The amygdala differentially regulates defensive behaviors evoked by CO2

Taugher, Rebecca J.; Dlouhy, Brian J.; Kreple, Collin J.; Ghobbeh, Ali; Conlon, Mackenzie M.; Wang, Y.; Wemmie, John A.

doi:10.1016/j.bbr.2019.112236

Cited by 11 publications

(5 citation statements)

References 56 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Emotion is thought to depend at least in part on the amygdala. The amygdala is critical for mediating defensive responses to a variety of threats, including freezing and fight-and-flight responses (37,38), where altering respiration can be crucial for survival. Thus, a pathway by which the amygdala influences breathing might be advantageous from an evolutionary perspective.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

Rhone¹,

Kovach²,

Harmata³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

BACKGROUND. Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown. METHODS. We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine-learning algorithm was used to delineate brain regions that inhibit respiration. RESULTS. In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 subjects (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine-learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons. CONCLUSIONS. A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.

show abstract

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

Rhone¹,

Kovach²,

Harmata³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

show abstract

“…The predominant sensor of extracellular pH in the central and peripheral nervous system is thought to be acid-sensing ion channels (ASICs) ( Pattison et al, 2019 ). This family of trimeric pH-activated sodium-selective ion channels couples extracellular acidification to numerous physiological and pathophysiological consequences including synaptic transmission and plasticity ( Du et al, 2014 ; Kreple et al, 2014 ; Liu et al, 2016 ; Uchitel et al, 2019 ; Yu et al, 2018 ), fear memory consolidation and expression ( Du et al, 2017 ; Taugher et al, 2020 ; Taugher et al, 2017 ; Taugher et al, 2014 ), epilepsy ( Ziemann et al, 2008 ), and ischemia-induced cell death ( Wemmie et al, 2013 ; Xiong et al, 2004 ). However, in many of these cases, the duration of extracellular acidosis is quite long.…”

Section: Introductionmentioning

confidence: 99%

Topography and motion of acid-sensing ion channel intracellular domains

Couch

Berger

Kneisley

et al. 2021

eLife

View full text Add to dashboard Cite

Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by decreases in extracellular pH. The intracellular N and C terminal tails of ASIC1 influence channel gating, trafficking, and signaling in ischemic cell death. Despite several x-ray and cryo-EM structures of the extracellular and transmembrane segments of ASIC1, these important intracellular tails remain unresolved. Here we describe the coarse topography of the chicken ASIC1 intracellular domains determined by FRET, measured using either fluorescent lifetime imaging or patch clamp fluorometry. We find the C terminal tail projects into the cytosol by approximately 35 Å and that the N and C tail from the same subunits are closer than adjacent subunits. Using pH-insensitive fluorescent proteins, we fail to detect any relative movement between the N and C tails upon extracellular acidification but do observe axial motions of the membrane proximal segments towards the plasma membrane. Taken together, our study furnishes a coarse topographic map of the ASIC intracellular domains while providing directionality and context to intracellular conformational changes induced by extracellular acidification.

show abstract

“…Briefly, Urbach–Wiethe patients show no fear and avoidance behavior to external threats such as snakes, tarantulas, and a range of traumatic life events, but exhibit a significantly higher rate of CO 2 -evoked fear and panic than a sample of demographically-matched healthy participants ( Feinstein et al, 2013 ; Feinstein et al, 2022 ). In mice, electrolytic lesions of the amygdala inhibited fear-like behavior (freezing); however, the ventilatory response was not tested ( Taugher et al, 2020 ). In pediatric subjects, electrical stimulation of the medial subregion of the basal nuclei, cortical and medial nuclei induces apnea ( Rhone et al, 2020 ); similar procedures in the lateral and basolateral amygdala of adults also results in respiratory inhibition ( Dlouhy et al, 2015 ).…”

Section: Early Life Stress Alters Non-medullary Structures With Co ...mentioning

confidence: 99%

Estrogens, age, and, neonatal stress: panic disorders and novel views on the contribution of non-medullary structures to respiratory control and CO2 responses

et al. 2023

View full text Add to dashboard Cite

CO2 is a fundamental component of living matter. This chemical signal requires close monitoring to ensure proper match between metabolic production and elimination by lung ventilation. Besides ventilatory adjustments, CO2 can also trigger innate behavioral and physiological responses associated with fear and escape but the changes in brain CO2/pH required to induce ventilatory adjustments are generally lower than those evoking fear and escape. However, for patients suffering from panic disorder (PD), the thresholds for CO2-evoked hyperventilation, fear and escape are reduced and the magnitude of those reactions are excessive. To explain these clinical observations, Klein proposed the false suffocation alarm hypothesis which states that many spontaneous panics occur when the brain’s suffocation monitor erroneously signals a lack of useful air, thereby maladaptively triggering an evolved suffocation alarm system. After 30 years of basic and clinical research, it is now well established that anomalies in respiratory control (including the CO2 sensing system) are key to PD. Here, we explore how a stress-related affective disorder such as PD can disrupt respiratory control. We discuss rodent models of PD as the concepts emerging from this research has influenced our comprehension of the CO2 chemosensitivity network, especially structure that are not located in the medulla, and how factors such as stress and biological sex modulate its functionality. Thus, elucidating why hormonal fluctuations can lead to excessive responsiveness to CO2 offers a unique opportunity to gain insights into the neuroendocrine mechanisms regulating this key aspect of respiratory control and the pathophysiology of respiratory manifestations of PD.

show abstract

The amygdala differentially regulates defensive behaviors evoked by CO2

Cited by 11 publications

References 56 publications

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

Topography and motion of acid-sensing ion channel intracellular domains

Estrogens, age, and, neonatal stress: panic disorders and novel views on the contribution of non-medullary structures to respiratory control and CO2 responses

Contact Info

Product

Resources

About