Supplement: Hippocampal Electrophysiology and Myelinogenesis in Health Cognitive Aging

Grants and Contracts Details


Study 1 to be completed: White matter localization of inflammation. To determine which gene networks and biochemical pathways were most closely associated with the upregulation of myelinogenic genes during brain aging, we conducted a large microarray analysis of gene expression in laser-capture microdissection (LCM)-separated myelinated white matter and gray matter regions in hippocampus of young-adult and aged male rats. Remarkably, the Laser-capture microdissection technology revealed that inflammatory responses in rat hippocampus during normal aging originate almost exclusively in myelinated fibers. In addition, the inflammatory/immune response was far and away the strongest genomic aging signal in the white matter and it correlated with cognitive decline. It also preceded the upregulation of myelinogenic genes. Together, these results have led us to conclude that inflammatory upregulation is apparently the primary aging-related pathogenic process in myelinated fibers, whereas the upregulation of myelinogenic genes may be a secondary compensatory response. This study in rats shows for the first time that brain neuroinflammation during normal aging is almost exclusively a phenomenon localized in myelinated fiber tracts. Therefore, part of the requested funds will be allocated to personnel effort and for modest supplies for completion of immunohistochemical and microarray analyses of interactions among glial cell types and submitting a manuscript on these important and novel findings. Study 2 to be completed: Control of inflammation by white matter oligodendrocytes. This study reports the striking and novel observation that viral mediated overexpression of the negative epigenetic regulator HDAC2 in oligodendrocytes widely activates the microglial-based inflammatory response. We discovered this regulatory pathway while using AAV vectors driven by the myelin basic protein promoter to overexpress the epigenetic regulator Histone Deacetylase 2 (HDAC2) in oligodendrocytes as a means of long-term intervention in the myelinogenic process. HDAC2 has previously been shown to be a co-regulator of gene expression and to modulate memory and LTP. Unexpectedly, we found that, rather than producing strong modulation of myelinogenic genes, AAV-mediated overexpression of HDAC2 induced widespread upregulation of inflammatory genes, which are expressed primarily by microglia. These results suggest that transcriptional events in the nuclei of oligodendrocytes regulate the nuclear response of microglia, perhaps explaining why neuroinflammation is predominantly localized in white matter tracts.
Effective start/end date9/1/098/31/16


  • National Institute on Aging


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