Dopamine neuron stimulation induces context-dependent abnormal involuntary movements in healthy rats

Julia Hunter; Alexandra Bova; Andrew Stevens; Daniel K Leventhal

doi:10.1016/j.isci.2022.103974

Dopamine neuron stimulation induces context-dependent abnormal involuntary movements in healthy rats

iScience. 2022 Feb 22;25(3):103974. doi: 10.1016/j.isci.2022.103974. eCollection 2022 Mar 18.

Authors

Julia Hunter¹, Alexandra Bova², Andrew Stevens¹, Daniel K Leventhal^{1

3

4

5}

Affiliations

¹ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
² Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Parkinson Disease Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Neurology, VA Ann Arbor Health System, Ann Arbor, MI 48105, USA.

Abstract

With continued levodopa treatment, most patients with Parkinson disease (PD) develop levodopa-induced dyskinesias (LIDs)-abnormal involuntary movements (AIMs) characterized primarily by chorea. Clinically, LIDs depend on nigrostriatal degeneration and sensitization to repeated levodopa doses. However, the degree of dopamine denervation is correlated with levodopa-induced changes in striatal dopamine. Therefore, pulsatile dopamine release may induce AIMs independently of nigrostriatal degeneration. We optogenetically stimulated dopamine neurons in healthy rats as they engaged in skilled reaching. Repeated stimulation induced progressive AIMs whose severity was modified by behavioral context. AIMs were milder with stimulation during reaches, and more severe if stimulation occurred between reaches. Despite gradual induction, AIMs recurred immediately with subsequent dopamine neuron stimulation. Thus, nigrostriatal denervation is not necessary for fluctuating striatal dopamine to induce AIMs, and behavioral context modulates AIM expression. Furthermore, pulsatile dopamine release induces persistent changes in motor circuits that are revealed by subsequent dopamine neuron activation in appropriate contexts.

Keywords: Behavioral neuroscience; Biological sciences; Cellular neuroscience.

Abstract

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