CROSS SPECIES TRANSPLANTATION OF CIRCADIAN BEHAVIOR

The long term goal of this research is to furnish an understanding of the complex neural substrates underlying the regulation of circadian behavior by utilizing a cross-species neural transplantation model. Increased knowledge of the functional organization of the hypothalamus and the circadian timing system is relevant to problems of sleep, jet lag and some kinds of serious affective disorders. The suprachiasmatic nucleus (SCN) of the anterior hypothalamus has been identified as a circadian oscillator and as an integral component of the endogenous biological timing system. However, the extent to which the SCN functions as an autonomous pacemaker, determining the period of expressed circadian behaviors, remains to be established. The specific aim of this proposal is to transplant the SCN from one species into an SCN-lesioned, arrhythmic host of a different species to determine whether the restored circadian behavior exhibits the species-typical behavior of the donor, the host, or a donor/host intermediate. The restoration of donor-specific circadian behavior will firmly establish the autonomy of SCN as a circadian pacemaker. The behavioral -marker assayed is the species-typical circadian period of wheel-running activity. Upon establishing host base-line circadian behavior, the host is rendered arrhythmic by lesioning the SCN. After monitoring post-lesion behavior, the SCN from a fetal donor of a different species is implanted into the lesion site of the host and behavior is monitored to assay the period of the restored activity. Behavioral analysis determines the functional capabilities of the graft. Histochemical procedures will verify the absence of the host SCN and immunocytochemical analysis at the light and electron microscopic level with species-specific monoclonal antibodies and antibodies for SCN peptides establish the extent of graft-host integration.