Alterations in Basal and Chemical Control of Breathing in a SN α-Synucleinopathy-based Rat Model of Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms; however, a growing body of evidence highlights the prominence of non-motor symptoms (NMS) in PD, which can precede motor dysfunction and significantly impact quality of life. Among the NMS, impaired central respiratory neural control—manifested as abnormal breathing patterns and alterations in chemical control of breathing—has garnered increasing attention due to its association with disease progression and mortality risk. While PD is associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN), another neuropathological feature in PD is the accumulation and aggregation of α-synuclein (α-syn; e.g., Lewy bodies). Since α-syn aggregation is capable of disrupting several cellular processes, which may even precede DA neuron loss, understanding the impact of α-syn aggregates on central respiratory neural control is warranted. To begin to address this issue, in adult female Sprague-Dawley rats α-syn preformed fibrils (PFFs) were injected with into the left SN to induce α-syn aggregate seeding; α-syn monomers (mono), which do not induce seeding, were used in a separate group of control rats. At 8-weeks after SN injection, rats were anesthetized with urethane and diaphragm EMG (EMG Dia ) activity and plethysmography recordings were obtained during spontaneous basal breathing behaviors (40% O 2 ) and in response to acute hypoxic (HVR; 12% O 2 , 90s), hypercapnic (HCVR; 7% CO 2 , 5 min), and combined hypoxic/hypercapnic (MCVR; 12% O 2 , 7% CO 2 , 3 min) gas exposures. We found no differences between the PFF- and mono-injected rats in average breathing rate, inspiratory duration (T I ), expiratory duration (T E ), or tidal volume during basal breathing; however, PFF-injected rats were more likely to have multiple spontaneous tachypneic episodes. While both PFF- and mono-injected rats had equivalent increases to respiratory rate and EMG Dia amplitude during the HVR, PFF-injected rats had a longer latency to onset of an HVR response. PFF-injected rats also exhibited an overall heightened HCVR that was characterized by enhanced increases in EMG Dia amplitude and fictive minute ventilation. Similarly, PFF-injected rats had a slightly increased MCVR that was characterized by enhanced increases in EMG Dia amplitude and fictive minute ventilation. The extent of α-syn seeding was assessed on transverse sections of the midbrain that contained the SN using pSer129-α-syn IHC, and these analyses revealed that α-syn aggregates were present in the left SN but not in other nuclei contained in these sections, and that some α-syn aggregates were present in DA (TH-ir) neurons albeit no substantial loss of DA neurons was observed. These findings demonstrate that α-syn PFF-injected rats exhibit aggregate seeding and some alterations in basal breathing pattern, time course of HVR behaviors, and magnitude of HCVR and MCVR behaviors. As these alterations notably occur in the absence of DA neuron loss, further study on respiratory-related NMS behaviors in synucleinopathy-based PD models is needed. Support: Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.