title: Reconsidering the role of glial cells in chronic stress-induced dopaminergic neurons loss within the substantia nigra? Friend or foe?
abstract: Exposure to psychological stress is known to seriously disrupt the operation of the substantia nigra (SN) and may in fact initiate the loss of dopaminergic neurons within the SN. In this study, we aimed to investigate how chronic stress modified the SN in adult male mice. Using a paradigm of repeated restraint stress (an average of 20h per week for 6weeks), we examined changes within the SN using western blotting and immunohistochemistry. We demonstrated that chronic stress was associated with a clear loss of dopaminergic neurons within the SN. The loss of dopaminergic neurons was accompanied by higher levels of oxidative stress damage, indexed by levels of protein carbonylation and strong suppression of both microglial and astrocytic responses. In addition, we demonstrated for the first time, that chronic stress alone enhanced the aggregation of α-synuclein into the insoluble protein fraction. These results indicate that chronic stress triggered loss of dopaminergic neurons by increasing oxidative stress, suppressing glial neuroprotective functions and enhancing the aggregation of the neurotoxic protein, α-synuclein. Collectively, these results reinforce the negative effects of chronic stress on the viability of dopaminergic cells within the SN.
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; NHMRC Centre of Research Excellence Stroke Rehabilitation and Brain Recovery, Heidelberg, VIC, Australia.
authors.forename: Lin Kooi
authors.initials: LK
authors.lastname: Ong
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors.forename: Zidan
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors.forename: Murielle
authors.initials: M
authors.lastname: Kluge
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Clifford
authors.initials: C
authors.lastname: TeBay
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zalewska
authors.affiliation: Hunter Medical Research Institute, Newcastle, NSW, Australia; School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Brain and Mental Health Research, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
authors.affiliation: School of Electrical Engineering and Computer Science, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Johnson
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; NHMRC Centre of Research Excellence Stroke Rehabilitation and Brain Recovery, Heidelberg, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; NHMRC Centre of Research Excellence Stroke Rehabilitation and Brain Recovery, Heidelberg, VIC, Australia. Electronic address: rohan.walker@newcastle.edu.au.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Walker
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein
keywords: Astrocytes; Chronic stress; Microglia; Neurodegeneration; Oxidative stress; Substantia nigra; α-Synuclein