Deconstruction and Control of Neural Circuits in Posttraumatic Epilepsy
Abstract
Post-traumatic epilepsy results from traumatic brain injury. This disorder is a major concern for our military forces and Veterans due to the increasing incidence of head injuries suffered in battle during the Global War on Terror. In particular, 440,000 Soldiers from the Iraq and Afghanistan wars have had or will experience traumatic brain injury, and more than 100,000 are expected to develop post-traumatic epilepsy. This disorder is often resistant to traditional treatments, which also have major side effects. The cellular origin of post-traumatic epilepsy remains unknown, and there is no cure. The type of epilepsy that develops after brain injuries is thought to result from changes in the connections among neurons in a brain area called the cortex. The cortex is the outermost region of the brain and is thus almost always involved in the primary brain injury. However, brain regions far from the initial injury may be damaged during the slow process that leads to post-traumatic epilepsy, which typically begins to occur weeks after the injury. For example, the thalamus is a deep brain structure whose cells connect to the cortex. Accumulating evidence implicates the thalamus in epilepsy resulting from cortical lesions. There are several reasons to believe that the thalamus is important for the development of post-traumatic epilepsy. These patients often have problems with attention, sensation, perception, consciousness, and sleep, which are all functions of the thalamus. Increases in the number of inflammatory molecules are seen in the thalamus after traumatic brain injury, suggesting that it has been damaged. Brain cells in the thalamus die or become abnormal after injury to the cortex, and the electrical activity of the thalamus also changes. Finally, suppressing activity in brain cells of the thalamus can control seizures resulting from cortical damage, without causing side effects. Our proposal takes a three-step approach to testing the importance of the thalamus in post-traumatic epilepsy, using a mouse model. First, we will focus on identifying the "hot spots" or regions of the brain that are abnormally active after traumatic brain injury. We will also use modern genetic tools that allow us to manipulate brain cell activity to determine which types of cells disrupt seizures when their activity is silenced. Second, we will focus on understanding whether the inflammatory response is responsible for generating these hot spots. Previous research has shown that inflammatory markers are increased in the brains of patients after traumatic brain injury and that these markers are expressed in hot spots in other forms of epilepsy. We hypothesize that changes initiated by the inflammation in the brain can lead to changes in its electrical activity, which can then lead to epilepsy. We will manipulate the expression of these markers through drugs and genetic tools to determine how they are involved in post-traumatic epilepsy. Third, we will test how restoring inhibitory cells, via transplantation, might prevent post-traumatic epilepsy, as various groups have successfully done for other types of epilepsy. We propose to improve upon this strategy by expressing specific tools within these inhibitory brain cells that will allow us to track and manipulate their activity with light. Briefly, the modified cells will be transplanted into the hot spots. We will determine if these transplanted cells integrate into the existing brain cell network, and we will also selectively manipulate their activity with light to determine if increasing their activity can stop seizures. As an important part of our preclinical study, we will transplant inhibitory cells of human origin, as these are most relevant for therapeutic intervention in human patients. The long-term goal of these studies is to develop strategies to control seizures and prevent the development of epilepsy with minimal side effects, which will greatly
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610576
Entities
People
- Jeanne T. Paz
Organizations
- The J. David Gladstone Institutes
- United States Army