Reversibility of Graft-Mediated Recovery: An Exploration of the Mechanisms behind Recovery of Motor Capability in Unilateral 6-OHDA Rats

At a preclinical level, stem cell therapy (SCT) is one of the most commonly investigated treatments for Parkinson’s disease (PD) due to the lack of long-term effectiveness in other treatments (e.g., L-DOPA) and the appeal of a regenerative approach to treating neurodegenerative disease. That being said, clinical research has shown that while SCT shows longer effect than alternative treatments in some cases, there is an issue with consistency of benefit as well as the gradual return of PD symptoms. Previous research of our lab has demonstrated that targeted stimulation of transplanted dopaminergic cells in coordination with behavior showed consistent benefit to animals that received this treatment, but this is an empirical finding. We cannot at this moment say why the stimulation worked—did the cells integrate with the host tissue and serve as an active driving force for motor capability, or did they alter the host tissue in some way (e.g., release of growth factors) that enabled the degenerating host tissue to regain function? To explore the plausibility of these possible mechanisms, we propose to repeat our previous optogenetic stimulation of transplants using LMO7, an excitatory luminopsin, which will be followed two days later by chemogenetic silencing of the graft using the non-CNO DREADD, KORD. Observation of the return or continued suppression of motor deficits, as measured by the swim test our lab developed for the unilateral 6-OHDA model and the CatWalk XT, will provide important clues as to how transplanted dopaminergic cells mediate behavioral recovery following stimulation.