A/Professor Jared W. Young, USA : "Delineating potential mechanisms underlying bipolar disorder using cross-species testing"

Speaker: 

A/Professor Jared W. Young
Department of Psychiatry, University of California,  San Diego, USA

Title: "Delineating potential mechanisms underlying bipolar disorder using cross-species testing"

Abstract: Bipolar disorder (BD) is a life-long, life-threatening psychiatric condition affecting between 2-5% of the worlds’ population.  The difficulty of living with BD is exemplified by the fact that 1 in 3 sufferers will attempt suicide in their life.  Every BD treatment discovered to-date was done so serendipitously - in-part because the complexity of the disorder has precluded identifying its underlying mechanisms.  BD is a unique disorder wherein sufferers cycle between periods of depression or mania, with states of euthymia in between.  Mania is the cardinal feature of BD however, and is therefore primarily where researchers have focused attempts to uncover its underlying neurobiology.  To-date, the only clear signs that differentiate BD from healthy participants is through behavioral assessment.  We have therefore utilized a cross-species behavioral assessment approach to determine whether: 1) Explicit genetic and environmental manipulations recreate behavioral aspects of BD; and 2) To determine potential novel targeted therapeutics.
Our initial studies quantified exploratory behavior in BD patients in an acutely manic episode using the Behavioral Pattern Monitor (BPM).  These patients exhibited a unique pattern of exploration including hyperactivity, hyperexploratory behavior, and straighter line movements that were distinct from acutely ill patients with schizophrenia and healthy participants.  This pattern was recreated in mice that exhibited either genetically or pharmacologically targeted reduced function of dopamine transporters (DATs), but not mice administered the mixed DAT/norepinephrine transporter blocker amphetamine.  The predictive validity of these models were confirmed when chronic valproate and lithium remediated some but not all aspects of hyperexploration in these mice, in a pattern consistent with BD sufferers.  Furthermore, we demonstrated that both BD mania sufferers and mice with reduced DAT exhibit increased risk-taking in the Iowa Gambling Task and impaired attention in the 5-choice continuous performance test.  Throughout these studies we identified numerous potential treatments for BD as well as potential circuits underlying explicit deficits in behavior.  
Beyond mania however, we explored potential mechanisms underlying the ‘holy grail’ of BD research; uncovering the mechanism underlying the switch between states (depression and mania).  How the same brain could produce wildly different behavioral profiles has remained a mystery, but our recent studies demonstrate that a modest reduction in DAT, coupled with environmental influences (photoperiods reflecting altered seasons), recreated aspects of switching in mice.  These studies have revealed critical brain regions underlying switching between behavioral states in addition to potential mechanisms underlying depression and mania. 
These studies provide insight into the mechanisms underlying BD, both during mania, euthymia, depression, and cycling between states.  These studies also identify potential treatments targeted at such mechanisms.  Importantly however, these studies also provide a framework on the approach toward delineating neural mechanisms underlying psychiatric conditions and their potential treatments.