This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human immunodeficiency virus (HIV) infection is a global health burden, affecting an estimated 40 million people worldwide. Over half those infected suffer from neurological symptoms, ranging from mild cognitive deficits to severe dementia and motor disorders;however the cellular mechanisms underlying neurological alterations following infection with HIV remain unclear. This project makes use of tissue samples collected from rhesus macaque monkeys inoculated with the simian immuno-deficiency virus (SIV), as a model for HIV.
The aim of this study is to establish a time-course for changes in neuronal morphology and connectivity following SIV infection in distinct brain regions that are likely to contribute to neurological deficits observed in patients with HIV. Our preliminary studies have focused on the hippocampus, a region of brain associated with spatial cognitive functions, and in which there is evidence for altered neuronal morphology in post-mortem tissue from patients infected with HIV. Our preliminary data indicate that following inoculation with SIV, a complex but robust pattern of changes occurs in the dendrite complexity of pyramidal neurons within the hippocampal CA1 subfield, the terminal zone of the tri-synaptic pathway. Following SIV infection, we observed an increase in the total amount of arbor within basal dendrites, and a corresponding increase in the inter-branch segment length, suggesting that dendritic segments are extending beyond their normal terminal fields within these neurons. In contrast, we did not observe an increase in total arbor length in apical dendrites, but instead found an increase in the number of branch segments, and a corresponding reduction in inter-branch length, suggesting that apical dendrite arbor undergoes re-arrangement in a manner consistent with the addition of new branch-points. These results are significant, because alterations in dendrite complexity and length are key indicators of changes in firing patterns of neurons, and of network properties within the brain. Our findings suggest that network firing is altered in hippocampal neurons in a manner that may depend on distinct afferent innervation of apical vs. basal dendrites. These results are in contrast to findings in post-mortem brain that display reduced dendritic arbor in hippocampal neurons, and may suggest that significant rearrangement of neuronal architecture precedes degenerative changes in neurons. We have now extended our analyses of hippocampal neurons from infected and control animals to include other hippocampal subfields, the CA3 and dentate gyrus, since these three regions support distinct aspects of cognitive function that may be differentially affected by SIV infection. We have also begun examining neurons within the dorsal thalamus, a region critical for attentional functions and sensory gating. We are continuing to collect samples for RNA analyses, and will use these, and archival specimens collected at the TNPRC in order to determine whether alterations in dendritic morphology occur in parallel with changes in key signaling molecules, such as glutamate receptors and their associated signaling molecules.
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