found a striking reduction or even absence of tyrosine hydroxylase (TH, the first and limiting enzyme of catecholamine synthesis) immunoreactivity in the dopaminergic neurons of the substantia nigra and ventral tegmental area, indicating possible early dysregulation of the dopaminergic neurotransmission under prolonged hypoxic conditions [16]. Experimental studies, however, have shown that perinatal hypoxia induces not only selective long-standing disturbances in the central dopaminergic systems of the mesencephalon [17,18], but also in the noradrenergic and serotonergic systems of the brainstem that persist into adulthood [17,18,19,20,21]. The purpose of the present study was to immunohistochemically investigate the expression of TH in the noradrenergic locus coeruleus (LC) neurons of the human neonate in relation to the degree of neuropathological hypoxic/ischemic brain injury.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

Pagida¹,

Konstantinidou²,

Korelidou³

et al. 2015

Dev Neurosci

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We have previously shown that perinatal hypoxic/ischemic injury (HII) may cause selective vulnerability of the mesencephalic dopaminergic neurons of human neonate. In the present study, we investigated the effect of perinatal HII on the noradrenergic neurons of the locus coeruleus (LC) of the same sample. We studied immunohistochemically the expression of tyrosine hydroxylase (TH, first limiting enzyme for catecholamine synthesis) in LC neurons of 15 autopsied infants (brains collected from the Greek Brain Bank) in relation to the neuropathological changes of acute or chronic HII of the neonatal brain. Our results showed that perinatal HII appears to affect the expression of TH and the size of LC neurons of the human neonate. In subjects with neuropathological lesions consistent with abrupt/severe HII, intense TH immunoreactivity was found in almost all neurons of the LC. In most of the neonates with neuropathological changes of prolonged or older injury, however, reduction in cell size and a decrease or absence of TH staining were observed in the LC. Intense TH immunoreactivity was found in the LC of 3 infants of the latter group, who interestingly had a longer survival time and had been treated with anticonvulsant drugs. Based on our observations and in view of experimental evidence indicating that the reduction of TH-immunoreactive neurons occurring in the LC after perinatal hypoxic insults persists into adulthood, we suggest that a dysregulation of monoaminergic neurotransmission in critical periods of brain development in humans is likely to predispose the survivors of perinatal HII, in combination with genetic susceptibility, to psychiatric and/or neurological disorders later in life.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

Pagida¹,

Konstantinidou²,

Korelidou³

et al. 2015

Dev Neurosci

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“…Taken together, perinatal depletion or excess of 5-HT (8,15) results in dysfunctions of neural networks. The 5-HT system is not the only one vulnerable to HI and specific loss of catecholaminergic neurons has been previously described following HI at P3, in the ventrolateral medulla and the nucleus tractus solitaries (29). In this study, we also showed significant changes in NA content in the medulla and in the spinal cord as well as for the DA content.…”

Section: Disturbances Of the 5-ht Na And Da System In Hi Micesupporting

confidence: 79%

Deficits of brainstem and spinal cord functions after neonatal hypoxia–ischemia in mice

et al. 2014

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Background: Perinatal cerebral hypoxia-ischemia (HI) can lead to severe neurodevelopmental disorders. Studies in humans and animal models mainly focused on cerebral outcomes, and little is known about the mechanisms that may affect the brainstem and the spinal cord. Dysfunctions of neuromodulatory systems, such as the serotonergic (5-HT) projections, critical for the development of neural networks, have been postulated to underlie behavioral and motor deficits, as well as metabolic changes. Methods: The aim of this study was to investigate brainstem and spinal cord functions by means of plethysmography and sensorimotor tests in a neonatal Rice-Vanucci model of HI in mice. We also evaluated bioaminergic contents in central regions dedicated to the motor control of autonomic functions. results: Mice with cerebral infarct expressed motor disturbances and had a lower body weight and a decreased respiratory frequency than SHAM, suggesting defects of brainstem neural network involved in the motor control of feeding, suckling, swallowing, and respiration. Moreover, our study revealed changes of monoamine and amino acid contents in the brainstem and the spinal cord of HI mice. conclusion: Our results suggest that monoaminergic neuromodulation plays an important role in the physiopathology of HI brain injury that may represent a good therapeutic target. i t is well documented that most cases of term neonatal encephalopathy are highly related to hypoxic-ischemic (HI) brain injury that occurs in utero or during delivery from a variety of intrapartum conditions (1). HI causes a combination of white and gray matter damage. Enlarged ventricules, loss of vulnerable oligodendrocyte progenitor cells, periventricular leucomalacia, astrogliosis, and microgliosis are typical features of HI damage (1,2). The neurological outcome in surviving children is variable, ranging from mild cognitive impairment to major disabilities including cerebral palsy, behavioral disorders, and motor deficits (3). Early MRI with diffusion tensor imaging in neonates after HI is increasingly used to obtain clinical information noninvasively and follows the brain injury (4). It is well established that there are volumetric reductions in certain brain areas of HI preterm infants including the thalamus, basal ganglia, and cerebral cortex. Only a few studies have examined neuronal injury in the brainstem in human neonates (5) or in animal models (6). Until now, no investigation has focused on the possible spinal cord defects following HI.Moreover, dysfunctions of some neuromodulators, such as the serotonergic system (5-HT) that is critical for the development of neuronal networks have been postulated to underlie behavioral and motor deficits (7). In addition, dysfunction of 5-HT neurotransmission is implicated in a host of physiological, metabolic, and behavioral changes in disease states such as epilepsy, Rett syndrome, Prader-Willi syndrome, and sudden infant death syndrome (8,9).The aim of this study was to investigate HI damage and the neurotransmitters s...

