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Unilateral Ablation of Pre-Bötzinger Complex Disrupts Breathing during Sleep but Not Wakefulness

¹ Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California

Correspondence and requests for reprints should be addressed to Jack L. Feldman, Ph.D., Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1763. E-mail: feldman{at}ucla.edu

Rationale: In adult rats, bilateral ablation of pre-Bötzinger complex (preBötC) neurokinin 1–expressing (NK1R) neurons leads to a progressive and irreversible disruption in breathing pattern, initially during sleep, eventually resulting in an ataxic breathing pattern during wakefulness.

Objectives: Here we determine whether ablation of fewer preBötC NK1R neurons leads to a persistent pattern of disordered breathing during sleep but not during wakefulness.

Methods: Adult male Sprague-Dawley rats (n = 12) were instrumented to record diaphragmatic, abdominal, and neck EMG, and EEG. Fourteen days later, a second surgery was performed to stereotaxically microinject into the preBötC on one side the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons.

Measurements and Main Results: Postinjection, rats were monitored within a plethysmograph until they were killed (Days 21–51). At Days 6–9 post–unilateral SP-SAP injection, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered, characterized by an increase in frequency of central sleep apnea and hypopneas (36.8 ± 7.4 episodes/h of REM vs. 6 ± 2.0 episodes/h in preinjection controls; P < 0.05), whereas breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP–injected rats, an ataxic breathing pattern did not develop during wakefulness. Rats that were monitored up to 51 days post–SP-SAP injection continued to have sleep-disordered breathing; breathing during wakefulness remained relatively stable. Histologic analysis of the ventrolateral medulla confirmed that NK1R neurons within the preBötC on the injected but not on the contralateral side of the medulla were ablated.

Conclusions: Gradual loss of preBötC NK1R neurons may be an underlying factor of sleep-disordered breathing, in particular of central sleep apnea.

Key Words: respiratory control • apnea • ventrolateral medulla • saporin • neurokinin 1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject An essential component of the respiratory rhythm generating circuitry in mammals is the pre-Bötzinger complex (preBötC). Bilateral ablation of the preBötC leads to deterioration of breathing, initially during sleep, progressing into wakefulness, then death. What This Study Adds to the Field Unilateral ablation of the preBötC in rats leads to disrupted breathing during sleep but not wakefulness.