The pre-Bötzinger complex: Generation and modulation of respiratory rhythm

Muñoz-Ortiz, J.; Muñoz-Ortiz, E.; López‐Meraz, María Leonor; Beltran-Parrazal, Luis; Morgado-Valle, Consuelo

doi:10.1016/j.nrleng.2018.05.006

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…Additionally, a secondary activity‐dependent change in glutamatergic expression within the HMN may occur following 24‐h exposure to hypercapnia due to its respiratory entrained rhythm and direct input from the VRC and medullary raphe (Muñoz‐Ortiz et al. ). The functional implications of the plasticity within these BRN is unclear, however the specific nuclei, as well as rostral‐caudal distribution of plasticity may provide insight into the functional effects.…”

Section: Discussionmentioning

confidence: 99%

Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats

et al. 2019

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Patients that retain CO2 with respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. However, little is known about the effects of chronic hypercapnia on the neurochemical mechanisms controlling brainstem respiratory nuclei (BRN). Common mechanisms of neuroplasticity involve changes in glutamate receptor expression/phosphorylation to modulate synaptic strength and network excitability, driven by changes in both AMPA (GluR) and NMDA (GluN) glutamate receptors. Accordingly, herein we tested the hypothesis that changes occur in glutamatergic signaling within the BRN during exposure to chronically elevated inspired CO2 (InCO2) induced hypercapnia. Healthy goats were euthanized after either 24 hours or 30 days of chronic exposure to 6% InCO2 or room air. The brainstems were extracted for western blot analyses to assess GluR and GluN receptor expression and phosphorylation state within the BRN. Compared to room air control goats, the following significant (P<0.05) changes were found after 24 hours of exposure to chronic hypercapnia: 1) AMPA receptor expression was greater, and NMDA receptor expression lower within the rostral solitary complex. 2) NMDA receptor expression/phosphorylation and APMA receptor phosphorylation were lower within the rostral ventrolateral medulla (VLM), while AMPA receptor expression/phosphorylation were greater in the caudal VLM. 3) AMPA receptor expression/phosphorylation were lower within the rostral retrotrapezoid nucleus. And, 4) NMDA receptor expression was greater within the caudal Raphe nucleus. The data indicate that within 24 hours of chronic hypercapnia changes have occurred in four BRN in GluR/GluN signaling which may contribute to an attenuated CO2‐induced hyperpnea and attenuated CO2 chemoreflex between 1 and 24 hours of hypercapnia (J. Physiol. 2018). GluR/GluN changes found at 24 hours of hypercapnia had returned to control levels after 30 days of hypercapnia. However, compared to room air control goats, the following significant (P<0.05) changes were found following 30 days of hypercapnia: 1) NMDA receptor phosphorylation was greater in the caudal ventral respiratory column, and 2) AMPA receptor expression was greater in the caudal RTN. The changes in GluR/GluN signaling between 24 hours and 30 days of chronic InCO2 may contribute to a sustained hyperpnea and normalization of the CO2 chemoreflex at 30 days. Support or Funding Information ‐Department of Veteran Affairs ‐NIH Grant 007852 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Section: Discussionmentioning

confidence: 99%

Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats

et al. 2019

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“…Males tend to exhibit periodic breathing in response to hypoxia more frequently than females (Pramsohler et al, 2019 ). Breathing patterns are heavily dependent on the pre-Bötzinger complex (pre-BötC; Smith et al, 1991 ; Buchanan, 2013 ; Del Negro et al, 2018 ; Muñoz-Ortiz et al, 2019 ). When neurons expressing neurokinin-1 receptors (NK1R) in the pre-BötC complex were bilaterally ablated in adult rats there was a progressive and irreversible disruption in breathing stability, which initially occurred only during sleep, but eventually led to ataxic breathing during wakefulness as well (Mckay and Feldman, 2008 ).…”

Section: Influence Of Sleep On Breathingmentioning

confidence: 99%

The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

Joyal

Kreitlow

Buchanan

2022

Front. Neural Circuits

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with refractory epilepsy. While the exact etiology of SUDEP is unknown, mounting evidence implicates respiratory dysfunction as a precipitating factor in cases of seizure-induced death. Dysregulation of breathing can occur in epilepsy patients during and after seizures as well as interictally, with many epilepsy patients exhibiting sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA). The majority of SUDEP cases occur during the night, with the victim found prone in or near a bed. As breathing is modulated in both a time-of-day and sleep state-dependent manner, it is relevant to examine the added burden of nocturnal seizures on respiratory function. This review explores the current state of understanding of the relationship between respiratory function, sleep state and time of day, and epilepsy. We highlight sleep as a particularly vulnerable period for individuals with epilepsy and press that this topic warrants further investigation in order to develop therapeutic interventions to mitigate the risk of SUDEP.

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“…16 We recorded changes in cardiorespiratory variables that accompanied seizures, together with the activity of respiratory-related neurons in the pre-Bötzinger complex, a key brainstem area for generating respiratory rhythm. 17,18 Status epilepticus evoked in acute preparations cannot, by definition, model SUDEP directly, but such models do present the opportunity for investigating fatal cardiorespiratory consequences associated with seizure activity. They are directly relevant to potential mechanisms of death in clinical status epilepticus and may lead to hypotheses on SUDEP that should be tested in chronic models of self-limiting seizures.…”

Section: Introductionmentioning

confidence: 99%

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats

et al. 2019

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Objective: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death. Methods: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. Results: Seizures caused hypertension, tachycardia, and tachypnea punctuated by recurrent transient apneas. Salivation increased considerably: in 11 of 12 rats, liquid with alkaline pH consistent with saliva was expelled from the mouth. Most transient apneas were obstructive: nasal airflow ceased, while, in 83%, efforts to breathe persisted as continued rhythmic activity of respiratory pre-Bötzinger neurons, inspiratory electromyography (EMG), and excursions of the chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases (16%) of incomplete apnea, but not in rare cases (1%) of transient central apneas. During transient obstructive apneas, the frequency of all inspiratory efforts decreased abruptly by ~30%, suggesting a resetting of the central respiratory rhythm generator. Twenty-two of thirty-one rats died, due either to obstructive apnea (12) or central apnea following progressive slowing of respiration (10). Most rats dying of central apnea had experienced several transient obstructive apneas.Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous reports on spreading depolarization in mouse models. Timing suggests that the DC shift is a consequence rather than cause of respiratory collapse.Cardiac activity continued for tens of seconds. Significance: Seizure activity in forebrain induces pronounced autonomic activation and disrupts activity in medullary respiratory centers, resulting in death from either obstructive or central apnea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of sudden unexpected death in epilepsy (SUDEP). K E Y W O R D SHeart rate, obstructive apnea, status epilepticus, SUDEP | 2347 JEFFERYS Et al.

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The pre-Bötzinger complex: Generation and modulation of respiratory rhythm

Cited by 14 publications

References 54 publications

Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats

Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats

The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats

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