Neurodegeneration in the centrally-projecting Edinger–Westphal nucleus contributes to the non-motor symptoms of Parkinson’s disease in the rat

Abstract

Background The neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson’s disease is much less understood than classical motor symptoms. Although, neurodegeneration of the Edinger–Westphal nucleus in human Parkinson’s disease is a known phenomenon, its possible significance in mood status has never been elucidated. In this work we aimed at investigating whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger–Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat. Methods Systemic chronic rotenone administration as well as targeted leptin–saporin-induced lesions of EWcp/UCN1 neurons were conducted. Rotarod, open field and sucrose preference tests were performed to assess motor performance and mood status. Multiple immunofluorescence combined with RNAscope were used to reveal the functional–morphological changes. Two-sample Student’s t test, Spearman’s rank correlation analysis and Mann–Whitney U tests were used for statistics. Results In the rotenone model, besides motor deficit, an anxious and depression-like phenotype was detected. Well-comparable neuron loss, cytoplasmic alpha-synuclein accumulation as well as astro- and microglial activation were observed both in the substantia nigra pars compacta and EWcp. Occasionally, UCN1-immunoreactive neuronal debris was observed in phagocytotic microglia. UCN1 peptide content of viable EWcp cells correlated with dopaminergic substantia nigra cell count. Importantly, other mood status-related dopaminergic (ventral tegmental area), serotonergic (dorsal and median raphe) and noradrenergic (locus ceruleus and A5 area) brainstem centers did not show remarkable morphological changes. Targeted partial selective EWcp/UCN1 neuron ablation induced similar mood status without motor symptoms. Conclusions Our findings collectively suggest that neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson’s disease in the rat.

Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway

“…The sucrose preference test (SPT), which serves as a means of assessing anhedonia responses in rats. The SPT was conducted as described previously with minor modifications [ 27 ]. Briefly, rats were placed individually in cages with two bottles of sucrose solution (1%, w/v) for an initial 24 h period followed by replacement of one of the bottles of sucrose solution with tap water for the second 24 h period.…”

Transient receptor potential ankyrin 1 ion channel expressed by the Edinger-Westphal nucleus contributes to stress adaptation in murine model of posttraumatic stress disorder

“…Our research team has been investigating the role of the EWcp in stress adaptation response and mood control ( Kozicz et al, 2001 ; Gaszner and Kozicz, 2003 ; Gaszner et al, 2004 ; Gaszner et al, 2007 , 2012 ; Rouwette et al, 2011 ; Kormos and Gaszner, 2013 ; Kormos et al, 2022 ; Ujvári et al, 2022 ). EWcp expresses urocortin 1 (UCN1) neuropeptide, which is a member of the corticotropin-releasing hormone (CRH) family.…”

Age-Dependent FOSB/ΔFOSB Response to Acute and Chronic Stress in the Extended Amygdala, Hypothalamic Paraventricular, Habenular, Centrally-Projecting Edinger-Westphal, and Dorsal Raphe Nuclei in Male Rats

“…They show FOS and FOSB/ΔFOSB neuronal activity in various acute and chronic stress models in rodents ( Gaszner et al, 2004 ; Turek and Ryabinin, 2005 ; Rouwette et al, 2011 ; Kormos et al, 2016 , 2022 ; Farkas et al, 2017 ; Kovács et al, 2018 ). The alteration of urocortinergic neuronal function affects mood status ( Ujvári et al, 2022 , for review, see Kozicz et al, 2011 ) and it is associated with suicide ( Kozicz et al, 2008 ).…”