Chemogenetic Modulation of Striatal Cholinergic Interneurons in DYT1 Dystonia
Abstract
Dystonia is a movement disorder characterized by twisting, repetitive movements, or abnormal postures. Dystonia is caused by many reasons: brain injury, stroke, genetically, sporadically, or by other diseases, such as Parkinson’s or Huntington’s disease, or drug side effects. Military members have an increased risk of traumatic brain injury and developing dystonia during both the combat operations and training period. Moreover, focal task-specific dystonia hand dystonia also occurs in military members. It is often called by different names based on the causal motor tasks, for example, writer’s cramp, typist’s cramp, computer operator’s cramp, and musician’s dystonia. In the military, it also occurs in rowers, rifle shooters, and pistol shooters. It also occurs in dart throwers, long-distance runners, table tennis players, and golfers. Focal task-specific dystonia hand dystonia is triggered by repeated specific motor tasks. Moreover, embouchure dystonia is one of the focal task-specific face dystonias, which is a lip, tongue, jaw, and/or facial muscle movement disorder caused by extensive training of musicians, such as military band woodwind and brass players. Although the brain injury model may seem more relevant to military members who have dystonic symptoms due to brain injury, it is difficult to reproduce the same symptoms in the experimental model. The advantage of the genetic dystonia model is the stability and reproducibility of the motor symptoms, which is very useful to analyze the detailed disease mechanism and to develop novel therapeutics. Although anti-cholinergic drug targeting the cholinergic system has been widely used to treat dystonia patients, it is not well understood how activation or inhibition of cholinergic neurons affects the posture and motor performance. The broad, long-term goals are understanding the cholinergic neuron’s activity in dystonia and developing novel therapeutics. This project will employ the chemogenetic technology to elucidate the direct relationship between the cholinergic neuronal activity and motor symptoms by modulating the neuronal activity. Finding the optimal drug concentration to cure the motor deficits in the mutant mice is a goal of this project. The stimulating and inhibiting modulations in the mutant mice will provide a critical insight toward the direction of developing novel therapeutics directly targeting the cholinergic neuronal activity. If modulation of the cholinergic neuronal activity has a cure effect in the dystonia mouse model, it will suggest that developing a drug directly targeting the cholinergic neuronal activity can be a novel approach for dystonia. The findings produced by this study will be useful to treat not only DYT1 dystonia patients, but also other dystonia patients working in the military office and field, such as those with writer’s cramp, typist’s cramp, computer operator’s cramp, rowers, and other dystonia patients in rifle and pistol shooters, as well as embouchure dystonia patients, injured military members, Veterans, and other family members who have dystonic symptoms by other reasons.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810099
Entities
People
- Fumiaki Yokoi
Organizations
- United States Army
- University of Florida