Abstract
BackgroundThe 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.MethodsSystemic 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.ResultsIn 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.ConclusionsOur 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.
Highlights
The neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson’s disease is much less understood than classical motor symptoms
Partial loss of Centrallyprojecting Edinger–Westphal nucleus (EWcp)/urocortin 1 containing (UCN1) neurons in the rotenone model is associated with depression‐like phenotype and increased anxiety Rotarod performance test (RPT) revealed that rotenone-treated rats were practically unable to stay on the rotating rod (1.75 ± 1.25 s) in contrast to vehicle-treated animals which ran 68.83 ± 15.37 s (Fig. 1A t(22) = 4.34; p = 0.002)
open field test (OFT) revealed that parkinsonian rats spent more time (Fig. 1C, t(21) = 2.36; p = 0.027) in the periphery suggesting increased level of anxiety
Summary
The neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson’s disease is much less understood than classical motor symptoms. Parkinson’s disease (PD) is characterized by classic motor symptoms including rigor, tremor and bradykinesia attributed to neurodegeneration in the substantia nigra pars compacta (SNpc) and consequent loss of striatal dopaminergic afferentation [1]. While the main neuropathological hallmarks of motor symptoms such as Lewy body (LB) and Lewy neurite accumulation as well as nigral neurodegeneration are relatively well-investigated [1], much less knowledge has collected explaining the non-motor psychiatric symptoms. Anxiety disorders as well as major depression have been linked with altered noradrenergic, serotonergic and dopaminergic neurotransmission [3], but the underlying neuropathology of PD-associated mood disorders is poorly understood. The currently available pharmacotherapeutic strategies sharing the goal to increase serotonin (5-HT) and/or norepinephrine levels in the brain, provide limited efficacy [4]
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