A team of researchers has discovered that mitochondrial health and location may be critical to why cognitive plasticity decreases with age.
Old mammals and new tricks
The adage ‘you can’t teach an old dog new tricks’ is true across a wide variety of organisms; neural plasticity decreases with age in rodents, non-human primates, and people [1]. This form of cognitive decline stems from changes in individual cells: the dendrites of prefrontal cortex neurons become less plastic [2], and the biochemistry of the synapses is altered [3]. This is accompanied by changes in brain metabolism [4].
This lack of cognitive plasticity often manifests itself in cognitive inflexibility and perseveration: needless, constant repetition when the reason for the original behavior has long since passed. To diagnose this in rodents, researchers often use an attention set shifting task that tests the animals’ ability to learn and apply novel facts when circumstances change [5].
The precise relationship between the brain’s physical changes with aging and the resulting lack of behavioral plasticity, especially at the individual level, has not been fully elucidated. These researchers, therefore, conducted both behavioral and in-depth proteomic testing to learn more about this relationship.
Changing the rules halfway through
In this study, the researchers had Black 6 mice learn two different sets of rules. In the first part, the mice would learn that pressing a button with two vertical lines or two horizontal lines would yield a food reward. In the second part, however, the rule changed; the lines stopped mattering, and it only mattered whether the button was the one on the left or the right.
Two different strains of Black 6 mice performed much differently on this task with aging. Overall, C57BL/6N mice demonstrated a significant age-related decline in their ability to learn the new rule. On the other hand, C57BL/6J mice, as a whole, showed much less of a decline; only some of the older mice of this strain performed notably worse than their younger counterparts. The researchers, therefore, chose to conduct all their future experiments on the J strain, looking for the reasons why some mice performed worse than others.
Many age-related changes in neuron structure appeared to have no discernible relationship to this decline. A loss of smaller dendrites, which lack spines, was not found to be correlated to this task, nor was a large axon-spine interface. The researchers also examined astrocytes around the synapses, but those were neither correlated with aging nor had any impact on this task.
Instead, presynaptic mitochondria found in larger axon-spine interfaces, despite not being associated with aging overall, were related to this form of cognitive decline in aged mice. The researchers then looked more closely at the involved proteins and genes, finding many candidates that appeared to be related, although the number of mice was too small to draw completely firm conclusions. The researchers’ most interesting finding was that differentially expressed genes with aging were largely different from those related to cognitive decline in these mice; therefore, this team concluded that the “neural mechanisms determining individual variability in cognitive inflexibility are distinct from chronological aging processes.”
As expected, many of the genes associated with cognitive decline involved the mitochondria, specifically the regulation of mitochondrial metabolism. Some of the genes were directly related to synapse management itself. Better mTOR signaling and, unsurprisingly, better amyloid protein handling were found to be associated with better cognitive performance. Mitochondrial proteins found in synapses were specifically found to be “more abundant in aged mice with greater cognitive inflexibility.”
Reducing oxidative stress appears to help
The researchers then performed another experiment using the mitochondrial antioxidant MitoQ, which had previously performed well against memory loss in mouse models of Alzheimer’s [6]. While it did not significantly improve the mice’s visual learning ability, it was found to have beneficial effects on the attention set task after 20 weeks of administration; the treated aged mice were able to adapt to the new rule faster than the untreated mice. It diminished some of the mitochondrial proteins in synapses, specifically those related to apoptosis, and it upregulated proteins related to aerobic respiration.
This is exploratory research, and, other than mitochondrial health and oxidative stress as a whole, the paper offers suggestions but not biochemical intervention targets. It suggests that presynaptic mitochondria may need to be specifically targeted, and it highlights the possibility that reactive oxygen species produced by mitochondria may be having deleterious downstream effects on neurons’ structural plasticity. Further work will need to be done to determine if there is any novel mitochondrial target that may restore older people’s ability to learn new things.
Literature
[1] Burke, S. N., & Barnes, C. A. (2006). Neural plasticity in the ageing brain. Nature reviews neuroscience, 7(1), 30-40.
[2] Bloss, E. B., Janssen, W. G., Ohm, D. T., Yuk, F. J., Wadsworth, S., Saardi, K. M., … & Morrison, J. H. (2011). Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. The Journal of Neuroscience, 31(21), 7831-7839.
[3] Morrison, J. H., & Baxter, M. G. (2012). The ageing cortical synapse: hallmarks and implications for cognitive decline. Nature reviews neuroscience, 13(4), 240-250.
[4] Lee, J., & Kim, H. J. (2022). Normal aging induces changes in the brain and neurodegeneration progress: review of the structural, biochemical, metabolic, cellular, and molecular changes. Frontiers in aging neuroscience, 14, 931536.
[5] Heisler, J. M., Morales, J., Donegan, J. J., Jett, J. D., Redus, L., & O’connor, J. C. (2015). The attentional set shifting task: a measure of cognitive flexibility in mice. JoVE (Journal of Visualized Experiments), (96), e51944.
[6] McManus, M. J., Murphy, M. P., & Franklin, J. L. (2011). The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. The Journal of Neuroscience, 31(44), 15703-15715.
View the article at lifespan.io
