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|Massachusetts General Hospital, USA
Harvard Medical School, USA
|Keynote: J Neurol Neurophysiol|
|Background & Aim: Histone deacetylase (HDAC) activities modify chromatin structure and play a role in learning and memory during developmental processes. Studies of adult mice suggest HDACs are involved in neural network remodeling in brain repair, but its function in drug addiction is less understood. We aimed to examine in vivo HDAC5 expression in a preclinical model of amphetamine-induced sensitization (AIS) of behavior. We generated specific contrast agents to measure HDAC5 levels by in vivo molecular contrast-enhanced (MCE) magnetic resonance imaging (MRI) in amphetamine-naÃ¯ve mice as well as in mice with AIS. To validate the MRI results, we used ex vivo methods including in situ hybridization, RT-PCR, immunohistochemistry and transmission electron microscopy. Methods: We compared the expression of HDAC5 mRNA in an acute exposure paradigm (A1) and in a chronic-abstinencechallenge paradigm (A7WA). Control groups for each of these exposure paradigms were given saline. To delineate how HDAC5 expression was related to AIS, we compared the expression of HDAC5 mRNA at sequences where miR-2861 is known to bind (miD2861). We synthesized and labeled phosphorothioated oligonucleic acids (sODN) of hdac5AS2 or miD2861 linked to SPION (superparamagnetic iron oxide nanoparticles), and generated HDAC5-specific contrast agents (30+20 nm, diameter) for MCE MRI; the same sequences were used for primers for TaqManÂ® analysis (RT-qPCR) in ex vivo validation. In addition, we used subtraction R2* maps to identify regional HDAC5 expression. Results: Chronic exposure to amphetamine reduced HDAC5 expression and induced behavioral sensitization immediately after amphetamine. We designed HDAC5 mRNA targeting nanoparticles (miD2861) based on miR2861 binding to HDAC5. We identified regional elevation of HDAC5 expression and progenitor cells in the lateral septum in living mouse brain using MCE MRI; miD2681 targets HDAC5 mRNA in vivo using MCE MRI with precision similar to that of RT-PCR; excessive miD2861 shorten the AIS from 40 minutes to 15 minutes after amphetamine in acute exposure; ex vivo validation methods confirm that EDNs do not accumulate in any particular cell type. Summary & Conclusion: The precise delivery of miD2861 may serve as a vehicle for monitoring network remodeling with target specificity and signal sensitivity after drug exposure that identifies brain repair processes in adult animals.|
Philip K. Liu, PhD, Associate Professor of Radiology, Harvard Medical School and Associate Biologist of Mass General Hospital. Director of Gene Transcript Targeting and Imaging, AA Martinos Center for Biomedical Imaging. CNY 149 (2301) Thirteenth Street,Charlestown, MA 02129.
Email: [email protected]
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