The pedunculopontine nucleus (PPN) helps control sleep/wake rhythms and modulates posture and locomotion. The proposed research will address three critical functional aspects (ascending, local and descending) of the PPN, the cholinergic arm of the Reticular Activating System (RAS). DESCENDING: Stimulation of the PPN using parameters which are known to induce locomotion in the decerebrate animal produced prolonged responses in caudal pontine (PnC) neurons. This mechanism has the property of switching target neurons from one state to another without the need for continuous driving. This may be a way for the PPN to induce changes in state, for example, from standing into locomotion. LOCAL: During a period of 10-30 days there is a dramatic decrease in the percent of REM sleep in the rat. Preliminary results suggest that there is an increase across this stage in the number of PPN neurons with low threshold spike (LTS) properties, a mechanism which alters the dynamic pattern of activity (bursting) in this area. There also appears to be a switch in the polarity of serotonergic input to intracellularly recorded PPN neurons, which is both excitatory and inhibitory before, but purely inhibitory after, 17 days of age. The proposed studies will characterize these modifications in order to understand how such local reorganization is manifested in the control of changes in state across this critical stage in development. ASCENDING: We will investigate the manner in which ascending projections of the RAS modulate the intralaminar thalamus to promote changes in arousal state, specifically, of PPN projections to parafascicular (Pf) neurons. Most PPN neurons project to intralaminar thalamus; however, there is little information on the synaptic relationships between the PPN and Pf, especially during development, an important gap to be bridged by these studies. We hypothesize that certain sleep pathologies have a developmental etiology. For example, disturbances in the process of decreasing REM sleep in development may lead to a number of disorders characterized by increased REM sleep drive in the adult. The proposed research, therefore, addresses an important problem with significant implications for certain neurological and psychiatric disorders which share increased REM sleep as a symptom with developmental etiology (e.g., schizophrenia, panic attacks, bipolar disorder, depression), and will provide a more integrated view of the concepts in this field. The proposed rat brainstem slice recording studies involve tracing intrinsic membrane properties, neurochemical control mechanisms and anatomical characteristics during a time in which PPN neurons undergo significant hypertrophy and changes in cellular properties and synaptic relationships, which might explain such developmental transformations into the adult form of the RAS.
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