Mechanisms underlying exercise regulation of adult hippocampal neurogenesis and related behaviours in adulthood and middle age

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dc.check.date2027-06-30
dc.check.infoControlled Access
dc.contributor.advisorNolan, Yvonne M.
dc.contributor.advisorO'Leary, Olivia
dc.contributor.advisorNicolas, Sarah
dc.contributor.authorCaruso, Maria Giovannaen
dc.contributor.funderScience Foundation Ireland
dc.date.accessioned2026-05-28T14:47:37Z
dc.date.available2026-05-28T14:47:37Z
dc.date.issued2025-12-31
dc.date.submitted2025-12-31
dc.descriptionControlled Access
dc.description.abstractThe proportion of people aged 60 years or older is increasing worldwide, and the number of people living with dementia is projected to triple by the year 2050. This represents a significant challenge for healthcare systems, economies, and social structures. Middle age, defined as spanning from aged 40 to 60 years in humans is a transient yet critical period of life. During middle age, physiological changes begin to emerge, which may increase vulnerability to developing physical and cognitive dysfunction in later life. Thus, the identification of early biological markers of ageing may be pivotal for the development of targeted interventions to promote healthy brain ageing. A sedentary lifestyle is a risk factor for age-related cognitive decline and dementia. In rodents, exercise in older age has been shown to protect against the age-related decline in adult hippocampal neurogenesis (AHN), the birth of new neurons in the dentate gyrus of the hippocampus. This unique form of neuroplasticity is responsible for the regulation of certain forms of memory and anxiety-like behaviours. However, less is known about the effects of exercise on AHN and associated behaviours during middle age, and the related mechanisms underpinning potential changes in AHN and behaviour. The gut microbiota has recently been identified as an important peripheral mediator of the effects of exercise on hippocampus-dependent behaviours and AHN, but there is limited knowledge on how exercise influences gut microbiota, serum metabolites, and their association with hippocampal processes. Contrasting evidence has been reported on the effects of different types of exercise on AHN and hippocampal-dependent behaviours in preclinical research. There is a paucity of comparative studies investigating those differences however, to explain the origin of those discrepancies. Thus, the aim of my thesis was to investigate central and peripheral mediators contributing to a decline in hippocampal-dependent behaviours in middle-aged rats, and identify regulators of exercise-induced AHN in young adult rats in order to examine if they can be harnessed to boost neurogenesis during middle age. Moreover, I investigated the effect of exercise on gut microbes and microbiota-derived serum metabolites in young adult rats, and examined their association with hippocampal processes. Lastly, I compared the effects of wheel running and treadmill exercise on spatial memory, AHN and possible mediators in the cerebrospinal fluid (CSF) in young adult rats. I found that the hippocampus of middle-aged rats displayed a pronounced decline in AHN and an accumulation in inflammatory, lipid-droplet rich microglia, both of which were associated with declined spatial learning and memory, and enhanced anxiety-like behaviours. Proteomic profiling of the hippocampus and CSF, in conjugation with serum metabolomics, and analysis of the gut microbiota composition identified dysfunctional lipid metabolism as a feature associated with midlife decline in hippocampal physiology and function. My work also revealed a novel central mechanism by which exercise affects hippocampal neurogenesis, as downregulation of the GTPase-activating protein, Rasal1, in the dorsal hippocampus was identified to be sufficient to mimic the neurogenic effects of exercise in the middle-aged rat brain. Investigation of peripheral mediators of exercise showed that tryptophan metabolizing gut microbes are affected by exercise. This was accompanied by enhancement of tryptophan metabolism in the host circulation and reduced hippocampal expression of the aryl hydrocarbon receptor, which others have reported is required for indole derived metabolites to regulate AHN. An association between tryptophan metabolites and hippocampal Rasal1 regulation was also identified, highlighting a possible pathway of exercise- gut-brain interaction for the stimulation of hippocampal neurogenesis. Lastly, the comparison of the exercise paradigms most frequently used in preclinical research revealed that treadmill exercise as well as wheel running had a mild anxiolytic effect, while only treadmill exercise enhanced spatial memory. This was in contrast with the enhancement in AHN observed exclusively in response to wheel running, suggesting that other mechanisms are involved in the exercise-induced stimulation of hippocampal functions, further supported by CSF proteome analysis. Taken together, my thesis provides novel preclinical insights in the field of ageing and exercise research. It opens avenues for the development of clinical diagnostic tools and highlights preventative strategies derived from the identification of early ageing biomarkers, before cognitive decline becomes too pronounced and irreversible. Furthermore, it proposes physical exercise as a preventative strategy to enhance hippocampal neurogenesis and associated functions that may decline during ageing, and provides novel pathways and targets for the development of therapeutic approaches that can mimic some of the beneficial effects of exercise. Such alternatives are particularly valuable in cases where physical exercise is not a feasible intervention for individuals with cognitive impairment or physical limitations.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCaruso, M. G. 2025. Mechanisms underlying exercise regulation of adult hippocampal neurogenesis and related behaviours in adulthood and middle age. PhD Thesis, University College Cork.
dc.identifier.endpage349
dc.identifier.urihttps://hdl.handle.net/10468/18934
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/Frontiers for the Future::Awards/19/FFP/6820/IE/Mechanisms underpinning the interplay between chronic neuroinflammation and exercise on cognitive function during middle age/
dc.rights© 2025, Maria Giovanna Caruso.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMiddle-age
dc.subjectExercise
dc.subjectAdult hippocampal neurogenesis
dc.subjectGut microbiota
dc.subjectHippocampal functions
dc.titleMechanisms underlying exercise regulation of adult hippocampal neurogenesis and related behaviours in adulthood and middle ageen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhD - Doctor of Philosophy
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