Intra-locus coeruleus LPS administration induces anxiety-like behavior, thermal hyperalgesia, and striatal lysosomal alterations: Relevance to Parkinson's disease.

Abstract

According to Braak's staging hypothesis, Parkinson's disease (PD) pathology may originate in extranigral regions, including the locus coeruleus (LC). In parallel, PD has been associated with lysosomal dysfunction. Here, we investigated whether intra-LC lipopolysaccharide (LPS) injection may produce behavioral alterations and lysosomal protein changes in the striatum and prefrontal cortex (PFC), regions critically implicated in PD pathology. Adult male Wistar rats received unilateral injections of saline or LPS (10 µg/2 µL) into the LC or striatum and were assessed for anxiety-like behavior, thermal hyperalgesia, and motor coordination. A separate cohort was sacrificed 15 days post-injection to assess lysosomal proteins (cathepsin D, β-glucocerebrosidase, Lysosomal Associated Membrane Protein 2 (LAMP2)) and α-synuclein (α-Syn). Intra-LC LPS induced anxiety-like behavior, reflected by reduced time spent in the center of the open field, and thermal hyperalgesia, as shown by shortened tail-flick latency, whereas intra-striatal LPS impaired locomotion and motor coordination, evidenced by reduced line crossings and decreased rotarod performance. Intra-LC but not intra-striatal LPS reduced LAMP2 levels in the striatum, while all other markers remained unchanged in both regions. These findings provide experimental support for Braak's hypothesis.