Time course of alterations in chemical control of breathing in conscious spontaneously breathing 6‐OHDA SN‐lesioned Parkinson's Disease rat model

Abstract

Respiratory dysfunction in Parkinson's Disease (PD) patients manifests as a variety of altered breathing patterns and chemical control of breathing deficits that are suggested to result from impairment of central respiratory control. Ongoing work in our laboratory has identified time‐dependent alterations in both basal inspiratory motor output and chemical control of breathing in the 6‐hydroxydopamine (6‐OHDA) neurotoxin‐induced unilateral substantia nigra (SN) lesion rat model. With reference to alterations in chemical control of breathing, our studies have been limited to examination of breathing behaviors at specified time points in acute terminal experiments; thus, the time course underlying the progressive nature of the changes observed is not known. Here, we begin to address this issue by examining the hypoxic (HVR; 12% O2, 3 min) and hypercapnic (HCVR; 7% CO2, 5 min) ventilatory responses using whole body plethysmography before and weekly for 4‐weeks after administration of 6‐OHDA into the SN of adult female Sprague‐Dawley rats; vehicle injected rats served as a control. For the HVR, we found that before injection into the SN, minute ventilation (MV) was increased by ~50% increase, which was mediated predominantly by an increase in breathing frequency (fb) but increases in tidal volume (VT) were noted in some rats; similar observations were noted in vehicle injected rats at the time points examined although some variability in magnitude of the responses were noted at various time points (but not in any specific pattern). In contrast, in 6‐OHDA injected rats, a markedly blunted HVR (~0–10% MV increase), in which fb and VT were minimally altered from pre‐hypoxic levels, was noted; this HVR alteration in behavior was stable over the time course examined albeit in a subset of rats, an HVR began to re‐emerge at the 4‐week post‐lesion time point. For the HCVR, we found that before injection into the SN, MV more than doubled due to similar magnitude increases in both fb and VT. In vehicle injected rats, there was a progressive increase in the magnitude of the HCVR ventilatory behaviors (MV, fb, VT) that stabilized over the 3–4 week post injection time point. In contrast in 6‐OHDA injected rats, the peak of the HCVR MV increase was similar at 5‐min of CO2 exposure, but the response during the initial 4‐min of CO2 exposure was blunted, especially at the 2–3 week post‐lesion time point. This deficit appeared to be mediated by attenuated fb and VT responses. These observations suggest that in conscious 6‐OHDA SN‐lesioned rats, chemical control of breathing undergoes progressive alterations albeit ventilatory behaviors associated with the HVR and HCVR appear to be differentially affected. It remains to be determined whether the ventilatory impairments noted in this PD rat model persist beyond the 4‐week time point studied here.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.