4.7 Article

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

Journal

NEUROBIOLOGY OF DISEASE
Volume 156, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105404

Keywords

Deep brain stimulation; Subthalamic nucleus; Parkinson's disease; Ventral tegmental area; 6-hydroxydopamine; Dopaminergic neurons; Neurorestoration; Mesolimbic system; Nigrostriatal system

Categories

Funding

  1. Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Centre CRC 1270 Electrically Active Implants (DFG) [SFB 1270/1-299150580]
  2. CRC 1270 Electrically Active Implants (DFG) [SFB 1270/1-299150580]

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The study revealed that animals treated with STN-DBS had significantly increased numbers of dopamine neurons and fibers, potentially improving sensorimotor neglect. This therapy not only affected the nigrostriatal system, but also had a significant impact on the mesolimbic system.
Background: 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. Objective/hypothesis: 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. Methods: 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. Results: 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. Conclusions: 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.

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