Locus coeruleus pathology mediates breathing dysfunction and sleep disruption in a mouse model of prodromal Parkinson’s disease

Respiration and sleep are essential, well-conserved physiological functions, but disruptions in these systems are common in Parkinson’s disease (PD), particularly in its earliest stages. The mechanistic cause of PD is not well understood; however, the disease is characterized by aggregated alpha-synuclein (α-syn) and cell death within the substantia nigra, leading to motor symptoms. However, preceding clinical diagnosis and coinciding with non-motor symptoms, α-syn pathology emerges early in specific brain regions, highlighting the need for more rapid detection and intervention. One such vulnerable brain region is the locus coeruleus (LC), known to modulate attention, sleep, and breathing, underscoring its relevance in early non-motor symptoms. To delineate the broad impact of localized α-syn accumulation, we employed a multi-scale approach spanning cellular to behavioral impacts, focusing on LC-associated functions such as breathing, wakefulness, and arousal, and leveraging machine learning analyses to differentiate disruption patterns. To study early PD, we bilaterally injected α-syn pre-formed fibrils (PFF) into the LC region of C57BL/6J mice. Immunohistochemistry demonstrated increased α-syn pathology within the peri-LC region. 1-and-3-months post-injection, we assessed for changes in sleep cycle, breathing with ventilatory challenges, and arousal and anxiety-like behaviors. At each timepoint, PFF-injected mice exhibit increased baseline respiratory rate, indicating disrupted LC networks involved in the control of breathing. Further, PFF-mice demonstrate a hyperarousal phenotype. To identify underlying cellular mechanisms, we utilized whole-cell patch clamp recordings to measure intrinsic LC neuron properties. Recordings reveal altered LC neuronal properties, with a transient increase in firing that progressively declines, ultimately exhibiting hypoexcitability. Our findings of dysfunctional breathing, sleep-wake cycles, and arousal suggest that LC pathology and altered intrinsic LC properties may underlie non-motor symptoms in prodromal PD. This abstract was presented at the American Physiology Summit 2026 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.