1. Molecular dissection of the circulating leukocyte pool: Which leukocytes get lonely?

s from the 18th Annual PNIRS Meeting 1. Molecular dissection of the circulating leukocyte pool: Which leukocytes get lonely? S. Cole , L.C. Hawkley , J.M. Arevalo , J.T. Cacioppo b UCLA, Medicine, 11-934 Factor Building, Los Angeles, CA 90095-1678, USA University of Chicago, USA We developed a bioinformatic strategy for identifying the specific leukocyte subset responsible for any observed change in the total transcriptome of the circulating PBMC pool. Transcript Origin Analysis (TOA) quantifies the extent to which each human gene is distinctively expressed by monocytes, plasmacytoid dendritic cells, NK cells, CD4+ or CD8+ T cells, or B lymphocytes. Differentially expressed genes are then tested for over-representation of transcripts originating predominately from each cell type. After validation in 5 studies involving experimental manipulation of gene expression in isolated leukocyte subtypes (p < .01 accuracy in each), we applied TOA to determine which leukocyte subset mediates the effects of long-term subjective social isolation (loneliness) on PBMC gene expression in 93 older adults participating in the Chicago Health, Aging, and Social Relationships Study. Results showed loneliness-related genes to derive primarily from plasmacytoid dendritic cells and monocytes, and to a lesser extent, B lymphocytes (all p < .01). Those dynamics reflected per-cell changes in the expression of inducible genes (i.e., not attributable to leukocyte subset prevalence), and related more strongly to the subjective experience of loneliness than to objective social network size. Evolutionarily ancient myeloid antigen presenting cells appear to have evolved a transcriptional sensitivity to socio-environmental conditions that may allow them to shift basal gene expression profiles to counter the changing microbial threats associated with hostile vs. affine social conditions. doi:10.1016/j.bbi.2011.07.004 2. Soluble IL-6 receptors induce behavior activating effects and co-localize with gp130 in the striatum and motor cortex A. Patel, D. Zhang, E.V. Kuzhikandathil, A. Siegel, S.S. Zalcman UMDNJ-NJMS, 183 South Orange Avenue, Newark, NJ 07103, USA Increased serum levels of inflammatory cytokines are evident in schizophrenic patients. Particularly strong links between IL-6 and its soluble receptor (sIL-6R) and illness severity have been observed suggesting that this cytokine and its binding protein are involved in the disease process. However, there is no evidence that sIL-6R’s affect relevant behaviors in animal models or that they localize in relevant brain regions. Here, we discovered in male Balb/c mice, that single injections of sIL-6R’s (0–2 lg, sc) induce marked dose-dependent behavior activating effects. For example, sIL-6R’s provoked significant increases in novelty-induced horizontal and vertical ambulatory movements. Of further importance, sIL-6R’s stimulated repetitive stereotyped movements, which included, turning, jumping, intense grooming, and vertical stereotypies. Because this behavioral phenotype is associated with activation of cortico-striato-thalamo-cortico (CSTC) circuits, we determined whether sIL-6R localizes in relevant cortico-striatal structures. We discovered that peripherally injected sIL-6R’s localize within the caudate-putamen, nucleus accumbens, and motor cortex. Of further significance, sIL6R co-localizes in these regions with gp130, which is a transmembrane protein through which sIL-6R’s modulate immune cell activity. Based on these findings, we suggest that after peripheral immune cell activation, sIL-6R’s shed from the cell surface of activated monocytes (and possibly other cells), enter the brain, and modulate activity in CSTC circuits associated with repetitive stereotyped movements and that are implicated in schizophrenia and other disorders in which repetitive stereotypies are expressed. doi:10.1016/j.bbi.2011.07.005 3. Role of dopamine D1 and D2 receptors in the development and expression of IL-2-induced repetitive stereotyped movements A. Patel, E.V. Kuzhikandathil, S.S. Zalcman UMDNJ-NJ Medical School, 183 South Orange Avenue, Newark,