Research: Basal Ganglia Circuitry and Disorders


 

The basal ganglia make up a brain region involved in motor control, motor skill learning, reward learning, cognition, and emotion. D1- and D2-medium spiny neurons (MSNs) in the striatum have emerged as a central focus to unravel how the cortico-striatal-thalamo-cortical (CSTC) circuitry may regulate behaviors, and how dysfunction of the circuitry may lead to major neurological and psychiatric disorders and drug addiction. As a leading group in the molecular genetic analyses of D1- and D2-MSNs, the Yang lab previously performed the first gene expression profiling of purified D1- and D2-MSNs and in the last several years, we have made significant strides toward understanding how the new MSN-subtype-specific genes may regulate behaviors and how dysfunction of the circuit may lead to behavioral abnormalities reminiscent of those in neuropsychiatric disorders and drug addiction. Our laboratory was the first to apply fluorescence activated cell sorting (FACS) to purify genetically-labeled D1-MSNs and D2-MSNs for gene expression profiling, and identified dozens of novel genes that are differentially enriched in the two MSN cell types. Subsequent functional studies of these genes using knockout mice revealed critical roles of Ebf1 in the postnatal development of D1-MSNs, and D1-MSN-specific Gpr6 in regulating instrumental conditioning in mice.

 

More recently, our laboratory has been focusing on studying the striatal circuitry in opiate pathological rewards. The Mu Opioid Receptor (Oprm1) is necessary for all the physiological effects of opioids in vivo, including analgesia, reward and dependence. Since Oprm1 is broadly expressed in the brain, the neuronal substrates in which Oprm1 expression is critical to aspects of opioid effects remain unclear. We devised a novel conditional BAC transgene rescue strategy to demonstrate targeted re-expression of Oprm1 in a subset of striatal D1-MSNs in the striosome (which normally express Oprm1 and directly project to DA neurons) in Oprm1 knockout background can restore opiate reward, but not analgesia or withdrawal. Our study provides novel insights into striatal circuit-specific molecular mechanisms underlying opiate reward in vivo.

 


 

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