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“…Previous studies have shown that the immature brainstem can be damaged by various unfavorable perinatal conditions, e.g., hypoxia-ischemia (2). Recent studies revealed that brain structure may be abnormal in preterm infants and preterm birth is associated with regional cerebral tissue reductions (3,4).…”

mentioning

confidence: 99%

Relative Maturation of Peripheral and Central Regions of the Human Brainstem From Preterm to Term and the Influence of Preterm Birth

Jiang

Brosi

et al. 2009

Pediatr Res

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Relative maturation of peripheral and central regions of the neonatal brainstem was studied using brainstem auditory evoked responses in 174 healthy preterm infants (gestational age 30 -36 wk). From 30-to 42-wk postconceptional age (PCA), I-III and III-V intervals shortened with increasing age. It was difficult to detect any apparent differences in maturational rate between the two intervals. However, III-V/I-III interval ratio decreased with increasing age, indicating that from preterm to term III-V interval shortens more than I-III interval. During term period (37-to 42-wk PCA), I-III interval was similar to term controls, but III-V interval was significantly longer and III-V/I-III interval ratio was significantly greater than controls at 37-to 38-wk PCA and 39 -40 wk PCA and was the same as controls at 41-42 wk. Therefore, from 30-to 42-wk PCA maturation of central regions of the brainstem, reflected by III-V interval, is relatively faster than peripheral regions, reflected by I-III interval which seems to be already more mature than III-V interval before 30 wk. Maturation in central regions in preterm infants is relatively delayed at early term, but "catches-up" later, whereas peripheral regions already reach normal level of maturation at early term. Preterm birth slightly delays early maturation of central brainstem regions. . Previous studies have shown that the immature brainstem can be damaged by various unfavorable perinatal conditions, e.g., hypoxia-ischemia (2). Recent studies revealed that brain structure may be abnormal in preterm infants and preterm birth is associated with regional cerebral tissue reductions (3,4). It remains unclear whether the rate of maturation in the more peripheral and more central regions of the brainstem is equal or different during earlier life and what influence the preterm birth exerts on this maturation. The understanding will help improve the care and management of very young infants, particularly for those who may be at risk of developmental abnormalities.In addition to detecting auditory abnormalities, brainstem auditory evoked responses (BAERs) have been used to study functional status and maturation of the, specifically auditory, brainstem (5-7). The responses, generating from specific brainstem auditory relay nuclei, are extremely complex and are under multiple inhibiting and facilitating influences from the rest of the CNS. Maturation of the BAER is associated with myelination of axons, formation of central synaptic connections, and axonal diameter and has been found to correlate with maturation of the brainstem, as well as the auditory pathway (8 -10). During early life, the BAER undergoes tremendous maturational changes, characterized by a shortening of wave latencies and an increase in wave amplitudes of the response (11-14). Furthermore, a shortening of the intervals between BAER wave peaks (i.e., interpeak intervals) with increasing age has been well documented.In BAER wave form, wave I, III, and V, the three major and reliable waves, originate fro...

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Selective Losses of Brainstem Catecholamine Neurons After Hypoxia-Ischemia in the Immature Rat Pup

Cited by 34 publications

References 45 publications

The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

Deficits of brainstem and spinal cord functions after neonatal hypoxia–ischemia in mice

Relative Maturation of Peripheral and Central Regions of the Human Brainstem From Preterm to Term and the Influence of Preterm Birth

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