Muscarinic‐2 and orexin‐2 receptors on GABAergic and other neurons in the rat mesopontine tegmentum and their potential role in sleep–wake state control

Abstract

Acetylcholine (ACh) plays an important role in the promotion of paradoxical sleep (PS) with muscle atonia through the muscarinic-2 receptor (M2R) in the mesopontine tegmentum. Conversely, orexin (Orx or hypocretin) appears to be critical for the maintenance of waking with muscle tone through the orexin-2 (or hypocretin-B) receptor (Orx2R), which is lacking in dogs having narcolepsy with cataplexy. In dual-immunostained material viewed under fluorescence microscopy, we examined the presence and distribution of M2R or Orx2R labeling on all neuronal nuclei (NeuN)-stained neurons or on glutamic acid decarboxylase (GAD)-stained neurons through the mesopontine tegmentum. Applying stereological analysis, we determined that many neurons bear M2Rs on their membrane ( approximately 6,300), including relatively large, non-GABAergic cells, which predominate (>75%) in the oral and caudal pontine (PnO and PnC) reticular fields, and small, GABAergic cells ( approximately 2,800), which predominate (>80%) in the mesencephalic (Mes) reticular formation. Many neurons bear Orx2Rs on their membrane ( approximately 6,800), including relatively large, non-GABAergic cells, which predominate (>70%) through all reticular fields, and comparatively few GABAergic cells ( approximately 700). In triple-immunostained material viewed by confocal microscopy, many large neurons in PnO and PnC appear to bear both M2Rs and Orx2Rs on their membrane, indicating that ACh and Orx could exert opposing influences of inhibition vs. excitation on putative reticulo-spinal neurons and thus attenuate vs. facilitate activity and muscle tone. A few GABAergic cells bear both receptors and could as PS inhibitor neurons serve under these different influences to control PS effector neurons and accordingly gate PS and muscle atonia appropriately across sleep-wake states.

Unilateral headache associated with a pontine infarction

“…Brain stem areas postulated to be involved in the pathogenesis of migraine include the locus coeruleus, the dorsal raphe and the dorsolateral pontine tegmentum. The raphe and dorsolateral pontine tegmentum are also implicated in sleep and sleep arousal; this may provide the anatomical correlate for this patient's nocturnal awakening and inability to return to sleep (10,11). MRI studies of naturally-occurring lesions and functional neuroimaging studies of migraineurs strongly implicate brain stem structures in the generation of migraine pain.…”

Cholinergic Modulation of Narcoleptic Attacks in Double Orexin Receptor Knockout Mice

“…The specific neural changes that enhance this coupling in the absence of orexin receptor signaling are not yet clear and several mechanisms alone or in combination may contribute. For example, muscarinic transmission may be more effective at inhibiting REM-off inhibitory neurons in atonia circuits due to the absence of an opposing orexin action [43], [44]. In addition, post-synaptic sensitivity to ACh may be increased on these neurons, as suggested by receptor binding studies in the pontine reticular formation of the narcoleptic canine, which found elevated mAChRs [45].…”

Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

“…Muscarinic receptors have a well documented role in mediating the vigilance-related effects of acetylcholine (Baghdoyan and Lydic 1999;Brischoux et al 2008;Imeri et al 1994;Jones 2004). Two muscarinic receptors, types 2 and 4 (M2R and M4R) are both G-protein-coupled and differ from each other in their tissue distribution and their physiologic effects (Wess 2004).…”