Deanery of Biomedical Sciences: The population of aged individuals is increasing worldwide, which has significant health and socio-economic implications. Brain aging is associated with synapse loss, cognitive decline, and heightened neuroinflammation. However this occurs on a spectrum: healthy ageing and cognitive stability is associated with less neuroinflammation, a state that is attributable in part, to the properties of microglia, brain-resident macrophages. In a healthy brain, microglia have a “homeostatic” transcriptional signature that distinguishes them from other macrophages. However, maintenance of this requires continued instruction from the brain microenvironment. In the aged brain, many “homeostatic” transcriptional signature genes are downregulated, which is thought to cause aberrant microglial function and neuroinflammation associated with impaired cognition. My research group is currently studying the mechanisms that promote microglial homeostasis with the aim to reveal ways to prevent harmful age-associated neuroinflammation and maintain cognitive function. We recently described a research tool for elucidating non-cell-autonomous control of gene transcription (Nature Protocols, 2018, PMID: 30250293). We found that neurons and astrocytes secrete proteins that promote microglial “homeostatic” transcriptional signature genes which are normally lost in the ageing brain (Cell Reports, 2021, PMID: 33761343). As part of this work, we identified one protein which we have now discovered to promote microglia homeostasis in vitro. The key goal of this PhD project will be to characterise the potential effects of TGF-ß2 on the modulation of microglial function and neuroinflammation in the ageing brain in vivo. To facilitate this, we have developed an inducible mouse TGF-ß2 KO model that will allow the spatial and temporal effects of transforming growth factor- ß2 (TGF-ß2) on microglial function and neuroinflammation to be defined in relation to cognitive abilities with advancing age. The latest advances in imaging (in vivo 2- photon (2P) microscopy combined with IHC/spatial transcriptomics) would allow microglia numbers/ function and phenotypes to be defined across the lifespan. Complementary analysis of microglia gene signatures (qRT-PCR, array) and inflammatory status in vitro (phagosome probes, morphological analysis, cytokine release) would be employed. Behavioural tasks would be used to assess animal cognition (Y-maze, novel object recognition) at different ages.