Dysfunctional dorsal raphe dopaminergic neurons and locus coeruleus noradrenergic neurons cause anxiety and depression in a Parkinson’s disease mouse model

Abstract

Abstract Parkinson's disease is a progressive neurodegenerative disorder whose symptoms appear in a longitudinal temporal pattern along the neuropathological burden. Before motor impairment, most patients suffer anxiety/depression, the most common and disabling emotional comorbidities. The anatomical and functional bases of these comorbidities are not well established, though some studies find that the dorsal raphe (DRN) and locus coeruleus (LC) nuclei are affected by Lewy pathology at early stages of the disease when affective symptoms appear. To establish the involvement of the DRN and LC in anxiety/depression, we use a progressive mouse model that accumulates pathological human alpha-synuclein under the TH promoter in dopaminergic and noradrenergic neurons. Molecular, neurophysiological, and behavioral investigations show that such accumulation in DRN dopaminergic neurons and LC noradrenergic neurons progressively alters neuronal integrity and catecholamine signaling in the target areas, the bed nucleus of stria terminalis (BNST) and central amygdala (CeA). The onset of these neuronal and circuit dysfunctions is directly linked to the appearance of anxiety and depression-like behaviors in this model that recapitulate the emotional symptoms present at the early stages of Parkinson’s disease.