Among the well-established roles of the neurotransmitter histamine (HA) is that as a regulator of the sleep-wake cycle, which early gained HA a reputation as a 'waking substance'. The tuberomammillary nucleus (TMN) of the posterior hypothalamus, which contains the sole source of neuronal HA in the brain, is reciprocally connected to the suprachiasmatic nucleus (SCN) which, in turn, is best known as the pacemaker of circadian rhythms in mammals. We report HA-immunoreactive (-ir) neurons in the mouse and rat SCN that neither display immunoreactivity (-iry) for the HA-synthesizing enzyme histidine decarboxylase (HDC) nor contain HDC mRNA. Further, HA-iry was absent in the SCN of HDC knockout mice, but present in appropriate control animals, indicating that the observed HA-iry is HDC dependent. Experiments with hypothalamic slice cultures and i.c.v. injection of HA suggest that HA in the SCN neurons originates in the TMN and is transported from the TMN along histaminergic fibres known to innervate the SCN. These results could indicate the existence of a hitherto unknown uptake mechanism for HA into neurons.Through HA uptake and, putatively, re-release of the captured HA, these neurons could participate in the HA-mediated effects on the circadian system in concert with direct histaminergic inputs from the TMN to the SCN. The innervation of the SCN by several neurotransmitter systems could provide a way for other systems to affect the HA-containing neuronal cell bodies in the SCN.
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