Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys

• Type of Material: Article
• Authors: Gunasingh Jeyaraj Masilamoni, Emory University; Olivia Groover, Emory University; Yoland Smith, Emory University
• Language: English
• Date: 2017-04-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2016.12.025
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 100
• Start Page: 9
• End Page: 18
• Grant/Funding Information: This work was supported by NIH/ORIP grant P51-OD011132 to the Yerkes National Primate Research Center, a grant from the National Parkinson Foundation and the NIH/NINDS grant P50-NS071669 (Udall Center grant).
• Keywords: HORSERADISH-PEROXIDASE; Neurosciences; Ultrastructure; LOCUS-CERULEUS LESIONS; Neurosciences & Neurology; Science & Technology; STRIATAL DOPAMINE; Parkinson's disease; INFLAMMATORY RESPONSES; SUBSTANTIA-NIGRA; Locus coeruleus; TEGMENTAL AREA; Noradrenaline; Substantia nigra; CHOLINERGIC NEURONS; Dopamine beta hydroxylase; OXIDATIVE STRESS; DISEASE; Norepinephrine; BETA-HYDROXYLASE; Ventral tegmental area; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Toxicology; Health Sciences, Medicine and Surgery

Abstract

There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30–40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~ 50–70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.