Effect of Intrastriatal 6-OHDA Lesions on Extrastriatal Brain Structures in the Mouse
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor and non-motor symptoms. The underlying pathology of non-motor symptoms is poorly understood. Discussed are pathological changes of extrastriatal brain structures. In this study, we characterized histopathological alterations of extrastriatal brain structures in the 6-hydroxydopamine (6-OHDA) PD animal model. Lesions were induced by unilateral stereotactic injections of 6-OHDA into the striatum or medial forebrain bundle of adult male mice. Loss of tyrosine hydroxylase positive (TH+) fibers as well as glia activation was quantified following stereological principles. Loss of dopaminergic innervation was further investigated by western-blotting. As expected, 6-OHDA injection into the nigrostriatal route induced retrograde degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), less so within the ventral tegmental area. Furthermore, we observed a region-specific drop of TH+ projection fiber density in distinct cortical regions. This pathology was most pronounced in the cingulate- and motor cortex, whereas the piriform cortex was just modestly affected. Loss of cortical TH+ fibers was not paralleled by microglia or astrocyte activation. Our results demonstrate that the loss of dopaminergic neurons within the substantia nigra pars compacta is paralleled by a cortical dopaminergic denervation in the 6-OHDA model. This model serves as a valuable tool to investigate mechanisms operant during cortical pathology in PD patients. Further studies are needed to understand why cortical dopaminergic innervation is lost in this model, and what functional consequence is associated with the observed denervation.
KeywordsParkinson’s disease 6-OHDA Nigrostriatal lesion Mouse Tyrosine hydroxylase Cerebral cortex
This study was supported by IZKF grants from the Faculty of Medicine (MK and ST). We thank Petra Ibold and Helga Helten for their valuable technical assistance.
Compliance with Ethical Standards
All procedures were conducted in accordance with local regulations and have been approved by the local Animal Commission (Iran and Rostock/Germany).
- 1.World Health Organization W (2006) Neurological disorders: public health challenges. World Health OrganizationGoogle Scholar
- 5.Blandini F, Levandis G, Bazzini E, Nappi G, Armentero M-T (2007) Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model. Eur J Neurosci 25(2):397–405. doi: 10.1111/j.1460-9568.2006.05285.x CrossRefPubMedGoogle Scholar
- 7.Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59(2):401–415. doi: 10.1016/0306-4522(94)90605-X CrossRefPubMedGoogle Scholar
- 9.Gravotta L, Gavrila AM, Hood S, Amir S (2011) Global depletion of dopamine using intracerebroventricular 6-hydroxydopamine injection disrupts normal circadian wheel-running patterns and PERIOD2 expression in the rat forebrain. J Mol Neurosci 45(2):162–171. doi: 10.1007/s12031-011-9520-8 CrossRefPubMedGoogle Scholar
- 10.Requejo C, Ruiz-Ortega JA, Bengoetxea H, Garcia-Blanco A, Herran E, Aristieta A, Igartua M, Pedraz JL et al (2016) Morphological changes in a severe model of Parkinson’s disease and its suitability to test the therapeutic effects of microencapsulated neurotrophic factors. Mol Neurobiol. doi: 10.1007/s12035-016-0244-1
- 21.Paxinos G, Franklin KBJ (2001) Mouse brain in stereotaxic coordinates, 2nd edn. Academic, San DiegoGoogle Scholar
- 29.Mangano EN, Peters S, Litteljohn D, So R, Bethune C, Bobyn J, Clarke M, Hayley S (2011) Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson’s disease. Neurobiol Dis 43(1):99–112. doi: 10.1016/j.nbd.2011.02.011 CrossRefPubMedGoogle Scholar
- 30.Li HP, Komuta Y, Kimura-Kuroda J, van Kuppevelt TH, Kawano H (2013) Roles of chondroitin sulfate and dermatan sulfate in the formation of a lesion scar and axonal regeneration after traumatic injury of the mouse brain. J Neurotrauma 30(5):413–425. doi: 10.1089/neu.2012.2513 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Alvarez-Fischer D, Henze C, Strenzke C, Westrich J, Ferger B, Höglinger GU, Oertel WH, Hartmann A (2008) Characterization of the striatal 6-OHDA model of Parkinson’s disease in wild type and α-synuclein-deleted mice. Exp Neurol 210(1):182–193. doi: 10.1016/j.Expneurol.2007.10.012 CrossRefPubMedGoogle Scholar
- 44.Anastasia A, Torre L, de Erausquin GA, Masco DH (2009) Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson’s disease. J Neurochem 109(3):755–765. doi: 10.1111/j.1471-4159.2009.06001.x CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Christopher L, Marras C, Duff-Canning S, Koshimori Y, Chen R, Boileau I, Segura B, Monchi O et al (2014) Combined insular and striatal dopamine dysfunction are associated with executive deficits in Parkinson’s disease with mild cognitive impairment. Brain 137(Pt 2):565–575. doi: 10.1093/brain/awt337 CrossRefPubMedGoogle Scholar
- 59.Spieles-Engemann AL, Behbehani MM, Collier TJ, Wohlgenant SL, Steece-Collier K, Paumier K, Daley BF, Gombash S et al (2010) Stimulation of the rat subthalamic nucleus is neuroprotective following significant nigral dopamine neuron loss. Neurobiol Dis 39(1):105–115. doi: 10.1016/j.nbd.2010.03.009 CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Lindenbach D, Conti MM, Ostock CY, Dupre KB, Bishop C (2015) Alterations in primary motor cortex neurotransmission and gene expression in hemi-Parkinsonian rats with drug-induced dyskinesia. Neuroscience. doi: 10.1016/j.neuroscience.2015.09.018
- 69.Guo L, Xiong H, Kim J-I, Wu Y-W, Lalchandani RR, Cui Y, Shu Y, Xu T et al (2015) Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson’s disease. Nat Neurosci 18(9):1299–1309. doi: 10.1038/nn.4082 http://www.nature.com/neuro/journal/v18/n9/abs/nn.4082.html#supplementary-information CrossRefPubMedPubMedCentralGoogle Scholar
- 74.Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ et al (2014) Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun 5:5245. doi: 10.1038/ncomms6245 CrossRefPubMedPubMedCentralGoogle Scholar