INDUCTION OF RAPID EYE-MOVEMENT SLEEP BY THE MICROINJECTION OF NERVE GROWTH-FACTOR INTO THE PONTINE RETICULAR-FORMATION OF THE CAT

Nerve growth factor is an endogenous protein which belongs to the neurotrophin family of trophic factors.(13) According to the neurotrophic hypothesis, neurotrophins are synthetized by target tissues and regulate the survival and phenotype of their innervating neurons.(12,13) Whereas these trophic molecules have been mainly thought to be involved in developmental processes, their existence in the central nervous system of the adult animal suggests that they may play a role in neuronal physiology. Recently, it has been reported that neurons that express messenger RNA for two neurotrophins, namely brain-derived neurotrophic factor and neurotrophin-3, are located medial to the locus coeruleus and ventral to the fourth ventricle.(6) This area corresponds to the latero-dorsal tegmental nucleus, which contains cholinergic neurons that have been implicated in the generation of rapid eye movement sleep.(11,21) In turn, the laterodorsal tegmental nucleus is reciprocally connected with the nucleus pontis oralis in the rostrodorsal pontine reticular formation,(20) which is an area that is involved in the initiation of the physiological patterns of activity that define the state of rapid eye movement sleep.(5,10,11) Scattered neurons in the nucleus pontis oralis express the low-affinity nerve growth factor receptor(18) which also binds the other neurotrophins with similar affinity.(12) In addition, neurons in the area of the nucleus pontis oralis have been reported to express a subtype of the neurotrophin high affinity receptors.(7) These membrane receptors, independently or in combination with the low affinity receptors, have been proposed to mediate the delayed, long-term effects of neurotrophins.(9,15) Based upon these data, we tested the hypothesis that neurotrophins may induce a delayed, long-term enhancement of rapid eye movement sleep by acting as a signal to upregulate the activity. of nucleus pontis oralis neurons that are implicated in the generation of this state, We found that the microinjection of nerve growth factor, the prototypic neurotrophin, into the nucleus pontis oralis elicited with a relatively short latency a behavioral state which was polygraphically identical to rapid eye movement sleep, This finding indicates that nerve growth factor is capable of inducing a rapid change in the activity of nucleus pontis oralis neurons related to rapid eye movement sleep and raises the intriguing possibility that neurotrophins may be implicated in the generation of this behavioral state.