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

Abstract

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...

Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

“…In this model, a selective, significant decrease in numbers of 5-HT-positive neurons was noted in rostral raphe nuclei (dorsal raphe), while there was no change in the caudal raphe nuclei projecting to spinal cord, such as raphe magnus (Reinebrant et al 2010), similar to observation in a mouse model of neonatal asphyxia (Takeuchi et al 1992). Recently, increased levels of spinal serotonin, similar to our study, have been reported after unilateral carotid ligation and hypoxia in neonatal mice (Bellot et al 2014). Rodent models of perinatal brain injury, however, do not produce overt motor deficits and muscle hypertonia as in our rabbit model.…”

Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

“…[42] Disruption of the brainstem and spinal cord serotonergic system has also been proposed to account for the motor defects observed in neonatal mice using the Rice– Vanucci hypoxic-ischemic injury model. [43] Future studies in our UCO model investigating damaged neural pathways, such as serotonergic system pathway, after neonatal HIE may reveal cellular mechanisms of axonal degeneration relevant to the development of CP.…”

Altered Motoneuron Properties Contribute to Motor Deficits in a Rabbit Hypoxia-Ischemia Model of Cerebral Palsy

“…The exact causes of the changes in MN physiology observed here are unclear, but they could result from the increase in spinal monoamines that occurs after developmental HI injury in both rodents and rabbits (Bellot et al, 2014;Drobyshevsky et al, 2015). Serotonin is generally thought of as a neurotransmitter and neuromodulator, but developmental disruption in 5HT is associated with neurological disorders including autism, Rett syndrome, Down's syndrome and, more recently, CP (Bar-Peled et al, 1991;Whittle et al, 2007;Bellot et al, 2014;Yang et al, 2014;De Filippis et al, 2015;Drobyshevsky et al, 2015;Muller et al, 2016;Wirth et al, 2017). Serotonin increases MN excitability in neonatal and juvenile mice, rats and guinea pigs (Wang and Dun, 1990;Ziskind-Conhaim et al, 1993;Hsiao et al, 1997Hsiao et al, , 1998, and likely has the same effect on rabbit MNs.…”

“…It's been shown in previous studies that HI injury during late gestation in rabbits can result in a variety of neurologic and muscular damage, including muscle stiffness (Derrick et al, 2004), loss of neurons in cortical layers 3 and 5, white matter injury, thinning of the corticospinal tract (Buser et al, 2010), cell death in the spinal cord and decreased numbers of spinal MNs (Drobyshevsky and Quinlan, 2017), increased sarcomere length, decreased muscle mass and hyperreflexia (Synowiec et al, 2019). There is also an increase in spinal monoamines which could increase the excitability of spinal neurons and thus promote spasticity (Bellot et al, 2014;Drobyshevsky et al, 2015). Thus, changes observed in spinal MNs in the rabbit model could be directly compared to motor deficits.…”