Objective: To demonstrate feasibility and proof-of-concept for a bilateral rat model of Parkinson’s disease (PD) undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN) using optogenetics.

Background: STN-DBS alleviates crucial motor symptoms in PD, but may worsen some motor and non-motor manifestations. The neurobiological underpinnings of these effects remain unclear. Mechanistic investigations in humans are confounded by variations in anatomy, disease severity and duration and medication. An animal model allows control of these factors and virally targeted optogenetics enables the selective activation of specific STN output pathways to determine their role in DBS.  We implemented an optogenetic approach to investigate the neurobiology of specific STN efferents in DBS-related motor improvements in a rat model of PD.

Method: Male Sprague-Dawley rats (N=4) underwent stereotaxic surgery to bilaterally infuse 6OHDA into the dorsolateral striatum (7.5 ug/2uL), inject a viral vector to the STN (resulting in expression of an excitatory opsin protein in glutamatergic neurons), and to place STN optic fibers. Behavioral assessments were performed before and after surgery, after sham DBS (Day 21-28 post surgery), and after DBS (Day 28-35). For DBS, light was bilaterally delivered to STN (130Hz pulse trains) for 30min to engage opsin-expressing neurons. No light was delivered in sham session. PD-like akinesia was measured using a forelimb stepping task, and spontaneous motor behavior was quantified.

Results: 6OHDA decreased tyrosine hydroxylase in the dorsolateral striatum.  Stepping number decreased and distance to first step increased, while spontaneous motor behavior was unchanged, confirming a mild parkinsonian phenotype. Excitatory opsin proteins were highly expressed in STN efferent sites. DBS transiently restored forelimb stepping, but did not alter spontaneous motor activity.  With six repeated DBS sessions, oral dyskinesias emerged in two animals.

Conclusion: STN-DBS in PD-like rats transiently improved motor deficits. The outcomes were consistent with the rapid on- and offset of STN-DBS motor benefits in humans. Ongoing investigations with this model are interrogating the circuit and non-motor effects of chronic, repeated STN-DBS.

Supported in part by NIH NS127037. We appreciate the intellectual contributions of Amanda Persons, PhD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/optogenetic-deep-brain-stimulation-rescues-motor-behavior-in-a-rat-model-of-mild-parkinsons-disease/