Selective Activation of Cholinergic Basal Forebrain Neurons Induces Immediate Sleep-wake Transitions

Han, Yong; Shi, Yao; Wang, Xi; Zhou, Rui; Tan, Zhibing; Wang, Hao; Li, Xiaoming; Chen, Zhong; Feng, Guoping; Luo, Minmin; Huang, Zhi‐Li; Duan, Shumin; Yu, Yan-Qin

doi:10.1016/j.cub.2014.02.011

Cited by 124 publications

(100 citation statements)

References 27 publications

(34 reference statements)

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“…4d). This finding is similar to that of a recent study 37 , but different from another study using optogenetic activation 38 . In addition to differences in the stimulation protocol, there may be differences in the brain-state classification criteria.…”

Section: Discussionsupporting

confidence: 65%

Basal forebrain circuit for sleep-wake control

et al. 2015

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The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the BF circuit by recording and optogenetically perturbing the activity of four genetically defined cell types across sleep-wake cycles and by comprehensively mapping their synaptic connections. Recordings from channelrhodopsin-2 (ChR2)-tagged neurons revealed that three BF cell types, cholinergic, glutamatergic and parvalbumin-positive (PV+) GABAergic neurons, were more active during wakefulness and rapid eye movement (REM) sleep (wake/REM active) than during non-REM (NREM) sleep, and activation of each cell type rapidly induced wakefulness. By contrast, activation of somatostatin-positive (SOM+) GABAergic neurons promoted NREM sleep, although only some of them were NREM active. Synaptically, the wake-promoting neurons were organized hierarchically by glutamatergic→cholinergic→PV+ neuron excitatory connections, and they all received inhibition from SOM+ neurons. Together, these findings reveal the basic organization of the BF circuit for sleep-wake control.

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Section: Discussionsupporting

confidence: 65%

Basal forebrain circuit for sleep-wake control

et al. 2015

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“…Carbachol injection into the basal forebrain of cats increased wakefulness (39). A recent study optogenetically activated cholinergic neurons in the basal forebrain during wake, NREM sleep, and REM sleep (35). Activation of basal forebrain cholinergic neurons during NREM sleep induced transitions to wake and REM sleep.…”

Section: Implications For the Role Of Ppt And Ldt Cholinergic Neuronsmentioning

confidence: 99%

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

Dort

Zachs

Kenny

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

244

159

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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...

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“…Cholinergic basal forebrain cells show maximal discharge rates during wake and paradoxical sleep and burst in synchronization with cortical theta-rhythms (24). Stimulation of the basal forebrain leads to desynchrony of cortical EEGs (25,26). Optogenetic activation of forebrain cholinergic neurons causes animals to transition from slow wave sleep to wake (27,28).…”

mentioning

confidence: 99%

The cholinergic forebrain arousal system acts directly on the circadian pacemaker

Yamakawa

Basu

Cortese

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7-to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system. arousal | phase shift | nonphotic | sleep/wake | brain stimulation T he states of wake and sleep in mammals are regulated by interactions between brainstem and forebrain regions (1, 2), with some areas actively promoting sleep and others promoting wake. The allied circadian clock located in the suprachiasmatic nuclei (SCN) (3) provides temporal structure to behavior and physiology. The sleep/wake systems and circadian systems interact (4), with the circadian system providing temporal input to the sleep and wake systems, thus promoting both states, and ensuring that these behaviors occur at species-specific times of day (5).The activity of the SCN is endogenously regulated and tightly linked to behavioral state. SCN electrical activity is highest during the day, when nocturnal rodents are asleep, with higher activity during rapid-eye-movement (REM) sleep than during slow wave sleep (6). During the waking phase, SCN activity is suppressed by spontaneous behavior (7). Critically, triggering activity or wakefulness, so-called "nonphotic zeitgebers" (time givers), during the sleep phase can reset the phase of the circadian clock (8, 9). There is an inverse relationship between the size of the phase shift due to sleep deprivation (SD) and the amount of effort required to maintain wakefulness during the procedure (8). Specifically, animals that remain awake and alert on their own exhibit large phase shifts, whereas those that require frequent intervention to maintain wakefulness do not shift. These factors su...

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Selective Activation of Cholinergic Basal Forebrain Neurons Induces Immediate Sleep-wake Transitions

Cited by 124 publications

References 27 publications

Basal forebrain circuit for sleep-wake control

Basal forebrain circuit for sleep-wake control

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

The cholinergic forebrain arousal system acts directly on the circadian pacemaker

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