Experimental studies indicate that hypoxia to the fetus, a common occurrence in many birth complications in humans, results in long-term disturbances of the central dopaminergic (DA) systems that persist in adulthood. Because dysregulation of DA systems is involved in the pathophysiology of many neurological and psychiatric disorders, we investigated the effects of perinatal hypoxia on the mesencephalic DA neurons of the human neonate using immunohistochemistry. We studied the expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme in catecholamine synthesis, in substantia nigra, and ventral tegmental area of 18 neonates in relation to the age and severity/duration of hypoxic injury estimated by neuropathological criteria. In severe/abrupt perinatal hypoxia, intense TH staining was observed in substantia nigra, ventral tegmental area, and, surprisingly, in the nonpreganglionic Edinger-Westphal nucleus. In severe/prolonged hypoxia, there was a striking reduction or even absence of TH immunoreactivity in all the mesencephalic nuclei. These observations suggest that at early states of perinatal hypoxia, there is a massive increase in dopamine synthesis and release that is followed by feedback blockage of dopamine synthesis through inhibition of TH by the end product dopamine. Early dysregulation of DA neurotransmission could predispose infant survivors of severe perinatal hypoxia to dopamine-related neurological and/or cognitive deficits later in life.

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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.

In the rat, experimental manipulations that cause activation of the magnocellular neurosecretory neurones result in the synthesis, in addition to vasopressin (AVP) and oxytocin (OXY), of other neurotransmitters or peptides, including tyrosine hydroxylase (TH), the first and rate limiting enzyme for catecholamine biosynthesis. In the human neonate, our previous study showed that TH was selectively increased in AVP neurones of subjects that died from prolonged perinatal hypoxia. The purpose of the present study was to quantitatively investigate the expression of TH, AVP, OXY and neurophysin in magnocellular neurones of the human neonate in relation to the severity/duration of perinatal hypoxia, as estimated by neuropathological criteria. Autopsy was performed after obtaining parental written consent for diagnostic and research purposes. The intensity of the immunohistochemical reactions and the cellular/nuclear size were measured in the dorsolateral supraoptic nucleus using a computerised image analysis system. We showed that prolonged perinatal hypoxia resulted in the activation of the magnocellular neuroendocrine neurones of the human neonate, as indicated by their increased neuronal and nuclear size. OXY neurones appeared larger than the AVP ones at birth, possibly indicating an active role of foetal OXY during labour or even earlier. The gradual increase in the duration of the insult resulted in the reduction of intracellular AVP content, in parallel with a dramatic increase in the expression of TH, indicating a functional interaction of these peptides under neuronal activation. Ιsolated evidence in our series, obtained from an infant of a diabetic mother, raises the probability that in the case of hyperglycaemia the above pathogenetic mechanisms are diversified.

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