The role of exercise and NMNAT1 on functional and behavioural aspects of brain ageing in the mouse

Taylor, Helen Lynette (2019) The role of exercise and NMNAT1 on functional and behavioural aspects of brain ageing in the mouse. PhD thesis, University of Nottingham.

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Ageing is a complex process that occurs in every living organism and is the result of interactions between genetics and the environment. As we age, the risk of developing a number of diseases like Alzheimer’s disease, cardiovascular disease and cancer increases significantly. However, not everyone will develop any of these illnesses, and may instead undergo ‘healthy ageing’, a process broadly defined in humans as “ageing in the absence of illness”. Healthy ageing can be promoted by, amongst other things, regular exercise and caloric restriction. Previous research has shown that caloric restriction can delay the onset of the negative impacts of ageing, and also extend maximum lifespan. These effects are regulated via the activity of the NAD+ dependent deacetylase SIRT1, and overexpression of SIRT1 can have the same effect as caloric restriction. Exercise also promotes improved health with ageing, thought the underlying mechanisms are not fully understood.

Here, we aimed to investigate the impact of long-term exercise in an ageing mouse model, and how changing the expression of the NAD+ biosynthetic enzyme NMNAT1 could impact on ageing in both sedentary and voluntary exercise conditions. For this we compared two colonies of mice: transgenic overexpression of NMNAT1 (TG) and heterozygous knockout of NMNAT1 (Het). We also included the wildtype (WT) littermates from both colonies. We focused on four key areas that are known to be affected in ageing: behaviour, adult neurogenesis, miRNAs as blood biomarkers of healthy ageing and hippocampal gene expression.

In order to ensure that our behavioural results were ecologically relevant, we first determined how the phase of the light cycle under which behavioural tests are performed can alter the behaviour outcomes in mice that had access to a running wheel. Within the literature there is conflicting data on how exercise affects behaviour in a mouse, mainly focused on the effect on anxiety. Half of the mice were given access to a running wheel for one month before the behavioural tests. At the end they all underwent a series of behavioural tests, either under white light or in the dark. When the tests were performed in the light it appears as though the mice that exercise go into the open areas of the elevated plus maze less which can be interpreted as the mice being more anxious. However, when the same test was performed in the dark this did not happen. We also found that all mice showed increased activity in all of the tests when under dark conditions, as mice are nocturnal and are more active at night. From these results we decided to perform all other behavioural tests in the dark phase of the light/dark cycle.

Afterwards, we focused on the impact of exercise and NMNAT1 genotype on ageing. Male mice of all three genotypes (WT, Het and TG) grew to 18 months of age under group housed conditions. At both 11 and 18 months of age, all of the mice underwent a series of behavioural tests for cognition, anxiety and locomotor activity. From 12 to 18 months of age, the mice either had access to a running wheel or remained sedentary but with a broken wheel to control for environmental enrichment. All mice received an injection of BrdU at 17 months of age. We also had a group of young (2-month old) male and female mice from all three genotypes, and we compared the levels of adult neurogenesis in the young and old mice.

In WT mice, exercise tended to increase/maintain cognitive ability with age. In the brains of these mice, we found an increase in the number of new cells in the brain becoming neurons and surviving long enough to mature and potentially integrate into the neuronal network. Exercise also increased the expression of miR-21-5p in the blood plasma of WT mice, a miRNA that has previously been shown to have a role in the regulation of neural stem/progenitor cell (NPC) proliferation in the adult brain.

When we compared the levels of adult neurogenesis in the young and aged mice of all three genotypes, we saw a significant decrease with age in all groups. This comparison has not been done in Het and TG mice before, and we saw some slight variations between the different genotypes with age.

When comparing adult neurogenesis in the WT and Het mice, we saw a significant increase in the NPC proliferation and immature neuron numbers in the Het mice. However, exercise reduced the number of proliferating cells in the Het mice.

In the brains of TG mice, we saw an increase in the number of new cells becoming immature neurons and the number of cells surviving long enough to mature. Exercise had no significant effect on adult neurogenesis in TG mice. We saw a significant increase in miR-21-5p in the TG mice in comparison to the WT mice, similar to the increase seen with exercise in the WT mice. The expression of miR-92a-5p and miR-21a-3p was significantly decreased in TG mice that had exercised. Both of these miRNAs have been previously linked with regulating adult neurogenesis. Finally, we saw a significant increase in the expression of BDNF in the hippocampus of TG mice that had exercised.

We saw no significant changes with exercise or genotype in the hippocampal expression of NMNAT2, SIRT1, NAMPT, Ezh2 or Utx.

Overall, we concluded that prolonged voluntary exercise has a significant impact on adult neurogenesis and circulating miRNA expression in aged mice but does not significantly affect the behaviour of the mice or gene expression in the hippocampus. Changing the expression of NMNAT1 also impacts adult neurogenesis and circulating miRNA expression in aged mice and can impact the effect that exercise has in aged mice.

Further research is required to fully understand the underlying mechanisms behind the changes we have found in this study, both with exercise and the change in NMNAT1 expression.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Toledo-Rodriguez, Maria
Ebling, Francis
Keywords: Thesis, NMNAT1, Ageing, Exercise, Behaviour, Cognition, Anxiety, Neurogenesis, miRNA, Hippocampus, Neuroscience
Subjects: Q Science > QL Zoology
Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 56106
Depositing User: Taylor, Helen
Date Deposited: 19 Jul 2019 04:40
Last Modified: 19 Jul 2021 04:30

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