👤 Ryan D D Beveridge

Persistent neuroadaptations following chronic psychostimulant exposure include reduced striatal dopamine D2 receptor (D2R) levels. The signaling of D2Rs is initiated by Gαi/o proteins and terminated by regulator of G protein signaling (RGS) proteins. The purpose of this study is to examine the association of the drug taking behavior and gene expression profile of D2/D3Rs, and their associated signaling proteins in the ventral tegmental area (VTA) and nucleus accumbens (NAc) using a rodent model of amphetamine (AMPH) self-administration. Rats were allowed to self-administer AMPH (0.187 mg/kg/infusion for a maximum of 40 injections in 6h daily sessions) for 5 days during which rats showed an escalated rate of AMPH intake across days. AMPH self-administration induced profound brain region-dependent alterations of the targeted genes. There was a positive correlation of the messenger ribonucleic acid (mRNA) levels of RGS10 between the VTA and the NAc in the control animals, which was abolished by AMPH self-administration. AMPH self-administration also produced a negative correlation of the mRNA levels of RGS7 and RGS19 between the two brain regions, which was not present in the control group. Furthermore, AMPH taking behavior was associated with changes in certain gene expression levels. The mRNA levels of RGS2 and RGS4 in both the VTA and NAc were positively correlated with the rate of AMPH intake. Additionally, the rate of AMPH intake was also positively correlated with RGS10 and negatively correlated with RGS17 and the short form of D2Rs mRNA level in the VTA. Although there were significant changes in the mRNA levels of RGS7 and RGS8 in the NAc, none of these measures were correlated with the rate of AMPH intake. The present study suggested that short-term AMPH self-administration produced pronounced changes in the VTA that were more associated with AMPH taking behavior than changes in the NAc. Show less

Here, we identify coiled-coil domain-containing protein 13 (Ccdc13) in a genome-wide RNA interference screen for regulators of genome stability. We establish that Ccdc13 is a newly identified centriolar satellite protein that interacts with PCM1, Cep290 and pericentrin and prevents the accumulation of DNA damage during mitotic transit. Depletion of Ccdc13 results in the loss of microtubule organisation in a manner similar to PCM1 and Cep290 depletion, although Ccdc13 is not required for satellite integrity. We show that microtubule regrowth is enhanced in Ccdc13-depleted cells, but slowed in cells that overexpress Ccdc13. Furthermore, in serum-starved cells, Ccdc13 localises to the basal body, is required for primary cilia formation and promotes the localisation of the ciliopathy protein BBS4 to both centriolar satellites and cilia. These data highlight the emerging link between DNA damage response factors, centriolar and peri-centriolar satellites and cilia-associated proteins and implicate Ccdc13 as a centriolar satellite protein that functions to promote both genome stability and cilia formation. Show less