The suprachiasmic nucleus(SCN) of the hypothalamus is the site of a clock that is responsible for generating circadian (daily) rhythms in humans and other mammals. While the SCN controls circadian rhythms in a spectacular variety of behavioral and physiological responses, little is known of the mechanisms or pathways by which the SCN communicates temporal information to the rest of the brain. In the proposed experiments, neural transplantation of the fetal SCN will be used to study the """"""""hands"""""""" of the circadian clock. Our recent work using polymer-encapsulated SCN grafts suggest that at least one clock output, locomotor rhythmicity, is controlled by a diffusible signal. Furthermore, by varying the site of implantation we have shown that putative targets for this signal are restricted to a subset of normal efferent targets of the SCN, specifically in the medial hypothalamus and midline thalamus. We propose to extend these findings and examine the output signals and targets mediating other physiologically important circadian rhythms, such as those in drinking, body temperature and heart rate, as well as locomotor rhythms.
The specific aims are:(1) to determine which rhythms are restored by SCN grafts and whether or not a single graft restores multiple rhythms; (2) to determine whether or not restoration of specific rhythms is dependent upon graft innervation of targets in the host brain; and (3) to determine if different rhythms are mediated by different target sites in the host brain. These studies take advantage of the use of circadian mutant animals as sources of donor tissue, so that when recovery of function occurs it can be unambiguously attributed to the transplanted clock. Importantly, the use of polymer-encapsulated grafts allows us to directly test whether neural efferents are necessary for restoration of specific rhythms. This research will address fundamental questions about the mechanism of action of the mammalian circadian pacemaker. In addition, because this transplant model represents one of the clearest examples of behavioral recovery after grafting, these studies will also provide more general information regarding restoration of function following damage to the adult mammalian brain.
