
만성적인 도파민 신경세포 과활성화는 실질적인 도파민 신경세포 퇴행을 유발하며, 이는 파킨슨병의 주요 특징인 흑질 도파민 신경세포의 선택적 취약성과 복측 피개 영역 신경세포의 상대적 내성을 재현한다.


coremsg

Parkinson’s disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

### Competing Interest Statement

The authors have declared no competing interest.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration

만성적인-중뇌-도파민-신경세포-과활성화가-선택적인-도파민-신경세포-퇴행을-유발한다


만성적인 중뇌 도파민 신경세포 과활성화가 선택적인 도파민 신경세포 퇴행을 유발한다
