Dopaminergic Modulation of Orbitofrontal Cortex Neuronal Activity In Vivo

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pittsburgh
Investigators Name
McCracken, Clinton B., PhD

Tourette’s syndrome (TS) is a complex disorder that negatively affects the lives of thousands of people worldwide. Studies to date suggest that TS is associated with dysfunction along particular brain processing loops, and specifically, circuits involving the frontal cortex, basal ganglia, and thalamus. While the motor aspects of TS such as tics are relatively well known, evidence has begun to accumulate suggesting that TS has a substantial psychiatric component that likely involves functional deficits in the prefrontal sub-region of the brain, known as the orbitofrontal cortex (OFC). The OFC is critically involved in executive behavior, and plays a prominent role in response inhibition. Unfortunately, regulation of neuronal activity in the OFC is poorly understood, particularly in comparison to more medial prefrontal areas. Given the demonstrated role of the OFC in impulsive behaviors and its potential contribution to TS symptomatology, we plan to examine how OFC neuronal activity is modulated by inputs from different brain areas. Specifically, we will determine how spontaneous and evoked activity in the OFC is modulated by dopamine, a neurotransmitter known to be associated with many TS symptoms. In order to most effectively evaluate the effects of dopamine on OFC activity, we will employ a systems-oriented approach in anesthetized rats. We will examine how dopaminergic input from the ventral tegmental area (VTA) and excitatory projections from the mediodorsal thalamus interact to affect neuronal firing in the OFC. We also plan to combine electrical and chemical stimulation of these regions in combination with local or systemic administration of drugs to better understand the neurochemical specificity of the observed effects on OFC neurons. These studies have a number of clinical implications. They may further our understanding of frontal cortical function by enabling comparison between processing in different prefrontal subregions, and may shed light on the basic physiology of a neural circuit thought to underlie certain pathologies seen in TS. This in turn will hopefully aid in the development of more efficacious treatments to combat this debilitating disorder. Clinton B. McCracken, Ph.D. University of Pittsburgh, Pittsburgh, PA Award: $40,000 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2008-2009