Tg(Th-Cre)FI172Gsat ( Th-Cre) defines neurons that are required for full hypercapnic and hypoxic reflexes

Biol Open. 2017 Aug 15;6(8):1200-1208. doi: 10.1242/bio.026823.

Abstract

The catecholaminergic (CA) system has been implicated in many facets of breathing control and offers an important target to better comprehend the underlying etiologies of both developmental and adult respiratory pathophysiologies. Here, we used a noninvasive DREADD-based pharmacogenetic approach to acutely perturb Tg(Th-Cre)FI172Gsat (Th-Cre)-defined neurons in awake and unrestrained mice in an attempt to characterize CA function in breathing. We report that clozapine-N-oxide (CNO)-DREADD-mediated inhibition of Th-Cre-defined neurons results in blunted ventilatory responses under respiratory challenge. Under a hypercapnic challenge (5% CO2/21% O2/74% N2), perturbation of Th-Cre neurons results in reduced fR, [Formula: see text] and [Formula: see text] Under a hypoxic challenge (10% O2/90% N2), we saw reduced fR, [Formula: see text] and [Formula: see text], in addition to instability in both interbreath interval and tidal volume, resulting in a Cheyne-Stokes-like respiratory pattern. These findings demonstrate the necessity of Th-Cre-defined neurons for the hypercapnic and hypoxic ventilatory responses and breathing stability during hypoxia. However, given the expanded non-CA expression domains of the Tg(Th-Cre)FI172Gsat mouse line found in the brainstem, full phenotypic effect cannot be assigned solely to CA neurons. Nonetheless, this work identifies a key respiratory population that may lead to further insights into the circuitry that maintains respiratory stability in the face of homeostatic challenges.

Keywords: Brainstem; Catecholamine; DREADD; Hypercapnic reflex; Hypoxic reflex; Respiration.