Repeated Methamphetamine Administration Differentially Alters Fos Expression in Caudate-Putamen Patch and Matrix Compartments and Nucleus Accumbens

Background: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (‘‘sensitization’’) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix. Methodology/Principal Findings: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but no

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Fos expression in the patch and matrix compartments of the dorsomedial caudate-putamen as a function of pretreatment, challenge, and bregma level.

<p>Left panels (a and c), Fos expression across rostral-caudal levels. Right panels (b and d), Fos expression collapsed across levels. Asterisk denotes significant interaction between pretreatment and challenge (values = Mean±SEM).</p

Images of MOR and Fos immunostained tissue.

<p>(a) Image of MOR immunoreactivity in the striatum. (b) Placement of templates used for analysis of Fos expression in the dorsal caudate-putamen and nucleus accumbens core and shell. (c) Left, closeup image of MOR immunostained tissue displaying the patch and matrix compartments. Middle, closeup image of Fos expression. Right, overlay of the left and middle images demonstrating Fos expression in patch compartments.</p

Fos expression in the patch and matrix compartments of the dorsolateral caudate-putamen as a function of pretreatment, challenge, and bregma level.

<p>Left panels (a and c), Fos expression across rostral-caudal levels. Right panels (b and d), Fos expression collapsed across levels. Asterisk denotes significant interaction between pretreatment and challenge (values = Mean±SEM).</p

Locomotor sensitization to cocaine is associated with increased Fos expression in the accumbens, but not in the caudate

Behavioral sensitization following repeated intermittent cocaine administrations is thought to involve alterations in cocaine regulation of neural activity within the accumbens and caudate brain regions. Although Fos immunohistochemistry and c-fos in situ hybridization have frequently been used to assess changes in cocaine-induced neural activity following prior cocaine exposure, these techniques have rarely been used to examine neural activity in the accumbens of behaviorally sensitized animals. In the present experiment, we compared the ability of increasing doses of cocaine to induce Fos in the accumbens and caudate of rats following a treatment procedure (7 once daily injections of 15 mg/kg of cocaine or the saline vehicle) shown to produce robust and persistent (1 week) locomotor sensitization. In sensitized animals, there was a leftward shift in the dose-response curve for cocaine induction of Fos in the accumbens, but not in the caudate. These results provide the first parametric evidence for sensitization of cocaine-induced Fos expression in the accumbens

ALICE Technical Design Report on Forward Detectors : FMD, T0 and V0

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ALICE Technical Design Report of the Computing

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