It is not surprising that maps of our surroundings are one of the brain’s strongest memories. So indelible are they that they are often used as mnemonic devices. Yet, little is known about synchronized neural and genetic activity patterns that drive and are shaped by these strong memory traces that encode maps of the places we venture into.

In a new study published in Nature, scientists measured the activity of neurons in the hippocampus using calcium imaging while simultaneously monitoring gene expression in mice engaged in a virtual reality task that required spatial learning, to uncover a neurogenetic mechanism that shapes and stabilizes spatial maps in the brain. The study, a multi-lab collaboration among scientists at the Blavatnik Institute at the Harvard Medical School (HMS), established that the expression of a transcription factor called Fos helps the brain use specialized cells and code for places, to create and solidify spatial maps. The findings could lend new insights into mechanisms of spatial mapping and the disruption of these mechanisms in patients suffering from injuries to the brain, or neurodegeneration.

Michael Greenberg, PhD, professor of neurobiology (right) and Christopher Harvey, PhD, associate professor of neurobiology (left) at Harvard Medical School, are senior authors of the study.

Senior author of the study, Christopher Harvey, PhD, an associate professor of neurobiology at HMS, said, “This research connects across different levels of understanding to make a pretty direct link between molecules and the function of circuits for behavior and memory that underlie the formation and stability of spatial maps.”

The hippocampus is critical for learning and memory, including the formation of spatial memory in both mice and humans. Earlier studies have established the presence of “place cells” in the hippocampus that activate and deactivate selectively when an animal is engaged in navigation to construct a mental map of the space.

Harvey said, “My lab has studied spatial navigation for years, including how place cells form a map of the environment and form spatial memories. The molecular mechanisms that underlie those processes have been difficult to study in the behaving animal.”

Harvey’s team, including lead author and research fellow Noah Pettit, and graduate student Lynn Yap, collaborated with Michael Greenberg, PhD, a professor of neurobiology at HMS, whose lab studies Fos activity. Earlier work from Greenberg’s team showed that minutes after a neuron is activated, it expresses Fos. Their work also showed Fos mediates different types of neural plasticity—the capacity of neurons to change structurally and functionally, including plasticity accompanying spatial learning and memory.

However, whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression was associated with or influenced spatial coding was unclear. Harvey said, “There have been a lot of studies on Fos and place cells, but this is one of the first papers that directly connect the two.”

In what Greenberg called a “technical tour de force,” Pettite and the team used a 360° virtual reality maze, developed in Harvey’s lab together with calcium imaging and gene expression measures to investigate the role of Fos expression in enlisting the activity of place cells.

They found, within hours of performing a navigation task, hippocampal neurons in mice with high Fos expression were more likely to form accurate “place fields”—clusters of place cells that signal spatial position—than those with low Fos expression. Neurons with high Fos expression also formed place fields that were more reliable over time in indicating spatial position as the mouse repeated the same task on subsequent days. In addition, they found eliminating Fos expression in a subset of neurons in the hippocampus reduced the accuracy and stability of spatial maps compared to neurons with normal Fos expression.

“This tells us that on a moment-to-moment basis as the mouse is navigating, the neurons that induce Fos have very robust information about the mouse’s spatial position, which is the key variable needed to solve and remember the task,” said Pettit.

“Fos seems to be important for maintaining the stability and accuracy of place cells and representing a spatial map in the brain over time,” added Greenberg.

These findings open new avenues of investigation. In future experiments, Harvey is interested in probing how Fos may help establish spatial memories during sleep, while Greenberg plans to investigate how Fos helps the brain form and maintain stable spatial maps and understand the function of Fos when spatial memories are transferred from the hippocampus to other regions of the brain.

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