Project ID NS-MH2024_59


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Mental Health & Psychological Sciences, Social, Genetic & Developmental Psychiatry CentreWebsite

Hippocampal ageing and cognitive decline: From genetic associations to cellular risk mechanisms

Background: The hippocampus is a specialized brain region that governs learning, memory and mood. During ageing, the hippocampus shrinks and this is hypothesized to contribute to age-related cognitive decline. Within this PhD project, the student will use a combination of statistical genetic approaches and cellular neuroscience to explore the mechanisms underlying age-related hippocampal volume loss. They will further explore whether specific blood-based factors are capable of modifying the rate of volume loss by stimulating adult hippocampal neurogenesis.

Overarching aim: To equip an enthusiastic PhD student with a multidisciplinary skill set that they will use to explore why our hippocampi shrink with age and how we might preserve hippocampal volume for longer, in order to slow down cognitive decline.

Techniques: Transcriptome-wide association studies; Mendelian Randomisation; Neural Stem Cell Culture; Genome editing (e.g., CRISPR) or gene overexpression and downregulation; gene expression analyses (e.g., scRNA Seq, qPCR), immunocytochemistry and high-content imaging.

Objectives for each year:

Year 1 (Rotation): To use neuroimaging genome-wide association study data to perform a transcriptome-wide association study in order to impute which genes are upregulated or downregulated in the hippocampus in association with greater age-related volume loss.

Year 2: To test if genetic risk factors for age-related hippocampal loss exert their effects by impacting adult hippocampal neurogenesis, using an in vitro model.

Year 3: To infer whether specific blood-based factors modify rates of age-related hippocampal loss and cognitive decline, using large genetic datasets and Mendelian Randomisation.

Year 4: To test whether specific blood-based factors protect hippocampal cells from premature cell ageing, using an in vitro model.

Representative Publications

The serum metabolome mediates the concert of diet, exercise, and neurogenesis, determining the risk for cognitive decline and dementia. Du Preez A, Lefèvre-Arbogast S, Houghton V, de Lucia C, Low DY, Helmer C, Féart C, Delcourt C, Proust-Lima C, Pallàs M, Ruigrok SR, Altendorfer B, González-Domínguez R, Sánchez-Pla A, Urpi-Sardà M, Andres-Lacueva C, Aigner L, Lucassen PJ, Korosi A, Manach C, Samieri C, Thuret S. Alzheimers Dement. 2022 Apr;18(4):654-675. doi: 10.1002/alz.12428.

Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells. de Lucia C, Murphy T, Maruszak A, Wright P, Powell TR, Hartopp N, de Jong S, O’Sullivan MJ, Breen G, Price J, Lovestone S, Thuret S. Aging Dis. 2021 Dec 1;12(8):2151-2172. doi: 10.14336/AD.2021.0409.

Inter-individual variation in genes governing human hippocampal progenitor differentiation in vitro is associated with hippocampal volume in adulthood. Powell TR, Murphy T, Lee SH, Duarte RRR, Lee HA, Smeeth D, Price J, Breen G, Thuret S. Sci Rep. 2017 Nov 8;7(1):15112. doi: 10.1038/s41598-017-15042-z

Rafagnin Duarte, R. R., Pain, O., Furler, R. L., Nixon, D. F., Powell, T. R. (2022) Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene. iScience, 25, 9, 104854. DOI: 10.1016/j.isci.2022.104854

Palmos, A. B., Duarte, R. R. R., Smeeth, D. M., Hedges, E. C., Nixon, D. F., Thuret, S., Powell, T. R. (2020) Telomere length and human hippocampal neurogenesis. Neuropsychopharmacology, 45, 2239–2247. DOI: 10.1038/s41386-020-00863-w

Smeeth, D. M., Dima, D., Jones, L., Jones, I., Craddock, N., Owen, M. J., Rietschel, M., Maier, W., Korszun, A., Rice, J. P., Mors, O., Preisig, M., Uher, R., Lewis, C. M., Thuret, S., Powell, T. R. (2019) Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility. Psychoneuroendocrinology, 106, 284-292. DOI: 10.1016/j.psyneuen.2019.04.011