Understanding what's behind the nervous system's adaptive responses in order to correct the effects of chronic drug use and other stressors
THE PROBLEM
Chronic drug exposures and chronic stressors in general, such as brain injury or maternal deprivation in neonates, induce long-term adaptive changes in the sensitivity of the nervous system as it seeks to maintain normal neuronal function in the face of the altered properties induced by the drug or stressor. Some of these adaptations are beneficial but others may be deleterious, particularly after the inducing drug or stressor has been removed. The mechanisms underlying these adaptations are still poorly understood. It is our underlying hypothesis that a better understanding of the processes underlying these adaptive responses of the nervous system will lead to the identification of novel therapeutic approaches to correct the functional deficits resulting from chronic drug or stressor exposure.
"Over many years we have used the techniques of neurochemistry and immunohistochemistry to identify adaptations induced by chronic drug or stressor exposure."
OUR APPROACH
Over many years we have used the techniques of neurochemistry and immunohistochemistry to identify changes in the expression and function of neuropeptides, neurotransmitters, their receptors, and down-stream signaling proteins, and the cellular locations of their expression in the central nervous system, to identify adaptations induced by chronic drug or stressor exposure. More recently, we have worked collaboratively with many labs, and in particular with the laboratory of Dr. Fereshteh Nugent at USU, to explore correlations between changes in neuropeptide, receptor, or signaling molecule expression and functional changes measured by electrophysiological or behavioral approaches.
RESEARCH DISCOVERIES
Early studies from the lab showed that chronic opiate drug exposures altered receptor signaling, and could be prevented by protein synthesis inhibitors. Many years later we returned to evaluating synaptic changes after morphine treatment, showing that such changes could be prevented by inhibition of histone deacetylase (HDAC) a regulator of ep[igenetic changes in gene expression. In collaboration with Dr. Nugent, we also showed that synaptic changes in discrete brain nuclei that could be prevented by HDAC inhibitors were also induced by severel early life stress, suggesting similarities in the induced adaptive responses between the effects of drug treatments and severe stress exposure. We have also conducted studies on neural injury, showing roles for neuropeptides including the opioid peptides, dynorphin and nociceptin- orphanin FQ in facilitating neural damage. In another series of studies we have initiated an analysis of changes in brain and circulating lipids following brain injury, seeking to identify both mechanisms of injury and potential biomarkers predicting the severity of the injury and the long-term consequences of the altered lipid expression.