Effect of Intrastriatal 6-OHDA Lesions on Extrastriatal Brain Structures in the Mouse

Abstract

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.

A Cortical Pathogenic Theory of Parkinson’s Disease

“…Non-invasive brain stimulation techniques, on the other hand, perturb cortical circuits to induce long-lasting plasticity that resembles the long-term potentiation and depression (LTP/LTD) of synaptic strength observed in animal models (Hallett, 2007;Polanía et al, 2018). In highly asymmetric PD patients, the symptomatic motor cortex is characterized by a loss of intracortical inhibition (Kojovic et al, 2012(Kojovic et al, , 2015, possibly a compensatory mechanism (Blesa et al, 2017), and a loss of LTP/LTD-like plasticity induced by non-invasive brain stimulation techniques (Kishore et al, 2012;Kojovic et al, 2012Kojovic et al, , 2015, which is consistent with cortical findings obtained in animal models of dopamine depletion (Paillé et al, 2010;Hsieh et al, 2015;Guo et al, 2015;Schirinzi et al, 2016;Becker et al, 2018). Conversely, the pre-symptomatic motor cortex exhibits minimal if any alterations of corticospinal and intracortical excitability (Kojovic et al, 2012(Kojovic et al, , 2015, but important alterations of cortical plasticity.…”

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy

“…The most vulnerable region in PD is considered to be the nigrostriatal axis and only a very limited number of studies have described PD damage progression in regions such as cerebral cortex (Cassarino et al, 1997;Fahn, 2003;Garcia-Esparcia et al, 2018;Becker et al, 2018), which is essential to address the development of new and more efficient therapeutic strategies.…”

Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease

“…Microglia reactivity was estimated by quantifying cell morphology. To this end, a ramification index (RI) was calculated as published previously by our group [35]. The RI is mathematically defined as: RI = maximum cell projection area (A p )/cell area (A c ).…”

“…In contrast, in activated microglial cells or macrophages, the cell area and the maximum projection area are almost identical. Consequently, a fully activated microglia cell takes an RI value close to one [35].…”