Impact of aging on basal and hypoxic respiratory behaviors in short‐ and long‐term 6‐OHDA‐induced SN lesion PD rat models

Abstract

Parkinson's Disease (PD) is a progressive neurodegenerative disease often associated with aging, as it typically occurs in individuals over the age of 50. As such, investigating features and mechanisms of PD becomes complicated since molecular changes to dopaminergic (DA) neurons, subsequent neuronal loss, and downstream alterations to non-DA neurotransmitter systems can progress over decades to cause the various motor and non-motor symptoms (NMS), which can be further compounded by changes caused by normal aging. Amongst the earliest symptoms to arise in PD patients, respiratory abnormalities are a common feature, and ongoing work in our laboratory has focused on characterizing respiratory dysfunction phenotypes in preclinical PD rat models produced by 6-hydroxydopamine (6-OHDA) neurotoxin-induced lesion of the nigrostriatal pathway. These studies are typically conducted in rats aged 3-4 months at 2-4 weeks following lesion. To begin to understand the impact of aging on PD-related respiratory abnormalities, the current study evaluated basal and hypoxic (12% O2; 90s) respiratory behaviors in ~38-week-old urethane-anesthetized spontaneously breathing female Sprague-Dawley rats that received a unilateral substantia nigra (SN) 6-OHDA injection at either 2-weeks (short-term lesion; STL) or 24-weeks (long-term lesion; LTL) before being studied; SN vehicle (STV; LTV) injections served as controls. We found that LTL rats had higher basal breathing frequencies and slightly reduced burst-to-burst frequency and amplitude variability than LTV rats (which is similar to our observations in the younger SN 6-OHDA vs vehicle injected rats) while STL rats had lower breathing frequencies with slightly increased burst-to-burst amplitude variability compared to STV rats, with STV rats exhibiting breathing frequencies similar to LTL rats. The overall burst-to-burst frequency variability was greater in LTL and LTV rats compared to STL and STV rats, but STL rats exhibited greater burst-to-burst inspiratory duration (TI) and expiratory duration (TE) variability compared to STV rats; LTL rats had reduced burst-to-burst variability in these behaviors compared to LTV rats. Evaluation of the hypoxic ventilatory response revealed that LTL rats exhibit a blunted increase in frequency and amplitude in response to hypoxia compared to LTV and STL rats, with STL rats exhibiting an exaggerated hypoxic frequency increase compared to STV rats. While the increases in frequency were primarily mediated by decreases in TE in all groups, LTV rats also had reduced TI and they exhibited a larger post-hypoxic frequency decline due to a substantial increase in TE. Regardless of lesion (or vehicle injection) time, all of the older rats had a substantial delay in recovery following hypoxia. In contrast, younger SN 6-OHDA (compared to vehicle) injected rats exhibited an exaggerated frequency but blunted amplitude response to hypoxia, which rapidly recovered to pre-hypoxic levels. These data demonstrate that in older rats, the timing of the lesion may differentially affect the components underlying PD-related abnormalities in respiratory behaviors. Additional studies are needed to identify the mechanisms responsible.