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Disruption of raph serotonergic neural projections to the cortex: a potential pathway contributing to remote loss of brainstem neurons following neonatal hypoxic-ischemic brain injury

Reinebrant, HE;Wixey, JA;Buller, KM;

Neuronal injury is a key feature of neonatal hypoxic-ischemic (HI) brain injury. However, the mechanisms underpinning neuronal losses, such as in the brainstem, are poorly understood. One possibility is that disrupted neural connections between the cortex and brainstem may compromise the survival of neuronal cell bodies in the brainstem. We investigated whether brainstem raph serotonergic neurons that project to the cortex are lost after HI. We also tested if neuroinflammation has a role in disrupting brainstem raph projections. Postnatal day 3 (P3) rats underwent unilateral carotid artery ligation followed by hypoxia (6% oxygen for 30 min). A retrograde tracer, choleratoxin b, was deposited in the motor cortex on P38. On P45 we found that retrogradely labelled neurons in the dorsal raph dorsal, ventrolateral, interfascicular, caudal and ventral nuclei were lost after P3 HI. All retrogradely labelled neurons in the raph nuclei were serotonergic. Numbers of retrogradely labelled neurons were also reduced in the ventromedial thalamus and basolateral amygdala. Minocycline treatment (45 mg/kg 2h post-HI, 22.5 mg/kg daily P4-P9) attenuated losses of retrogradely labelled neurons in the dorsal raph ventrolateral, interfascicular and ventral raph nuclei, and the ventromedial thalamus. These results indicate that raph neurons projecting to the cortex constitute a population of serotonergic neurons that are lost after P3 HI. Furthermore, neuroinflammation has a role in the disruption of raph and thalamic neural projections. Future studies investigating the cellular mechanisms of axonal degeneration may reveal new targets for interventions to prevent neuronal losses after neonatal HI.