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“Copy number variation (CNV) is a major source of genetic variation among humans. In addition to existing as benign polymorphisms, CNVs can also convey clinical phenotypes, including genomic disorders, sporadic diseases and

complex human traits. CNV results from genomic rearrangements that can represent simple deletion or duplication of a genomic segment, or be more complex. Complex chromosomal rearrangements (CCRs) have been known for some time but their mechanisms have remained elusive. Recent technology advances and high-resolution human genome analyses have revealed that complex Pritelivir molecular weight genomic rearrangements can account for a large fraction of non-recurrent rearrangements at a given locus. Various mechanisms, most of which are DNA-replication-based, for example fork

stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR), have been proposed for generating such complex genomic rearrangements and are probably responsible for CCR.”
“Methamphetamine (METH) causes partial depletion of central monoamine systems and cognitive dysfunction in rats and humans. We have previously shown and now further show that the positive correlation between BAY 11-7082 expression of the immediate-early gene Arc (activity-regulated, cytoskeleton-associated) in the dorsomedial (DM) striatum and learning on a response reversal task is lost in rats with METH-induced striatal dopamine loss, despite normal behavioral performance and unaltered N-methyl-D-aspartate (NMDA) receptor-mediated excitatory VE-822 price post-synaptic currents, suggesting intact excitatory

transmission. This discrepancy suggests that METH-pretreated rats may no longer be using the dorsal striatum to solve the reversal task. To test this hypothesis, male Sprague-Dawley rats were pretreated with a neurotoxic regimen of METH or saline. Guide cannulae were surgically implanted bilaterally into the DM striatum. Three weeks after METH treatment, rats were trained on a motor response version of a T-maze task, and then underwent reversal training. Before reversal training, the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) or an Arc antisense oligonucleotide was infused into the DM striatum. Acute disruption of DM striatal function by infusion of AP5 impaired reversal learning in saline-, but not METH-, pretreated rats. Likewise, acute disruption of Arc, which is implicated in consolidation of long-term memory, disrupted retention of reversal learning 24 h later in saline-, but not METH-, pretreated rats. These results highlight the critical importance of Arc in the striatum in consolidation of basal ganglia-mediated learning and suggest that long-term toxicity induced by METH alters the cognitive strategies/neural circuits used to solve tasks normally mediated by dorsal striatal function. Neuropsychopharmacology (2012) 37, 885-895; doi: 10.1038/npp.2011.