Molecular Codes for the Establishment of Functionally Segregated Dopaminergic Circuits

PROJECT SUMMARY Dopamine (DA) is important for many behaviors such as motivation, learning, and movement. Malfunction of DA signaling is related to various psychiatric and motor symptoms, and DA-related drugs are commonly used to treat schizophrenia, ADHD, OCD, autism, personality disorders, and mood disorders. Although DA regulates various behaviors, it had been believed that the role of DA neurons is uniform: to signal "reward prediction error" (RPE), the discrepancy between actual and predicted reward value. Recently however, we and others showed that DA neurons projecting to different regions in the striatum exhibit distinct properties and serve distinct functions. We found that DA in the anterior striatum (AS), central and posterior striatum (CS/PS), and `tail' of the striatum (TS) signal canonical RPE, regulate the execution of skills, or signal threat prediction error, respectively. Therefore, dopaminergic projections from the midbrain to the AS, CS/PS, and TS must be differentially and precisely established for them to regulate our brain functions properly. However, the manner and molecular mechanisms by which specific dopaminergic connections are established in the striatum are unknown. To address this question, we have searched for synaptic, homophilic cell-adhesion molecules that are differentially expressed in the AS, CS/PS, and TS. We identified that three Protocadherins (PCDHs), PCDH17, PCDH10, and PCDH19, are selectively expressed in the AS, CS/PS, or TS, respectively, during development and in adults. Furthermore, in the midbrain, PCDH17, 10, and 19 are expressed by DA neurons projecting to the AS, CS/PS, or TS, respectively. Based on these expression patterns, we hypothesize that PCDH17, 10, and 19 are the molecular codes for the AS-, CS/PS-, and TS-projecting DA neurons, respectively, and that they play critical roles for the establishment of functionally segregated DA circuits. To test these ideas we have generated novel mouse lines in which Cre is expressed under the Pcdh promoters, and constitutive (null) and conditional knockout (KO) mice for each of the three PCDHs. Using these mouse lines, we propose to: Aim 1: Determine whether PCDH17, 10, and 19 are the molecular codes for functionally segregated DA neurons in adults. Aim 2: Investigate the effects of inactivation and activation of PCDH-expressing DA neurons during various stages of development. Aim 3: Examine the role of PCDH proteins in the establishment of specific DA connections. We will use interdisciplinary approaches with molecular/cell biological, histological, mouse genetic, electron microscopic, electrophysiological, in vivo recording/imaging, and behavioral techniques to address these aims. Our work will molecularly define functionally distinct DA circuits and reveal how specific DA circuits establish in the mammalian brain. PCDH17/10/19 are implicated in different disorders: PCDH17 in mood disorders and schizophrenia, PCDH10 in autism and OCD, and PCDH19 in epilepsy and personality disorders. Thus, our study may also provide a link between specific DA circuits to certain disorders and suggest novel strategies to treat these devastating disorders.