Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

Evaluation of Cavitation Erosion Behavior of Commercial Steel Grades Used in the Design of Fluid Machinery

The erosion response under cavitation of different steel grades was assessed by studying the erosion rate, the volume removal, the roughness evolution, and the accumulated strain energy. A 20 kHz ltrasonic transducer with a probe diameter of 5 mm and peak-to-peak amplitude of 50 lm was deployed in distilled water to induce damage on the surface of commercial chromium and carbon steel samples. After a relatively short incubation period, cavitation induced the formation of pits, cracks, and craters whose features strongly depended on the hardness and composition of the tested steel. AISI 52100 chromium steel showed the best performance and is, therefore, a promising design candidate for replacing the existing fluid machinery materials that operate within potential cavitating environments

Tidal dynamics in the Gulf of Maine and New England Shelf : an application of FVCOM

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): C12010, doi:10.1029/2011JC007054.The unstructured-grid, Finite-Volume Community Ocean Model (FVCOM) was used to simulate the tides in the Gulf of Maine (GoM) and New England Shelf (NES) for homogeneous and summer stratified conditions. FVCOM captures the near-resonant nature of the semidiurnal tide and energy flux in the GoM and the complex dynamics governing the tide in the NES. Stratification has limited impact on tidal elevation, but can significantly modify the tidal current profile. Internal tides are energetic in the stratified regions over steep bottom topography, but their contribution to the total tidal energy flux is only significant over the northeast flank of Georges Bank. The model suggests that the tidal flushing-induced eddy east of Monomoy Island is the dynamic basis for the locally observed phase lead of the M2 tide. The southward propagating tidal wave east of Cape Cod encounters the northeastward propagating tidal wave from the NES south of Nantucket Island, forming a zone of minimum sea level along a southeast-oriented line from Nantucket Island. These two waves are characterized by linear dynamics in which bottom friction and advection are negligible in the momentum balance, but their superposition leads to a strong nonlinear current interaction and large bottom stress in the zone of lowest sea elevation.This research is supported by the U.S. GLOBEC Northwest Atlantic/Georges Bank Program NSF (OCE-0234545, 0227679, 0606928, 0726851 and 0814505) to Changsheng Chen and Qixchun Xu and NSF grant (OCE-02-27679) and the WHOI Smith Chair to Robert Beardsley and Richard Limeburner. The tidal model-data comparison on Nantucket Sound/Shoals is partially the result of research sponsored by the MIT Sea Grant College Program, under NOAA grant NA06OAR4170019, MIT SG project 2006-R/RC-102, 2006-R/RC-103, 2006-R/RC-102, 2006-R/RC-107, 2008-R/RC-107), 2010-R/RC-116 and the NOAA NERACOOS Program for the UMASS team. C. Chen’s contribution is also supported by Shanghai Ocean University International Cooperation Program (A-2302-11-0003), the Program of Science and Technology Commission of Shanghai Municipality (09320503700), the Leading Academic Discipline Project of Shanghai Municipal Education Commission (project J50702), and Zhi jiang Scholar and 111 project funds of the State Key Laboratory for Estuarine and Coastal Research, East China Normal University (ECNU).2012-06-1

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here, we show that repeated cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. We show further, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1, or local knockout of Rac1 from floxed Rac1 mice, is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 mutant, or light activation of a photoactivatible form of Rac1, blocks the ability of repeated cocaine to produce this effect. Downregulation of Rac1 activity in nucleus accumbens likewise promotes behavioral responses to cocaine, with Rac1 activation producing the opposite effect. These findings establish an important role for Rac1 signaling in mediating structural and behavioral plasticity to cocaine