Comparison of basal and hypoxic respiratory behaviors in 6-OHDA and rotenone induced SN lesion Parkinson's disease rat models
Authors: Wadolowski Robert , Solomon Irene 
Published: May 2023

Parkinson’s disease (PD) is the second most prominent neurodegenerative disease in the world and is increasing in incidence. PD symptomology includes both motor- and non-motor symptoms (NMS). Respiratory deficits are a common PD NMS, likely caused by alterations in brainstem neurotransmission; several studies have begun to address respiratory deficits utilizing nigrostriatal pathway site-targeted 6-OHDA neurotoxin induced models of PD. While these models exhibit a loss of dopaminergic (DA) neurons in the substantia nigra (SN), they do not exhibit pathological changes such as α-synuclein aggregates or tau tangles which may play crucial roles in PD pathology. To better capture these additional features and more accurately reflect the development of PD, pesticide-based models are used albeit little is known about the respiratory deficits in these models. To begin to address this issue, we examined basal breathing behaviors and the acute hypoxic ventilatory response (HVR) in the SN 6-OHDA PD rat model and a PD rat model generated by unilateral SN injection of the pesticide rotenone (ROT); SN vehicle injections served as controls for each model (VehROT; Veh6-OHDA). At 2-weeks after SN injection, diaphragm EMG activity was recorded in urethane-anesthetized adult female Sprague-Dawley rats under baseline conditions (40% O2) and during and after an acute hypoxic (HYP) challenge (12% O2, 90 s), and the timing and patterning features of the EMG bursts were analyzed. We found that rats in all groups had a similar basal breathing rate of 86-89 bpm though ROT and 6-OHDA rats had slightly shorter TI and slightly longer TE, resulting in lower inspiratory duty cycles than their respective controls. During HYP, all groups displayed increased respiratory activity; however, ROT and 6-OHDA rats reached their peak increases at a later time than their respective controls. While 6-OHDA rats showed an attenuated HVR burst amplitude increase during the early- and mid-HYP response and a slightly reduced HVR frequency increase than Veh6-OHDA rats, ROT rats exhibited a larger HVR burst amplitude and frequency increase than VehROT rats. Surprisingly, differential magnitude increases in HVR burst amplitude were noted in Veh6-OHDA and VehROT rats (17% and 30% above baseline, respectively). 6-OHDA rats also had a milder post-HYP breathing frequency decline (PHFD) than Veh6-OHDA rats, while ROT rats had a more severe PHFD but recovered to basal breathing frequency more rapidly than rats in other groups. These findings indicate that DA neuron depletion exerts an impact on respiratory behaviors during the HVR; however, differences in the mechanisms of destruction may contribute to the different respiratory behaviors noted during and following HYP in these two models, warranting further study into the differences between them. Additionally, care must be given to better understand how injected vehicle solutions affect respiratory behaviors in control rats in these types of studies.

Support: Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.