Patterned Stimulation of the Chrimson Opsin in Glutamatergic Motor Thalamus Neurons Improves Forelimb Akinesia in Parkinsonian Rats

• Published in: Neuroscience Vol. 507; pp. 64 - 78
• Main Authors: Kip, E., Bentall, L., Underwood, C.F., Hughes, S.M., Parr-Brownlie, L.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.12.2022
• Subjects: 6-hydroxydopamine; AAV5; Akinesia; Animals; Chrimson; Complex patterns; Deep Brain Stimulation; Forelimb; Humans; Motor Neurons; Motor thalamus stimulation; Opsins; Oxidopamine - toxicity; Parkinson Disease; Rats; Thalamus - physiology; BG; ChR2; 6-OHDA; LV; STN; DPX; Complex patterns; GFP; DBS; ANOVA; Motor thalamus stimulation; SN; Mthal; PBS; AAV5; GPi; MCx; Akinesia; DAB; TBS; SNpc; DAPI; VA; PBS-T; 6-hydroxydopamine; PB; CaMKII; PD; TH; AAV; VL; VM; SEM; Chrimson
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2022.10.026

[Display omitted] •Impaired motor thalamus and cortex activity causes parkinsonian movement deficits.•Examined utility of optogenetic stimulation with the red-shifted opsin, Chrimson.•Stimulated Chrimson in motor thalamus glutamatergic neurons in parkinsonian rats.•Akinesia was improved by low frequency stimulation with complex and tonic patterns.•Viability of optogenetic stimulation in large brains is improved with Chrimson. Parkinson’s disease (PD) is a motor disorder charactertised by altered neural activity throughout the basal ganglia-thalamocortical circuit. Electrical deep brain stimulation (DBS) is efficacious in alleviating motor symptoms, but has several notable side-effects, most likely reflecting the non-specific nature of electrical stimulation and/or the brain regions targeted. We determined whether specific optogenetic activation of glutamatergic motor thalamus (Mthal) neurons alleviated forelimb akinesia in a chronic rat model of PD. Parkinsonian rats (unilateral 6-hydroxydopamine injection) were injected with an adeno-associated viral vector (AAV5-CaMKII-Chrimson-GFP) to transduce glutamatergic Mthal neurons with the red-shifted Chrimson opsin. Optogenetic stimulation with orange light at 15 Hz tonic and a physiological pattern, previously recorded from a Mthal neuron in a control rat, significantly increased forelimb use in the reaching test (p < 0.01). Orange light theta burst stimulation, 15 Hz and control reaching patterns significantly reduced akinesia (p < 0.0001) assessed by the step test. In contrast, forelimb use in the cylinder test was unaffected by orange light stimulation with any pattern. Blue light (control) stimulation failed to alter behaviours. Activation of Chrimson using complex patterns in the Mthal may be an alternative treatment to recover movement in PD. These vector and opsin changes are important steps towards translating optogenetic stimulation to humans.