In the short time since the hypocretin/orexin peptide system was discovered,1'2 a remarkable body of evidence has accumulated indicating this system's important role in regulating feeding, energy metabolism and arousal.3-6 Considerable progress has also been made identifying the CNS targets and actions of the two hypocretin/orexin peptides (Hcrt/Orx-A and -B) [cf 7]. We have been interested in understanding the actions of Hcrt/Orx on brainstem cholinergic and monoaminergic systems since these systems are involved with controlling arousal and sleep. Considering the extensive innervation by Hcrt/Orx afferents8 and the robust expression of orexin receptor message in these structures,9 it is likely that important components of the wake-promoting and REM suppressing abilities of Hcrt/Orx10'11 are mediated through actions on these systems.12-14 Here we discuss some of our recent findings concerning Hcrt/Orx actions on both the cholinergic and non-cholinergic neurons of the laterodorsal tegmental (LDT) nucleus which form part of the ascending cholinergic reticular system.15'16
The laterodorsal (LDT) nucleus and neighboring pedunculopontine (PPT) tegmental nucleus contain mesopontine cholinergic (MPCh) neurons which are intermixed with numerous non-cholinergic neurons - some of which are GABAergic.17 These MPCh neurons express high levels of the enzyme nitric oxide synthase NOS,18'19'20 which serves as a convenient marker and functions to produce nitric oxide (NO) in response to neural activity both locally21 and at their terminals.22 These MPCh neurons have wide-spread projections which include key targets in the thalamus [for review 23], pontine reticular formation (mPRF24'25-27 and midbrain dopamine regions).28'29
* C. S. Leonard, C. J. Tyler, S. Burlet, S. Watanabe and K. A. Kohlmeier Dept. of Physiology, New York Medical College, Valhalla, NY 10595
Functionally, stimulation of MPCh neurons promotes long-lasting EEG desynchronization via thalamic afferents30 and the release of dopamine from the VTA and SN neurons.31,32 In addition, MPCh neurons play a significant role in generating REM sleep and the associated muscle atonia [for review 33] via projections to the mPRF34 where cholinergic stimulation produces a REM-like state.35-38 These sites are of particular interest since muscarinic stimulation of this region in narcoleptic dogs evokes cataplexy at doses that are ineffective in normal dogs.39 Moreover, microdialysis of atropine into the mPRF blocks the effects of systemic physostigmine to increase attack frequency39 and mPRF acetylcholine levels are elevated during these attacks,40 suggesting that exaggerated cholinergic transmission to the mPRF is a key trigger of cataplexy.
Based on these observations and the strong evidence that disruption of Hcrt/Orx signaling produces narcolepsy/cataplexy,41,42 we initially hypothesized that Hcrt/Orx would inhibit MPCh neurons. Contrary to our original hypothesis, we found that Hcrt/Orx excites mouse MPCh neurons through both direct and indirect mechanisms and potently stimulates the elevation of intracellular calcium in these neurons.
Was this article helpful?
Metabolism. There isn’t perhaps a more frequently used word in the weight loss (and weight gain) vocabulary than this. Indeed, it’s not uncommon to overhear people talking about their struggles or triumphs over the holiday bulge or love handles in terms of whether their metabolism is working, or not.