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Title: The role of VIP in neuro-immune modulation of hippocampal neurogenesis
Author: Khan, Damla
ISNI:       0000 0004 5351 0186
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2014
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Hippocampal neurogenesis occurs within the subgranular zone of the dentate gyrus and is important for learning and memory. Neurogenesis is impaired in many pathological conditions; an observation that may account for learning and memory deficits in patients suffering from these conditions. Studies on immune-deficient mice show reduced hippocampal neurogenesis and associated learning and memory impairments in mice devoid of CD4+ T lymphocytes. Neuropeptides are potential candidates for mediating neuro-immune interactions. Vasoactive Intestinal Peptide (VIP) is a neuropeptide, released by firing interneurons from the stem cell niche, that modulates hippocampal neurogenesis via VPAC1/2 receptors. VIP receptors are also present on T lymphocytes. Microglia are innate immune cells that regulate hippocampal neurogenesis. They are ideally placed to communicate with T lymphocytes that normally reside outwith the brain parenchyma. Given the nescience underlying T lymphocyte regulation of hippocampal neurogenesis, we sought to investigate the hypothesis that VIP modulates T lymphocytes to release cytokines to regulate hippocampal neurogenesis via interaction with microglia. We have shown that T lymphocytes supernatant increases the proliferation of hippocampal nestin-expressing cells. This effect is further enhanced under VIP treatment via VPAC1 receptor subtype. Examining possible cytokine involvement, we found that IL-4 mediates proliferation. Using Mac-1-SAP to deplete resident microglia, we demonstrated that supernatant acts primarily via microglia to increase supernatant effects. T lymphocytes induce microglia to upregulate cytokines and mediators such as IL-10 and BDNF. Phenotyping showed an additional neurogenic effect under VIP treated supernatant. Our results show VPAC1 receptor subtype expressed by CD4+ T lymphocytes mediates VIP proliferative effects on hippocampal precursor cells via IL-4 cytokine release. Microglia are key for mediating this effect via release of mediators. The findings of this study implicate a novel mechanism for VPAC1 CD4+ T lymphocyte receptor as a neuro-immune mediator of hippocampal neurogenesis, and from a therapeutic perspective, shows that the effect can be pharmacologically manipulated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; QR180 Immunology