Striatal Gene Expression and Behavioral Changes Driven by Hippocampal Stimulation:Regulation by Dopamine

Grant Type
Basic
Grant Year
1998
Institution Location
MO
Institution Organization Name
Washington University
Investigators Name
Bardgett, Mark, PhD

Evidence suggests that perturbations in the striatum, a brain region which regulates psychomotor function, may contribute to the pathophysiology of Tourette Syndrome. The striatum receives excitatory inputs from the hippocampus, and many studies have demonstrated that this brain region plays a key role in adaptive responses to new or novel stimuli. It is possible that overactivity in the hippocampus may generate inappropriate motor responses to specific stimuli, including stress, via its connections with the striatum, and contribute to the symptoms of Tourette Syndrome. Basic research aimed at characterizing the effects of hippocampal stimulation on striatal function may reveal important new insights into the causes of Tourette Syndrome. We have recently examined the effects of hippocampal stimulation on striatal function by studying: (1) locomotor activity in laboratory animals after hippocampal stimulation, and (2) the expression of immediate-early genes in striatal neurons after hippocampal stimulation. Immediate early genes are “turned on” or induced by intracellular messengers that are activated by neuronal stimulation. Neuronal immediate-early gene expression has been used to document regionally-specific patterns of neuronal activation in the brain and to determine which kinds of neurons respond to stimulation. Immediate-early genes can also activate a cascade of other genes, and this cascade has been implicated in long-term changes in neuronal plasticity. Our studies to date have shown that hippocampal stimulation in laboratory rats elevates locomotor activity and the expression of the immediate-early gene, c-fos, in neurons located in the ventral striatum. Moreover, these effects are prevented when the animals are treated with drugs that block dopamine receptors. These data suggest that hippocampal stimulation increases neuronal activation in the striatum and that this activation is associated with increased locomotor activity. Moreover, the effects of hippocampal stimulation on striatal gene expression and motor behavior appear to require dopamine. Using immediate-early gene expression as a marker of neuronal activity, the goal of the proposed studies is to further characterize the behavioral effects of hippocampal stimulation and registration of hippocampal signals in the striatum. In our first set of investigations, we will identify which kinds of striatal neurons are activated by hippocampal stimulation and their location. In other studies, we will test the effects of specific dopamine receptor antagonists and novel psychotherapeutic drugs on behavioral and genetic responses to hippocampal stimulation. The results should provide important basic information regarding the impact of hippocampal activity on striatal function and offer a unique contribution to our understanding of the pathophysiology of Tourette Syndrome and its treatment. Mark E. Bardgett, Ph.D. Washington University Medical School, St. Louis, MO Award: $38,529 Tourette Association of America Inc. – Research Grant Award 1998