Control of Breathing

Dempsey, Jerome A.; Welch, Joseph F.

doi:10.1055/s-0043-1770342

Cited by 7 publications

(5 citation statements)

References 218 publications

(317 reference statements)

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“…The control of breathing is also impacted by well established “closed loop” physiologic feedback mechanisms regulating lung volume and arterial blood gases 47, 48 . For example, if DREADD-induced activation of the diaphragm leads to increased alveolar ventilation, and metabolic rate is not impacted, then arterial CO 2 values will decrease and the overall neural drive to breathe will also decrease.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

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Impaired diaphragm activation contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We conducted experiments to determine if expression of an excitatory DREADD (designer receptors exclusively activation by designer drugs) in the mid-cervical spinal cord would enable respiratory-related activation of phrenic motoneurons to increase diaphragm activation. Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive DREADD expression in C4 ventral horn motoneurons, targeting the phrenic motoneuron pool. Diaphragm EMG was recorded during spontaneous breathing at 6-8 weeks post-AAV delivery. The selective DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in a ChAT-Cre rat model were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT assessed using whole-body plethysmography. Subsequently, direct nerve recordings confirmed that J60 evoked a >50% increase in inspiratory phrenic output. The data show that mid-cervical spinal DREADD expression targeting the phrenic motoneuron pool enables ligand-induced, sustained increases in the neural drive to the diaphragm. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

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Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

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“…This sequence of events leads to a rise in sympathetic activity and a decline in parasympathetic activity [39]. It is possible that the observed negative correlation between BF and RMSSD was due to the activation of β 2 adrenergic receptors in the airway smooth muscles, causing bronchodilatation with a subsequent reduction in airflow resistance [40]. This would make the breathing frequency easier to increase with the intensity of physical activity-the principle of minimal effort.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Cardio-Respiratory Relationship during and after Exercise in Healthy Recreative Male Subjects: A Pilot Study

Malović,

Zeković,

Zeković

et al. 2024

Applied Sciences

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Background: Understanding the responses of the cardio and respiratory systems during exercise, as well as their coupling in post-exercise recovery, is important for the prescription of exercise programs in physically recreative subjects. Aim: In this work, we aimed to set up an adjusted experiment to evaluate the relations and changes in parameters obtained from an analysis of cardiac and respiratory signals under three physiological conditions: relaxation, exercise, and post-exercise recovery. Material and Methods: Simultaneously recorded ECG (RR intervals) and respiratory signal during relaxation, bicycle ergometry exercise until submaximal heart rate (HR), and recovery in 10 healthy men were analyzed. The exercise included consecutive phases of 3 min in duration with a constant workload. Parasympathetic cardiac control (RMSSD), heart rate (HR), breathing frequency (BF), and respiratory cycle amplitude (RCA) were calculated. Anthropometric data were also collected. Results: Based on time series analysis, our results show that: (1) during exercise, an increase in HR was related to a reduction in HR variability and RMSSD, while an increase in BF was related to an increase in RCA, and (2) during recovery, HR and RCA significantly decreased, while RMSSD had a biphasic response. The results of multiple linear regressions showed that the averaged HR, RMSSD, and BF during 3 min segments of recovery were determined by several calculated and collected parameters. Conclusions: The parameters from the analysis of respiratory signals and RR interval time series under conditions of relaxation and exercise, along with anthropometric data, contributed to the complexity of the post-exercise recovery of cardiopulmonary parameters after submaximal HR exercise in healthy recreative males.

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“…Phase II describes an exponential increase in

with a time constant of 60–90 s. Phase III describes a

plateau (i.e., steady‐state) beginning approximately 3 min after exercise onset. A successful exercise hyperpnoea is defined by regulation of arterial

(

) near its set‐point (∼40 mmHg) due to proportional increases in

and

(Dempsey & Welch, 2023 ). However, it must be appreciated that good

regulation (i.e., ±2 mmHg of rest) is not evidence of a single mechanism that gives rise to precise

coupling.…”

Section: Part I: the Ventilatory Control Systemmentioning

confidence: 99%

Inaugural Review Prize 2023: The exercise hyperpnoea dilemma: A 21st‐century perspective

Welch,

Mitchell

2024

Experimental Physiology

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During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO2 pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the ‘exercise hyperpnoea dilemma’ can finally be solved. In this review, new perspectives are offered in the hope of stimulating original ideas based on modern neuroscience methods and current understanding. We first describe the ventilatory control system and the challenge exercise places upon blood‐gas regulation. We highlight relevant system properties, including feedforward, feedback and adaptive (i.e., plasticity) control of breathing. We then elaborate a seldom explored hypothesis that the exercise ventilatory response continuously adapts (learns and relearns) throughout life and ponder if the memory ‘engram’ encoding the feedforward exercise ventilatory stimulus could reside within the cerebellum. Our hypotheses are based on accumulating evidence supporting the cerebellum's role in motor learning and the numerous direct and indirect projections from deep cerebellar nuclei to brainstem respiratory neurons. We propose that cerebellar learning may be obligatory for the accurate and adjustable exercise hyperpnoea capable of tracking changes in life conditions/experiences, and that learning arises from specific cerebellar microcircuits that can be interrogated using powerful techniques such as optogenetics and chemogenetics. Although this review is speculative, we consider it essential to reframe our perspective if we are to solve the till‐now intractable exercise hyperpnoea dilemma.

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Control of Breathing

Cited by 7 publications

References 218 publications

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Assessment of Cardio-Respiratory Relationship during and after Exercise in Healthy Recreative Male Subjects: A Pilot Study

Inaugural Review Prize 2023: The exercise hyperpnoea dilemma: A 21st‐century perspective

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