HABENULA AND THALAMUS CELL TRANSPLANTS RESTORE NORMAL SLEEP BEHAVIORS DISRUPTED BY DENERVATION OF THE INTERPEDUNCULAR NUCLEUS

The preceding companion study (Eckenrode et al., 1992) showed that cell suspension transplants of fetal habenula cells placed near the interpeduncular nucleus (IPN) following lesions of the fasciculus retroflexus (FR) restore the normal pattern of substance P (SP) staining in habenular target subnuclei of the IPN in both perinatal and adult hosts, and restore ChAT staining in the IPN of perinatal hosts. Similarly placed transplants of fetal thalamus cells only restore ChAT staining in the IPN of adult hosts. In this study, we examined the functional significance of these restored staining patterns. We used a behavioral measure of the integrity of REM-stage and non-REM-stage sleep, the "flower pot" test, and assayed (1) normal adult rats, (2) FR-lesioned control animals (neonatal or adult operates), (3) animals receiving FR lesions and transplants of fetal habenula cells (perinatal or adult hosts), and (4) animals receiving FR lesions and transplants of fetal thalamus cells (adult hosts). FR lesions decrease markedly the muscle atonia component of REM sleep and reduce duration of sleep episodes. Transplants that restore SP staining in the IPN (habenular transplants into either perinatal or adult lesion hosts) restore normal frequency of REM atonia; transplants that restore ChAT staining (habenular transplants into perinatal hosts or thalamic transplants into adult hosts) restore normal duration of sleep episodes. The number of SP-immunoreactive cells in the transplants predicts recovery of REM atonia, and the number of ChAT cells in habenular (but not thalamic) transplants predicts restoration of sleep duration. We conclude that the IPN is important in the regulation of normal sleep patterns, and particularly that transmitter-specific innervation of habenular SP targets modulates the integrity of REM sleep, while transmitter-specific innervation of habenular cholinergic targets modulates sleep duration, but only when the cholinergic innervation is mediated by normal habenular afferents.