Pharmacogenetic Modulation of the Noradrenergic System Reveals Protective and Vulnerable Roles in the Neonate Autoresuscitation Reflex
Authors: Morales Fatima Beatriz Saldana , McKinney Andrew Michael , Martinez Vena Kay , Jiang Xiaolong , Ray Russell Scott 
Published: June 2021

A key feature of neonatal respiration is the autoresuscitation reflex, which restarts breathing and cardiac function after an infant has fallen into respiratory arrest and bradycardia due to extreme hypoxic conditions. Abnormalities in this reflex have been hypothesized to play a role in life threatening pathologies such as Sudden Infant Death Syndrome (SIDS), where infants are often found face down, resulting in asphyxiation and death. Disruptions to the development and maturation of the brainstem autonomic neural circuitry, including the noradrenergic (NA) system, are thought to be an underlying factor in SIDS. Despite the number of studies implicating the NA system in cardiorespiratory control and in SIDS pathology, the role of the NA system in the autoresuscitation reflex remains poorly understood. We hypothesize that the NA system plays a critical role in modulating the neonatal autoresuscitation reflex and that increased NA tone may offer a protective effect.

To test this hypothesis, we pharmacogenetically excited and inhibited the whole NA system in P7‐P8 mice by expressing neuro‐excitatory (hM3D) and inhibitory (hM4D) clozapine‐N‐oxide (CNO) activated DREADD receptors throughout all NA producing cells utilizing conditional DREADD and DBH_FlpO mouse lines developed in the Ray lab. Respiratory parameters were measured using a modified facemask pneumotachograph while recording heart rate (HR) through an electrocardiogram (ECG). To induce the autoresuscitation reflex, pups were given a brief exposure to mild hypercapnic anoxia (3%CO2, 97%N2) to induce respiratory arrest and bradycardia. Upon apnea, anoxia was reversed by flushing the pneumotachograph with room air to facilitate the autoresuscitation reflex and recovery. Pups were exposed to repeated bouts of hypercapnic anoxia, followed by recovery periods, until succumbing. We recorded HR and respiratory waveforms continuously throughout the assay. We obtained the number of episodes before death, exposure time, time until first gasping (gasp latency), and frequency of gasping (Gasp ƒB). HR and eupnea recovery were also analyzed. Differences between experimental mice and littermate controls were assessed by a repeated measurement two‐way ANOVA. A p‐value< 0.05 was considered statistically significant. Bonferroni correction was used where multiple comparisons were necessary.

Contrary to our hypothesis, preliminary data suggests that acute excitation of the NA system during the anoxic challenge results in a decreased number of successful autoresuscitation events, a higher gasp latency and frequency, and longer delay time to recovery heart rate and eupnea during the last episode. Conversely, when the NA system was inhibited, pups showed a tendency to survive more episodes than controls with a longer exposure time before they succumbed. These results suggest that the NA system might act as an acute modulator of the autoresuscitation reflex, an important neonatal reflex implicated in SIDS pathology.

Support or Funding Information

McNair Medical Institute, March of Dimes Award #1‐FY18‐403, Basil O'Connor Starter Scholar Research Award, R01HL130249, CJ Foundation for SIDS Research Award

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.