Mitochondria in presynaptic terminals linked to poorer rule switching in aged mice
Mitochondria in presynaptic terminals linked to poorer rule switching in aged mice
On September 14, Aging Cell published a study investigating why aged mice of the same age differ in their ability to shift a learned response. The authors examined the medial prefrontal cortex, a region of the frontal cortex required for this kind of switching, and tested MitoQ, an antioxidant that accumulates in mitochondria.
Mice were first trained to earn a reward by touching one of two lines on a screen. The rule was then changed: the reward now required touching one side of the screen, regardless of which line appeared. This task reveals whether an animal can abandon a learned response and acquire a new one.
In the key experiments, the authors worked with male C57BL/6J mice, a standard laboratory strain. All animals learned the initial task equally well, but after the rule change, accuracy in the final session varied widely among the aged animals. The researchers looked for a structural correlate of this behavioral reorganization in animals that had already mastered the original task.
They first examined synapses, the contacts between neurons, in the medial prefrontal cortex. Three-dimensional electron microscopy showed that synapse density decreased with age. Among the aged mice, task accuracy did not correlate with either the density or the size of these contacts. A different picture emerged for the fraction of synapses whose presynaptic terminal contained a mitochondrion: the higher this fraction, the lower the accuracy in the final session.
The authors then analyzed proteins in a synapse-enriched fraction. In aged mice, lower accuracy corresponded to higher levels of mitochondrial proteins, including those involved in energy production. The authors separately compared proteins that changed with chronological age to proteins whose abundance correlated with accuracy within the aged group. The overlap between these two sets, in both whole tissue and the synapse-enriched fraction, was no greater than expected by chance. The authors therefore describe age-related changes and individual differences among same-aged animals as distinct sets of protein alterations.
The authors also tested an intervention: from week 55 to week 75, mice received either MitoQ or the structurally similar control compound dTPP in their drinking water. The final analysis included seven mice on MitoQ and five on dTPP. MitoQ improved performance on the rule-switching task, while acquisition of the initial task was equivalent between groups. In the synapse-enriched fraction, MitoQ-treated animals showed lower levels of mitochondrial and pro-apoptotic proteins, the latter being involved in initiating programmed cell death.
The authors consider mitochondria in presynaptic terminals a testable component of the explanation for why animals of the same age differ in their ability to reorganize behavior when conditions change.