Repairing the biological clock by neural transplantation

Abstract

The disruption of sleep/wake cycles in AlzheimerÍs Disease (AD) is often the precipitating factor leading to institutionalization. Two processes regulate the timing of sleep and wakefulness, a drive for sleep that accumulates during waking and dissipates during sleep, and a 24-hour circadian clock that modulates sleep and arousal. æWithout the circadian clock, sleep and wakefulness become fragmented. æææThe circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Degenerative changes in the SCN are likely to contribute to the disruption of circadian rhythms in AD patients. The SCN is composed of thousand of cells most of which are autonomous circadian oscillators. æCoupling among SCN cells is required to produce coherent circadian output for the regulation of multiple functions including the timing of sleep and wakefulness. æCoupling is mediated by a peptide called VIP and in mice lacking VIP (VIP-/-) circadian rhythms are disrupted. æææWe are using VIP-/- mice as a model of disrupted circadian rhythms and are transplanting wild type SCN into VIP-/- mice to test the hypothesis that the defective SCN can be repaired. æAn important part of the study is to correlate the anatomy and location of grafts with the restoration of rhythms. To accomplish this we are using immunohistochemistry to stain for the expression of VIP. æVIP should be an excellent marker of viable grafts since it is expressed in donor tissue but not in the host tissue. æWe have successfully developed the procedure and are beginning to analyze grafts.