A retrosplenial cortex perspective on circuit dysfunction during Alzheimer’s disease

Hallmarks of Alzheimer´s disease (AD) include extracellular aggregates of amyloid-beta that lead to cell death, loss of memory, and eventually death.

A variety of therapies can reduce amyloid-beta, this has, however, not led to a substantial alleviation of the symptoms. This illustrates that we don’t understand the key cortical circuits that link the cellular changes to behavior.

If we want to understand how AD disrupts higher-level processes such as memory, we must understand how AD affects cortical microcircuits.

To bridge this gap in knowledge I will study neural activity in the retrosplenial cortex, one of the earliest affected brain areas in AD.

This superficial cortical structure has the important advantage of allowing easy access with powerful optical methods to dissect circuit functions.

Inspired by recent findings that early-stage AD in humans can be detected using a spatial navigation task in virtual reality environments; the Vervaeke lab developed a similar task for mice.

I will use two-photon microscopy to monitor cells over months in AD mice that perform this navigation task, while the disease is progressing.

This offers the unique advantage that I can link changes in circuit activity to changes in cognitive performance over time. These experiments will enable, to date, the most comprehensive picture of cortical microcircuit dysfunction in AD. They will also provide an unprecedented platform for testing innovative therapies in behaving mice.