Functional Implications

Collectively, the picture that is emerging is one in which hypothalamic Hcrt/Orx neurons are capable of activating all elements of the brain arousal system. While the precise nature and timing of this Hcrt/Orx drive is not yet clear for each structure, hypothalamic Hcrt/Orx neurons are in an excellent position to coordinate the activity and interplay between arousal system elements. Consequently, it is expected that the loss of Hcrt/Orx peptides in narcolepsy would disfacilitate the entire arousal system and promote the excessive daytime sleepiness of this disorder.

As described above, considerable evidence also indicates MPCh neurons play specific roles REM sleep and REM atonia. Based on this evidence, we initially hypothesized that Hcrt/Orx might inhibit MPCh neurons and that the loss of Hcrt/Orx in narcolepsy would disinhibit MPCh neurons and result in exaggerated Ach release in the mPRF, which would promote cataplexy. Our findings appear to rule out this simple scenario and suggest that MPCh neurons are disfacilitated in the absence of Hcrt/Orx. The consequences of sustained disfacilitation are not known but might include an upregulation of post-synaptic mAchRs in the mPRF, as suggested to account for muscarinic receptor changes in narcoleptic dogs64 or changes MPCh neuron excitability or neurotransmitter-related enzymes.65

Our findings also suggest that the REM suppression by ICV injection of Hcrt/Orx occurs despite Hcrt/Orx mediated excitation of MPCh neurons. Several obvious possibilities to consider are: 1) that the REM on cholinergic neurons are the small fraction of MPCh neurons not excited by Hcrt/Orx; 2) that the excitation of MPCh neurons is overwhelmed by inhibition from elsewhere like the DR, which is more strongly excited by Hcrt/Orx that are MPCh neurons; and 3) that Hcrt/Orx works downstream of MPCh neurons to inhibit REM. Future physiological studies of mouse Hcrt/Orx-mutants should be of particular value in addressing these and other possibilities.

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