The long-term objectives of this work are to understand the mechanisms whereby the mammalian biological clock (the suprachiasmatic nucleus) mediates circadian rhythmicity, and to develop further a model for the functional analysis of neural tissue transplants in the hypothalamic region. To distinguish pacemaker from trophic or permissive effects of transplanted tissue, we will use tau period mutant animals as hosts and wild-type animals for fetal donor tissue. (The free-running period of the biological clock can readily be distinguished in these groups. In the proposed experiments, we will address the following questions: 1) Do grafts of the fetal suprachiasmatic nucleus (SCN) restore circadian rhythmicity via neural and/or diffusible signal(s)? We will test this hypothesis using polymer-encapsulated SCN. grafts. If the results suggest a diffusible signal, we will work towards identifying that signal. If the results suggest a role for neural efferents of the SCN, we will work towards specifying those efferents. 2) How does the site of placement of the SCN graft influence restoration of function? 3) Which part of the graft within the transplanted tissue is the """"""""functional"""""""" SCN?. 4), Do functional SCN 'grafts restore rhythms other than locomotor rhythms, such as rhythms of drinking, hoarding, gnawing and body temperature? In each experiment, immunocytochemical analyses will allow us to correlate the neuropeptide/transmitter organization of each graft with the restoration of circadian function in individual animals. The significance of the present research program derives from its potential to clarify the nature of the coupling signal (neural or humoral) by which SCN determines the phase and period of circadian 'rhythms, the locus (loci) of the endogenous oscillator mechanism(s), and the general contribution of this work to the understanding of potential of neural tissue grafts to restore hypothalamic function following damage.
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