The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior

Ziemann, Adam; Allen, Jason E.; Dahdaleh, Nader S.; Drebot, I.I.; Coryell, Matthew W.; Wunsch, Amanda M.; Lynch, Cynthia M.; Faraci, Frank M.; Howard, Matthew A.; Welsh, Michael J.; Wemmie, John A.

doi:10.1016/j.cell.2009.10.029

Cited by 370 publications

(496 citation statements)

References 56 publications

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“…A bioinformatic search of the chromosome segment comprising the 17q11.2-q12 region suggested the ACCN1 gene as the most interesting gene, as the acid-sensing ion channels (ASICs) may be involved in anxiety-related pathways. [25][26][27] The ACCN1 gene comprises a genomic region of approximately 1. Figure 1 An overview of the study design: in stage 1, we conducted a genome-wide scan, which detected significant association between PD and a twomarker segment (D17S1294-D17S1293) on chromosome 17.…”

Section: Genotypingmentioning

confidence: 99%

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

et al. 2011

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Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using singlenucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.

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Section: Genotypingmentioning

confidence: 99%

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

et al. 2011

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“…Functional MRI studies have shown that hypercapnia and hypoxia induced by brief apnea cause an increase in activity within the thalamus and cerebral cortex (23). There is recent evidence that acid sensing ion channels in the nucleus accumbens mediate a portion of the limbic response to hypercapnia (24), but the neurons and pathways responsible for the arousal response to hypercapnia have not been identified. Given the involvement of midbrain 5-HT neurons in sleep/wake regulation and their ability to sense pH changes, it has been proposed that midbrain 5-HT neurons initiate the arousal response to hypercapnia (11,13,25,26).…”

mentioning

confidence: 99%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

231

217

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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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“…One is to identify the physiological ligands. Wemmie and colleagues [78] demonstrated that ASIC1a in the amygdala is sufficient to detect CO 2 to elicit fear behavior. They also found that inhaled CO 2 reduces brain pH and evokes fearrelated behavior in mice, whereas eliminating or inhibiting ASIC1a markedly impairs this activity.…”

Section: Asics Acid-sensing Is Associated With Nociceptionmentioning

confidence: 99%

“…Blood CO 2 is converted into H + and HCO 3 -and detected by chemosensors in the nervous system. TASK1 channels in the brainstem [89] and ASIC1a in the amygdala [78] have been demonstrated to be important for CO 2 sensing. In addition, TRPA1 expressed in trigeminal neurons mediate CO 2 responses.…”

Section: Acid-sensing Receptors In Sensory System Sour Tastementioning

confidence: 99%

Proton production, regulation and pathophysiological roles in the mammalian brain

Zeng

2012

Neurosci. Bull.

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Abstract:The recent demonstration of proton signaling in C. elegans muscle contraction suggests a novel mechanism for proton-based intercellular communication and has stimulated enthusiasm for exploring proton signaling in higher organisms. Emerging evidence indicates that protons are produced and regulated in localized space and time. Furthermore, identification of proton regulators and sensors in the brain leads to the speculation that proton production and regulation may be of major importance for both physiological and pathological functions ranging from nociception to learning and memory. Extracellular protons may play a role in signal transmission by not only acting on adjacent cells but also affecting the cell from which they were released. In this review, we summarize the upstream and downstream pathways of proton production and regulation in the mammalian brain, with special emphasis on the proton extruders and sensors that are critical in the homeostatic regulation of pH, and discuss their potential roles in proton signaling under normal and pathophysiological conditions.

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The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior

Cited by 370 publications

References 56 publications

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

Central serotonin neurons are required for arousal to CO ₂

Proton production, regulation and pathophysiological roles in the mammalian brain

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The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior

Cited by 370 publications

References 56 publications

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

Central serotonin neurons are required for arousal to CO 2

Proton production, regulation and pathophysiological roles in the mammalian brain

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Product

Resources

About

Central serotonin neurons are required for arousal to CO ₂