Dorsal raphe neurons: depression of firing during sleep in cats

McGinty, Dennis; Harper, Ronald M.

doi:10.1016/0006-8993(76)90480-7

Cited by 843 publications

(380 citation statements)

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“…However, there are others who consider 5-HT to be a wakefulness promoter (4). Consistent with this, the firing rate of 5-HT neurons is fastest during waking (W), is slower during nonrapid eye movement sleep (NREM) and nearly ceases during rapid eye movement sleep (REM) (5,6). 5-HT neurons in the dorsal raphé nucleus project to thalamic, cortical, and other structures involved in sleep/wake transitions (7), and 5-HT can convert the firing patterns of thalamic reticular and thalamocortical neurons in slices from a bursting pattern seen in NREM to a tonic single-spiking pattern seen in W (8).…”

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confidence: 73%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

227

213

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There is a long-standing controversy about the role of serotonin in sleep/wake control, with competing theories that it either promotes sleep or causes arousal. Here, we show that there is a marked increase in wakefulness when all serotonin neurons are genetically deleted in mice hemizygous for ePet1-Cre and homozygous for floxed Lmx1b (Lmx1b f/f/p ). However, this only occurs at cool ambient temperatures and can be explained by a thermoregulatory defect that leads to an increase in motor activity to generate heat. Because some serotonin neurons are stimulated by CO 2 , and serotonin activates thalamocortical networks, we hypothesized that serotonin neurons cause arousal in response to hypercapnia. We found that Lmx1b f/f/p mice completely lacked any arousal response to inhalation of 10% CO 2 (with 21% O 2 in balance N 2 ) but had normal arousal responses to hypoxia, sound, and air puff. We propose that serotonin neurons mediate the potentially life-saving arousal response to hypercapnia. Impairment of this response may contribute to sudden unexpected death in epilepsy, sudden infant death syndrome, and sleep apnea.S erotonin [5-hydroxytryptamine (5-HT)] has long been implicated in the regulation of sleep and wakefulness. However, its specific role remains unclear and controversial (1). 5-HT is considered by some as a sleep-promoting agent, because both pharmacological depletion of 5-HT and chemical lesions of 5-HT neurons lead to insomnia in cats (1-3). However, there are others who consider 5-HT to be a wakefulness promoter (4). Consistent with this, the firing rate of 5-HT neurons is fastest during waking (W), is slower during nonrapid eye movement sleep (NREM) and nearly ceases during rapid eye movement sleep (REM) (5, 6). 5-HT neurons in the dorsal raphé nucleus project to thalamic, cortical, and other structures involved in sleep/wake transitions (7), and 5-HT can convert the firing patterns of thalamic reticular and thalamocortical neurons in slices from a bursting pattern seen in NREM to a tonic single-spiking pattern seen in W (8). 5-HT (along with norepinephrine, histamine, and acetylcholine) is considered by some to be part of the ascending arousal system (AAS), which regulates transitions from sleep to wakefulness (4). However, there is no direct evidence that 5-HT neurons are required for normal arousal, and there is some evidence that they promote NREM (1, 3). Given the complexity of the 5-HT system, it has been difficult to define the roles, either direct or indirect, of 5-HT in different aspects of sleep regulation.In vitro studies have shown that a subset of 5-HT neurons in both the medullary and midbrain raphé increases firing rate in response to a rise in CO 2 or decrease in pH (9). When studied in unanesthetized behaving mammals, similar results have been obtained in vivo by multiple groups (9). 5-HT neurons in both loci are also juxtaposed to large cerebral blood vessels, making them ideally situated to accurately monitor changes in arterial PCO 2 (10, 11). Medullary 5-HT neurons project to ...

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confidence: 73%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

227

213

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“…Serotonergic neurons of the midbrain raphe have been implicated in the control of affective and cognitive functions and in modulating the neural activities of networks across the sleep-wake cycle. Behaviorally related oscillations in the theta frequency range (4)(5)(6)(7)(8), which are most prominent in the hippocampus (1), are known to synchronize neuronal activity in a number of forebrain structures involved in these functions (2)(3)(4). Hippocampal theta oscillations occur selectively during exploratory behaviors and paradoxical sleep, whereas large-amplitude irregular activity is associated with quiet waking, consummatory behaviors, and slow-wave sleep (5,6).…”

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confidence: 99%

“…The majority of putative serotonergic neurons have been reported to be most active during waking, to decrease their firing rate during slow-wave sleep, and to cease firing during paradoxical sleep (7). ʈ The silencing of serotonergic cells during paradoxical sleep is currently considered an important regulatory signal that contributes to the maintenance of the theta rhythm in this state.…”

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confidence: 99%

Serotonergic neuron diversity: Identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm

