Circuit-Based Approach to Understanding Bipolar Disorder

This pilot grant tests the hypothesis that disruptions in corticothalamic interactions during critical periods of development can alter the circuit between prefrontal cortex, thalamus and limbic regions that is important for modulation of mood in disorders such as bipolar disorder (BD).  Neuroimaging studies of BD patients, especially in children and adolescents, have implicated abnormal modulation between the prefrontal cortex (PFC) and limbic regions, including the amygdala. Among the neuronal circuits that can potentially regulate interactions between the prefrontal cortex and amygdala is the thalamus. Supporting this idea are clinical case reports describing patients with ischemic lesions in thalamus presenting with acute manic-depressive symptoms or pure mania.  We have recently uncovered an important role for cortical feedback on development of feed-forward projections onto thalamus. Our findings suggest that local disruption in synaptic microcircuits could have global effects throughout the brain. Aberrant cortical feedback can alter feed-forward development and thus amplify the effects of an initially focal abnormality.  Here we will test the hypothesis that aberrant feedback from prefrontal cortex during developmental periods of enhanced plasticity could alter the connectivity of inputs from amygdala to thalamus.  We plan to characterize interactions between the mouse prefrontal cortex, thalamus and amygdala during development, and assess the response of these circuits to discrete cortical perturbations over normal development.