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Show 216 Shotaro Matsuoka Obsessive-compulsive behaviors (OCD) is an anxiety disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions)2. In mice, excessive grooming behaviors which lead to hair loss and lesions are equivalent of OCD-like behaviors in human and several separate studies have been done. These patho-logical behaviors in mice are assumed to be induced by several factors, including dysfunction of cortico-striatal pathways in the brain, however; the underlying pathological mechanisms are unknown. One study has shown that deletion of Sapap 3 protein, which is highly expressed in cortico-striatal circuitry, induced the excessive grooming behaviors and that synaptic transmission in glutamatergic cortico-striatal pathways was reduced in mice. Further it was shown that serotonin reuptake blockers alleviated the pathological grooming behaviors. A separate study has shown that the deletion of Hoxb8 gene induced the compulsive grooming in mice. Hox gene plays an important role in establishing body plans and the formation of tissues and organs including the hema-topoietic system, and with respect to Hoxb8, it is known to play a crucial role in maintenance and differentiation of myeloid progenitor cells, one of the two known sources of microglia. Microglia are a type of glial cells, which are present in the central nervous system. Although the origin of the microglia is still under discussion, it is widely accepted that bone marrow is one of the sources that give rise to a subpopulation of microglia, and 40% of total microglia in the brain is known to be derived from bone marrow compartment. Interestingly, it has been reported that microglia were the only detectable cells derived from Hoxb8 lineage in multiple brain areas that generates and implements the OCD-like behavior in mice. Second, conditional restriction of Hoxb8 deletion to the hemato-poietic system in mice induced the pathological phenotype without causing the nociceptive/ spinal cord defects, which was believed to be the causation of OCD-like behaviors in mice. Third, total number of microglia in adult mice brain was decreased by disruption of Hoxb8 function and the selective inactivation of Hoxb8-derived mi-croglia was sufficient enough to induce the OCD-like behaviors. Lastly, conditional deletion of mice Hoxb8 in the spinal cord only induced the nociceptic/spinal cord sensory defects without causing the compulsive grooming1. Despite the knowledge that deletion of Hoxb8 genes causes OCD-like behaviors in mice, phenotypic differences in the brain synapses caused by this procedure are not well known. However, several studies have implicated the dysfunction of cortico-striatal pathways in Hoxb8 mutant mice. Therefore, the investigators hypothesized that de-letion of Hoxb8 genes in mice will cause deficiency in cortico-striatal synapses, which will induces the compulsive grooming in mice and that phenotypic changes in these synapses will be observed. The investigators are currently carrying out the following experiments to gather experimental data: in order to examine the effects of Hoxb8 deletion in mice, the investigators are currently using Confocal microscopy for data acquisition, Imaris software for analyzing the Neuronal density and microglial density and perform morphologi-cal measurements to measure microglial primary, secondary and tertiary projections and synaptic measurements (pre and post synaptic). Transmission Electron Microscopic images of brain slices of both WT and Hoxb8 mutant mice (2WT cortex, 2 Mutant cortex, 2 WT striatum, 2 Mutant striatum) are being analyzed through the Viking: ultrastructural measurements of single synapse to measure PSD length, PSD thickness, Active zone length, Active zone thickness, Presynaptic diameter, and Postsynaptic diameter. Besides understanding the synaptic dysfunc-tions, behavioral abnormality is being observed by using various behavioral testing procedures. This includes Rotorod test for motor coordination of mice, SR lab systems for startle behaviors of mice, LABORAS platforms to determine the grooming behaviors, and Elevated Maze plus to examine the anxiety levels of mice. In summary, the research work will investigate the cellular defects associated with HoxB8 deletion and correlates with the behavioral abnormality. Bibliography 1. Chen, S., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., & Capecchi, R. M. (2010). Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice. Cell, 141(5), 775-785. doi:10.1016/j.cell.2010.03.055 2. Welch, M. J., Lu, J., Rodriguiz, M. R., Trotta, C. N., Peca, J., Ding, J., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, M. S., Richard J., Weinberg, N. C., Wetsel, C. W., Feng, G. (2007). Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. nature, 448(7156), 894-900. doi:10.1038/nature06104 EFFECTS OF HOXB8 GENE DELETION ON CORTICO-STRIATAL SYNAPSES AND BEHAVIORS IN MICE Shotaro Matsuoka (Naveen Nagarajan) Department of Human Genetics University of Utah Health sciences leap program spring 2012 Naveen Nagarajan |