Impulsive sensation seeking (ISS), the tendency and willingness to seek, and take risks for, novel and intense sensations and experiences is a characteristic feature of bipolar disorder (BD), particularly during manic episodes. High ISS often leads to risky decision-making and behaviors with deleterious consequences, including poor social and occupational function, injury, and even death. Identifying objective, neural markers of ISS would facilitate novel treatments for BD, perhaps through modulation of specific neuronal circuits. Work from our collaborators indicate a significant positive relationship between ISS and activity in the brain, especially in the left ventrolateral prefrontal cortex (vlPFC) to uncertain reward expectancy across unaffected and BD individuals, and a positive relationships among these measures and risky decision-making. Furthermore, pilot EEG data indicate a positive relationship between greater trait ISS and greater beta power (20-30Hz) within, and phase synchrony among, left vlPFC and other reward cortical regions during uncertain reward expectancy, using the same reward task as in the fMRI studies. While human fMRI and EEG studies can elucidate neurophysiological correlates of ISS and BD, only rodent studies can use invasive local field potential recordings (LFPs) to identify the precise neurophysiological mechanisms by which rodent homologs of high ISS and BD (Clock?19 mice, an experimental model with high ISS) predispose to risky decision making. Working closely with our collaborators, we have developed a novel reward/punishment expectancy task for mice, which mirrors the new task that we have been employing in the human studies described above. The development of this task will allow us to directly correlate reward expectancy with novelty seeking and risk taking behavior both in normal mice and Clock?19 mice, and determine the electrophysiological signatures across the brain in these animals during precise phases of this task. These studies will help inform the human work to determine the important circuits and frequencies of activity that should be targeted for future treatment of BD.
Bipolar disorder is a devastating disease. The current treatments are not effective in all people suffering from this disorder and many cause significant side effects. This proposal will help determine the underlying neuronal mechanisms that lead to impulsive sensation seeking and increased reward expectancy in bipolar disorder. This knowledge may be used to design future treatments that target the activity of specific neuronal pathways.