Kocsis

Varga

Dahan

et al. 2006

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

140

117

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The serotonergic system plays a key role in the regulation of brain states, and many of the known features of serotonergic neurons appear to match this function. Midbrain raphe nuclei provide a diffuse projection to all regions of the forebrain, and raphe neurons exhibit a slow metronome-like activity that sets the ambient levels of serotonin across the sleep-wake cycle. Serotonergic cells have also been implicated, however, in a variety of more specific functions that can hardly be related to their low-rate monotonous patterns of discharges. The amazing variety of serotonergic receptors and their type-specific distribution on cortical neurons also raise the possibility of a more intimate coordination between the activity of serotonergic neurons and their target cortical circuits. Here we report an unexpected diversity in the behavior of immunohistochemically identified serotonergic neurons. Two outstanding subpopulations were identified by using the in vivo juxtacellular recording and labeling technique. The first subpopulation of serotonergic cells exhibited the classic clock-like activity with no apparent short timescale interaction with the hippocampal electroencephalogram. The other subpopulation discharged action potentials that were phase-locked to the hippocampal theta rhythm, the oscillatory pattern associated with acquisition of information and memory formation. These results indicate that the ascending serotonergic system comprises cells involved in complex information processing beyond the regulation of state transitions. The heterogeneity of serotonergic neuron behavior can also help to explain the complexity of symptoms associated with serotonergic dysfunction.hippocampus ͉ juxtacellular labeling ͉ midbrain raphe ͉ neuronal oscillations T he serotonergic system is a primary target of psychotherapy that stresses the importance of serotonin in normal and abnormal brain functioning. Serotonergic neurons of the midbrain raphe have been implicated in the control of affective and cognitive functions and in modulating the neural activities of networks across the sleep-wake cycle. Behaviorally related oscillations in the theta frequency range (4-8 Hz), which are most prominent in the hippocampus (1), are known to synchronize neuronal activity in a number of forebrain structures involved in these functions (2-4). Hippocampal theta oscillations occur selectively during exploratory behaviors and paradoxical sleep, whereas large-amplitude irregular activity is associated with quiet waking, consummatory behaviors, and slow-wave sleep (5, 6). As in sleep, hippocampal activity spontaneously alternates between theta and nontheta states under urethane anesthesia.The majority of putative serotonergic neurons have been reported to be most active during waking, to decrease their firing rate during slow-wave sleep, and to cease firing during paradoxical sleep (7). ʈ The silencing of serotonergic cells during paradoxical sleep is currently considered an important regulatory signal that contributes to the maintenance of ...

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“…There is strong preclinical and clinical evidence that serotonin plays a role in suppressing REM sleep (McGinty and Harper 1976;Honda and Semba 1994;Luebke et al 1992;Portas et al 1996).…”

Section: In the Present Study We Hypothesized That The Remsuppressinmentioning

confidence: 99%

Rapid Tryptophan Depletion Plus a Serotonin 1A Agonist Competing Effects on Sleep in Healthy Men

Moore¹,

Seifritz

Schlosser

et al. 2001

Neuropsychopharmacology

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In the present study, we hypothesized that the REMsuppressing effects of 5-HT 1A receptor stimulation would counteract the REM-disinhibiting effects of rapid tryptophan depletion (RTD), and vice versa. We administered RTD plus ipsapirone (10 mg, p.o.) The rapid tryptophan depletion (RTD) paradigm (Young et al. 1985;Delgado et al. 1990) allows researchers to study the consequences of 5-HT system deactivation. In humans and animals, RTD has been shown to cause significant (but transient) reductions in the levels of tryptophan (TRP) in the blood, and to reduce the amount of 5-HT in the brain (for review, see Moore et al. 2000). RTD typically consists of a day's worth of a low-TRP diet, followed by ingestion of a TRP-free amino acid load, and RTD, but not the control TRP-containing condition, has been associated with myriad clinical and physiological effects. Relapse of depressive mood following RTD in recently remitted depressed patients has been reported (Delgado et al. 1990). In healthy subjects, mood responses as well as other behavioral measures have been somewhat inconsistent (Young et al. 1985;Barr et al. 1997).The sleep abnormalities often associated with depression are consistent with the notion of a pathophysiologic deficiency in serotonergic function in depression (Maes and Meltzer 1995). There is strong preclinical and clinical evidence that serotonin plays a role in suppressing REM sleep (McGinty and Harper 1976;Honda and Semba 1994;Luebke et al. 1992;Portas et al. 1996).RTD apparently disinhibits REM sleep measures in serotonin reuptake inhibitor (SRI)-treated patients in full remission ) and in healthy male control subjects ), using two different The Effects of REM Sleep of RTD plus Ipsapirone S41 strengths of RTD (100% and 25%). In SRI-treated patients, both RTD doses also reversed the reduced total sleep time and prolonged sleep latency observed at baseline. In normal males, both RTD doses significantly decreased REM latency compared with baseline, as well as significantly reduced total and free plasma TRP concentrations.Agonists at the 5-HT 1A receptor, such as ipsapirone, have been shown to inhibit REM sleep both in healthy subjects and in depressed patients (Gillin et al. 1994;Gillin et al. 1996;, and this effect presumably reflects predominantly post-synaptic receptor activity. In the present study, we examined the competing effects of 5-HT depletion and 5-HT stimulation on sleep. We predicted REM sleep measures with RTD plus placebo would be significantly enhanced compared with baseline as shown in previous studies with RTD alone, and that the combination of RTD and ipsapirone would produce REM measures with values intermediate between those obtained with either 5-HT manipulation alone. METHODS SubjectsTen healthy male subjects between the ages of 20 to 39 years (28.7 Ϯ 1.9, mean Ϯ SD) were recruited from the general public in the San Diego region through the UCSD Mental Health Clinical Research Center (MH-CRC). Eight Caucasian-Americans and two AfricanAmericans completed the study after givin...

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Dorsal raphe neurons: depression of firing during sleep in cats

Cited by 843 publications

References 24 publications

Central serotonin neurons are required for arousal to CO ₂

Central serotonin neurons are required for arousal to CO ₂

Serotonergic neuron diversity: Identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm

Rapid Tryptophan Depletion Plus a Serotonin 1A Agonist Competing Effects on Sleep in Healthy Men

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Dorsal raphe neurons: depression of firing during sleep in cats

Cited by 843 publications

References 24 publications

Central serotonin neurons are required for arousal to CO 2

Central serotonin neurons are required for arousal to CO 2

Serotonergic neuron diversity: Identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm

Rapid Tryptophan Depletion Plus a Serotonin 1A Agonist Competing Effects on Sleep in Healthy Men

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Product

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Central serotonin neurons are required for arousal to CO ₂

Central serotonin neurons are required for arousal to CO ₂