Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats

Veasey, Sigrid C.; Fornal, Casimir A.; Metzler, Christine W.; Jacobs, Barry L.

doi:10.1016/s0306-4522(96)00673-2

Cited by 118 publications

(102 citation statements)

References 23 publications

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“…Instead, our data support the hypothesis that a subset of 5-HT neurons plays the specific role of inducing arousal in response to hypercapnia. Hypercapnia directly activates midbrain 5-HT neurons (11,36). 5-HT release within the thalamus leads to a change in thalamocortical rhythms from a bursting pattern to a tonic pattern (8,37).…”

Section: Discussionmentioning

confidence: 99%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

231

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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Section: Discussionmentioning

confidence: 99%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

231

213

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“…Further, at least certain subpopulations of putative serotonergic DRN neurons are excited by the presentation of auditory and visual stimuli (Heym et al, 1982;Shima et al, 1986), and during rhythmic oral-buccal movements and in response to tactile stimulation (Fornal et al, 1996). Although extensive electrophysiological work has been devoted to examining the firing properties of putative serotonergic DRN neurons in behaving animals (Trulson and Jacobs, 1979;Trulson et al, 1981;Heym et al, 1982;Steinfels et al, 1983;Fornal et al, 1996;Veasey et al, 1997;GuzmanMarin et al, 2000;Sakai and Crochet, 2001), much less is known about the response properties of nonserotonergic DRN neurons. Experiments in chloral hydrate-anesthetized rats have demonstrated that stimulation of the sciatic nerve suppresses the firing of putative serotonergic DRN cells but increases the firing of putative nonserotonergic cells (Aghajanian et al, 1978).…”

Section: Discussionmentioning

confidence: 99%

Selective anterograde tracing of nonserotonergic projections from dorsal raphe nucleus to the basal forebrain and extended amygdala

Halberstadt

Balaban

2008

Journal of Chemical Neuroanatomy

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The dorsal raphe nucleus (DRN) contains both serotonergic and non-serotonergic projection neurons. Retrograde tracing studies have demonstrated that components of the basal forebrain and extended amygdala are targeted heavily by input from nonserotonergic DRN neurons. The object of this investigation was to examine the terminal distribution of nonserotonergic DRN projections in the basal forebrain and extended amygdala, using a technique that allows selective anterograde tracing of nonserotonergic DRN projections. To trace nonserotonergic DRN projections, animals were pretreated with nomifensine, desipramine and the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), 7 days prior to placing an iontophoretic injection of biotinylated dextran amine (BDA) into the DRN. In animals treated with 5,7-DHT, numerous nonserotonergic BDA-labeled fibers ascended to the basal forebrain in the medial forebrain bundle system. Some of these labeled fibers crossed through the lateral hypothalamus, bed nucleus of the stria terminalis, and substantial innominata. These fibers entered the amygdala through the ansa peduncularis and ramified within the central and basolateral amygdaloid nuclei. Other fibers entered the diagonal band of Broca and formed a dense plexus of labeled fibers in the dorsal half of the intermediate portion of the lateral septal nucleus and the septohippocampal nucleus. These findings demonstrate that the basal forebrain and extended amygdala receive a dense projection from nonserotonergic DRN neurons. Given that the basal forebrain plays a critical role in processes such as motivation, affect, and behavioral control, these findings support the hypothesis that nonserotonergic DRN projections may exert substantial modulatory control over emotional and motivational functions. Keywords amygdala; bed nucleus; 5,7-dihydroxytryptamine; septal nuclei; biotinylated dextran amine; tyrosine hydroxylase It is well known that the dorsal raphe nucleus contains more than half of all the serotonergic neurons in the brain (Leger and Wiklund, 1982) and is a source of projections that terminate extensively throughout the central nervous system (Vertes, 1991;Sim and Joseph, 1993;Vertes and Kocsis, 1994;Morin and Meyer-Bernstein, 1999 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. within dorsomedial (DRNdm), ventromedial (DRNvm), and lateral (DRNl) cell groups . It has been proposed that the activity of serotonergic DRN neurons plays an important role in the coordination of sensory processing and motor output with the sleep-wake-arousal cycle (Jacobs and Azmitia, 1992; Forn...

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“…In addition, some medullary and dorsal raphe neurons are activated by hypercapnia in vivo (Veasey et al, 1995), which could increase activity of multiple components of the respiratory system as well as increase responsiveness of RTN neurons to CO 2 , thereby contributing to the exquisite sensitivity of the respiratory outflow to pH (Richerson et al, 2005). Pontine and medullary serotonergic neurons have a state-dependent level of activity characterized by a much higher level of discharge during waking than during sleep (Veasey et al, 1995(Veasey et al, , 1997. During waking and at normal CO 2 levels, serotonergic input to RTN neurons could make a greater contribution to the ongoing activity of RTN neurons than CO 2 itself.…”

Section: Functional Significancementioning

confidence: 99%

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

Mulkey¹,

Rosin²,

West³

et al. 2007

J. Neurosci.

141

188

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Serotonin activates respiration and enhances the stimulatory effect of CO 2 on breathing. The present study tests whether the mechanism involves the retrotrapezoid nucleus (RTN), a group of medullary glutamatergic neurons activated by extracellular brain pH and presumed to regulate breathing. We show that the RTN is innervated by both medullary and pontine raphe and receives inputs from thyrotropin-releasing hormone (TRH) and substance P-expressing neurons. Coexistence of serotonin and substance P in terminals within RTN confirmed that lower medullary serotonergic neurons innervate RTN. In vivo, unilateral injection of serotonin into RTN stimulated inspiratory motor activity, and pH-sensitive RTN neurons were activated by iontophoretic application of serotonin or substance P. In brain slices, pH-sensitive RTN neurons were activated by serotonin, substance P, and TRH. The effect of serotonin in slices was ketanserin sensitive and persisted in the presence of glutamate, GABA, glycine, and purinergic ionotropic receptor antagonists. Serotonin and pH had approximately additive effects on the discharge rate of RTN neurons, both in slices and in vivo. In slices, serotonin produced an inward current with little effect on conductance and had no effect on the pH-induced current. We conclude that (1) RTN receives input from multiple raphe nuclei, (2) serotonin, substance P, and TRH activate RTN chemoreceptors, and (3) excitatory effects of serotonin and pH are mediated by distinct ionic conductances. Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH.

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Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats

Cited by 118 publications

References 23 publications

Central serotonin neurons are required for arousal to CO ₂

Central serotonin neurons are required for arousal to CO ₂

Selective anterograde tracing of nonserotonergic projections from dorsal raphe nucleus to the basal forebrain and extended amygdala

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

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Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats

Cited by 118 publications

References 23 publications

Central serotonin neurons are required for arousal to CO 2

Central serotonin neurons are required for arousal to CO 2

Selective anterograde tracing of nonserotonergic projections from dorsal raphe nucleus to the basal forebrain and extended amygdala

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

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Product

Resources

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Central serotonin neurons are required for arousal to CO ₂

Central serotonin neurons are required for arousal to CO ₂