Lateralization of circadian pacemaker output: Activation of left- and right-sided luteinizing hormone-releasing hormone neurons involves a neural rather than a humoral pathway.

Locomotor activity and luteinizing hormone (LH) secretion in golden hamsters share a common circadian pacemaker in the suprachiasmatic nucleus (SCN), but the rhythms do not seem to share a common output pathway from the SCN. Locomotion is believed to be driven by humoral factor(s), whereas LH secretion may depend on specific ipsilateral neural efferents from the SCN to LH releasing hormone (LHRH)-containing neurons in the preoptic area. In this paper we provide the first functional evidence for such efferents in neurologically intact hamsters by exploiting a phenomenon known as "splitting" in constant light, in which circa-12 hr (approximately 12 hr) locomotor activity bouts reflect an antiphase oscillation of the left and right sides of the bilaterally paired SCN. In ovariectomized, estrogen-treated (OVX + E2) female hamsters, splitting is also known to include circa-12 hr LH secretory surges. Here we show that behaviorally "split" OVX + E2 females exhibit a marked left-right asymmetry in immunoreactive c-Fos expression in both SCN and activated LHRH neurons, with the percentage of LHRH+/c-Fos+ double-labeled cells approximately fivefold higher on the side corresponding to the side of the SCN with higher c-Fos immunoreactivity. Our results suggest that splitting involves alternating left- and right-sided stimulation of LHRH neurons; under such circumstances, the functional activity of the neuroendocrine hypothalamus mirrors intrinsic side-to-side differences in SCN gene expression. The circadian regulation of reproductive activity depends on lateralized, point-to-point axonal projections rather than on diffusible factors.