Exercise boosts learning and memory

Exercise can boost your mood and improve heart and bone health. Now, a talented team uncovers the epigenetic mechanisms behind another good reason to hit the gym. Working out can help with learning and long-term memory via Acvr1c, a member of the TGF-beta family.

Gym rats—er, exercising mice—can learn under “subthreshold training” conditions after a workout, meaning that these mice can learn and remember things during situations in which non-exercising mice can’t. This phenomenon is at least partly due to brain-derived neurotrophic growth factor (Bdnf), which is epigenetically upregulated after movement. The effect lasts for a few days, a period that’s called a molecular memory window. Just a little movement during this post-exercising window boosts cognitive abilities under subthreshold conditions.

Marcelo Wood’s team (University of California, Irvine) wondered what other molecules were involved in this process. Here’s what they found after performing RNA-Seq on mouse hippocampus RNA following various exercise and training regimes:

A subset of 21 genes are upregulated after exercise regimes that boost long-term memory formation under subthreshold conditions
Bdnf and Acvr1c (type 1 activin A membrane receptor kinase) are upregulated compared to mice who were couch potatoes
Exercise alone, without memory training, upregulated Acvr1c

Then, with ChIP-Seq, they saw that the H3K27/Ac ratio at the Acvr1c and BdnfIV promoters genes was reduced by exercise, resulting in a more permissive epigenetic signature.

Acvr1c is a type I receptor of the TGF-beta family that can phosphorylate Smad 2/3 proteins, leading to complexes with Smad 4 and, ultimately, regulation of transcription. Here’s what happened when the team tweaked Acvr1c expression levels:

Mice infused with a kinase-dead mutant Acvr1c via AAV couldn’t learn as well as controls in an object memory location test
Long-term potentiation, a way that the brain strengthens neuronal synapses in response to experiences, was also impaired in mice infused with mutant Acvr1c
Overexpressing Acvr1c in the hippocampus had effects opposite to those listed above

Because the TGF-beta pathway is implicated in aging and in Alzheimer’s disease in humans, the pumped-up team tested whether Acvr1c was involved in these processes. Here’s what they found:

Acvr1c mRNA decreases with age in mouse and human hippocampus
Acvr1c mRNA declined more sharply in a mouse model of Alzheimer’s disease
In aging mice and in an Alzheimer’s model, Acvr1c overexpression improved object memory location performance, and long-term potentiation

The results bolster the team’s previous suggestion that certain patterns of exercise establish an epigenetic molecular memory window, a period of time when subthreshold training can be transformed into long-term memory. Overall, the team proposes boosting human ACVR1C probably could protect people against age- and potentially even Alzheimer’s-related declines in memory and learning, but more research is needed.

To learn more, get off the couch and move over to Nature Communications, May 2024