Objective/Rationale:
Altered neural activity in the subthalamic nucleus (STN) is believed to be key to Parkinson’s disease. Accordingly, deep-brain stimulation (DBS) delivered to the STN is a common treatment. Two drawbacks of DBS are that it requires a chronic implant and that stimulation is typically continuous. We are developing new methods to alter STN activity selectively by simple peripheral injection. In one version of our approach, changes in STN activity are imposed only when these neurons demonstrate maladaptive activity patterns, allowing normal function to continue uninterrupted otherwise.
Project Description:
In our strategy, bioluminescence is used to drive optogenetic reactions (BL-OG). ‘Optogenetics’ refers to the process of making cells sensitive to light, which provides a means for precise control of neural activity. Typically, the light used to control neurons is provided through a fiber optic implanted in the brain. ‘Bioluminescence’ is a process common in nature (e.g. in fireflies) by which a chemical reaction between an enzyme and a small molecule leads to light production. In the current project, we will express bioluminescent enzymes and optogenetic sensors in STN neurons. We will administer the appropriate small molecules peripherally
In one of the applications of the strategy we are developing, light production requires not only an appropriate small molecule, but also a high-level of ongoing neural bursting. The ‘burst’ activity pattern (a brief period of high frequency activity) shows over-expression in the STN in Parkinson’s patients, which is thought to be a cause of key symptoms. Our combined small molecule and ‘burst’ approach will allow us to interrupt ongoing activity by producing light only when aberrantly high levels of bursting are present.
We will conduct initial studies in reduced preparations and then transfer the strategies proved most effective for control of STN neurons to in vivo testing in behaving pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In all forms of the BL-OG approach we are testing, this method provides a minimally-invasive and biophysically-precise means of controlling this key clinical target, features that represent a significant potential advance over current DBS treatment strategies.
In a key experiment, we predict that STN control will only be triggered when aberrantly high levels of bursting are observed. This novel ‘homeostatic’ regulation can allow STN activity to proceed uninterrupted except when it shows this maladaptive activity pattern, thereby maintaining as much of the normal function of this structure as possible while still intervening as necessary.
Anticipated Outcome:
We will determine, in reduced preparations and in behaving models, the optimal combinations of BL-OG for effectively altering STN activity patterns, to prevent these neurons from showing sustained bursting or oscillations characteristic of Parkinson’s disease and believed to be causal in its symptoms. Prior studies indicate that the key elements of BL-OG are safe for chronic use. As such, success of this study could provide a specific road map for ultimate application in clinically relevant models and humans.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Final Outcome
This project achieved many of its desired goals. First, we achieved selective bioluminescent optogenetic (BL-OG) control over basal ganglia targets including the subthalamic nucleus and substantia nigra neurons. Second, we made key progress in a variety of key innovations (molecular engineering of BL-OG molecules and methodological details of substrate administration). We did not yet achieve activity-dependent control of nucleus behavior, but have continued these efforts since grant completion and believe they may be applicable to Parkinson’s treatment and related research within the year.