Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model

• Published in: Neurobiology of disease Vol. 156; p. 105404
• Main Authors: Fauser, Mareike, Ricken, Manuel, Markert, Franz, Weis, Nikolai, Schmitt, Oliver, Gimsa, Jan, Winter, Christine, Badstübner-Meeske, Kathrin, Storch, Alexander
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2021; Elsevier
• Subjects: 6-hydroxydopamine; Animals; Corpus Striatum - metabolism; Deep brain stimulation; Deep Brain Stimulation - methods; Dopaminergic neurons; Dopaminergic Neurons - metabolism; Female; Limbic System - metabolism; Male; Mesolimbic system; Neurorestoration; Nigrostriatal system; Oxidopamine - toxicity; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - therapy; Rats; Rats, Wistar; Substantia Nigra - metabolism; Subthalamic nucleus; Subthalamic Nucleus - metabolism; Tyrosine 3-Monooxygenase - metabolism; Ventral tegmental area; Ventral Tegmental Area - metabolism; Dopaminergic neurons; 6-hydroxydopamine; Parkinson's disease; Neurorestoration; Deep brain stimulation; Mesolimbic system; Subthalamic nucleus; Ventral tegmental area; Nigrostriatal system
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105404

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. The delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. We applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. After 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9–3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. Our data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease. [Display omitted] •Effects of chronic STN-DBS (3 to 6 weeks) were studied in stable hemiparkinson rats.•STN-DBS augments mesolimbic dopaminergic neurons and their projections.•STN-DBS dopaminergic plasticity effects outlasts the stimulation period for 3 weeks.•STN-DBS induces sustained neurorestorative effects in midbrain dopaminergic systems.•DBS neurorestorative effects are specific for STN-DBS and not observed in EPN-DBS.