HOW DO FETAL GRAFTS OF THE SUPRACHIASMATIC NUCLEUS COMMUNICATE WITH THE HOST BRAIN

Fetal grafts containing the hypothalamic suprachiasmatic nucleus (SCN) , the site of an endogenous circadian pacemaker, can reinstate behavio ral rhythms in lesioned recipients but the precise routes of communica tion between the graft and the host brain remain unknown. Grafts conta ining the SCN may convey temporal information to the host brain via ne ural efferents, diffusible factors, or a combination of both. We exami ned graft-host connections in anterior hypothalamic homografts (hamste r-to hamster) and heterografts (rat-to hamster) implanted in the third ventricle by: (a) applying the carbocyanine dye, diI, directly onto h omo- and heterografts in fixed tissue sections; and (b) using a donor- specific neurofilament (NF) antibody to immunocytochemically visualize heterograft efferents. DiI applied onto either homografts or heterogr afts labeled relatively few graft efferents which could be followed on ly short distances into the host brain. In contrast, NF-labeled hetero graft efferents were both more numerous and extended for longer distan ces into the host brain than anticipated on the basis of diI tract tra cing. The results suggest that anterior hypothalamic grafts implanted in the third ventricle provide substantial input to the adjacent host hypothalamus although it is not known whether these projections arise from SCN cells or from other extra-SCN hypothalamic tissue within thes e grafts. Nor is it known whether these projections are functional. To determine if neural efferents are required for the restoration of rhy thmicity after grafting, we have encapsulated fetal anterior hypothala mus in a permselective polymer which prevents neurite outgrowth but al lows diffusible signals to reach the host brain. Polymer-encapsulated grafts of fetal anterior hypothalamus from wild-type hamster fetuses h ave been implanted into the third ventricle of heterozygote tau mutant , SCN-lesioned hamsters. Because the free-running period of tau mutant hamsters is significantly shorter than that of wild-type hamsters, re stored rhythms when they occur can be unambiguously attributed to the presence of donor tissue. Encapsulated grafts that survive contain neu ropeptide cell markers characteristic of the intact SCN, but the survi val rate of encapsulated neural tissue is low. Nevertheless, if we fin d that even a few encapsulated grafts restore donor-specific rhythms, this would suggest that diffusible signals emitted from SCN grafts may be sufficient to support circadian function. It may be that the SCN i n the intact animal communicates with the rest of the brain by redunda nt signals, either efferent fibers or diffusible signals. alternativel y, different circadian rhythms may be mediated by distinct output sign als from the SCN.