Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep

Abstract

Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.rapid eye movement sleep | acetylcholine | optogenetics | mesopontine tegmentum | mouse R apid eye movement (REM) sleep is tightly regulated, yet the mechanisms that control REM sleep remain incompletely understood. Early pharmacological and unit recording studies suggested that ACh was important for REM sleep regulation (1, 2). For example, injection of cholinergic drugs into the dorsal mesopontine tegmentum reliably induced a state very similar to natural REM sleep in cats (3-6). Unit recordings from the cholinergic areas of the mesopontine tegmentum revealed cells that were active during wakefulness and REM sleep, as well as neurons active only during REM sleep (7-13). Electrical stimulation of the laterodorsal tegmentum (LDT) in cats increased the percentage of time spent in REM sleep (14), and activation of the pedunculopontine tegmentum (PPT) in rats induced wakefulness and REM sleep (15). If cholinergic PPT and LDT neurons are necessary for REM sleep to occur, as the early studies suggest, then lesioning the PPT or LDT should decrease REM sleep. In cats, lesions of the PPT and LDT do disrupt REM sleep (16, 17), but lesions in rodents have had little effect on REM sleep or increased REM sleep (18)(19)(20)(21)(22). Additionally, c-fos studies have found very few cholinergic cells activated under high-REM sleep conditions. When c-fos-positive cholinergic neurons in the PPT and LDT are found to correlate with the percentage of REM sleep, they still account for only a few of the total cholinergic cells in the area (23). Juxtacellular recordings of identified cholinergic neurons in the LDT found these cells had wake and REM active firing profiles, with the majority firing the highest during REM sleep (13). These discrepancies have led to alternative theories of REM sleep regulation, where cholinergic neurons do not play a key role (18, 19, 23, 24 and reviewed in 25, 26).The PPT and LDT are made up of heterogeneous populations of cells, including distinct populations of cholinergic, GABAergic, and glutamatergic neurons (27-29). Many GABAergic neurons are active during REM sleep, as indicated by c-fos (23), and both GABAergic and glutamatergic neurons have been found with maximal firing rates during REM sleep in the LDT and medial PPT (13...

Ancestral Circuits for the Coordinated Modulation of Brain State

“…However, some of these cell types have been implicated in other forms of arousal or brain state control. For instance, stressors activate centrally projecting neurons in the Edinger-Westphal nucleus that express CART (Kozicz, 2003; Giardino et al, 2012), and cholinergic neurons in the lateral dorsal tegmentum are involved in the regulation of sleep state (Kayama et al, 1992; Van Dort et al, 2015). Thus, cell types such as these may not only be involved in regulating alertness, but also, each may participate in elicitation of different multifaceted internal states for which alertness is recruited as one feature or useful component (as in anxiety, hunger, aggression, copulation, or attention; Aston-Jones and Cohen, 2005; Pfaff et al, 2008; Harris and Thiele, 2011; Anderson and Adolphs, 2014; Anderson, 2016).…”

A 63-Year-Old Man with Lewy Body Dementia and Multiple Symptoms

“…Neuroleptic drugs used to treat psychotic symptoms are often ineffective and worsen motor symptoms. 4 Visual hallucinations in patients with DLB are associated with cholinergic deficits, 2 and cholinesterase inhibitors are considered first-line therapy in treating hallucinations and behavioral disturbances in DLB. [3][4][5] Dopaminergic agents are frequently implicated in manifesting psychotic symptoms.…”

“…There is a large body of literature detailing the role of acetylcholine in regulating the sleep-wake cycle, the mechanisms of which corroborate the possibility of this hypothesis, but that are beyond the scope of this case report. 1,2 In brief, acetylcholine-enhancing medications, such as donepezil, may indiscriminately activate both the pons and basal forebrain, which have competing roles in sleep-wake physiology. 1,2 This could contribute to wakefulness and insomnia in the evening, and REM intrusion into wakefulness during the day.…”

“…1,2 In brief, acetylcholine-enhancing medications, such as donepezil, may indiscriminately activate both the pons and basal forebrain, which have competing roles in sleep-wake physiology. 1,2 This could contribute to wakefulness and insomnia in the evening, and REM intrusion into wakefulness during the day.…”

“…1,2 When the donepezil was discontinued, the patient's visual hallucinations, agitation, persecutory beliefs, tremor, and urinary urgency promptly diminished and he no longer required unscheduled psychotropic medications for behavioral agitation. One week after cessation of donepezil, the patient was administered rivastigmine.…”