Whenever we venture to a new place, our brain’s built-in GPS immediately kicks in and begins to form a spatial map of our surroundings. Over days and even weeks, this map can be solidified as a memory that we can recall to help us navigate more easily each time we return to that particular location.

The way the brain forms these spatial maps is incredibly complex – a process that involves a complex molecular interaction between genes, proteins and neural circuits to shape behavior. Unsurprisingly, the precise steps of this multiplayer interaction have eluded neurobiologists.

Today, scientists, thanks to a multilaboratory collaboration within the Blavatnik Institute of Harvard Medical School, have made a major advance in understanding the molecular mechanisms involved in the creation of spatial maps in the brain.

The new study, conducted on mice and published on August 24 in Natureestablishes that a gene called fos is a key player in spatial mapping, helping the brain use specialized navigation cells to form and maintain stable representations of the environment.

“This research bridges the different levels of understanding to establish a fairly direct link between molecules and the function of behavioral and memory circuits,” said lead author Christopher Harvey, associate professor of neurobiology at HMS. “Here we can understand what really underlies the formation and stability of spatial maps.”

If the results translate to humans, they will provide crucial new insights into how our brains construct spatial maps. Ultimately, this knowledge could help scientists better understand what happens when this process breaks down, as is often the case following brain injury or neurodegeneration.

Memory cards

The hippocampus sits deep in the temporal lobe of the brain and plays an essential role in learning, memory, and navigation for many species, including mice and humans. Scientists have long known that for navigation, the hippocampus contains specialized neurons called place cells that become selectively active when an animal is in different locations in space. By switching on and off as an animal moves through its environment, place cells essentially construct a map of the surrounding area that can be incorporated into a memory.

“My lab has studied spatial navigation for years, including how place cells map the environment and form spatial memories,” Harvey said, and yet “the molecular mechanisms underlying these processes have been difficult to study in the behaving animal”.

To investigate the molecular cascade involved in this mapping process, Harvey and first author Noah Pettit, neurobiology researcher at the Harvey Lab, teamed up with co-lead author Michael Greenberg, Nathan Marsh Pusey Professor of Neurobiology at HMS and the author Lynn Yap, a graduate of Harvard’s doctoral program in neuroscience, who did her doctoral work in the Greenberg lab.

Greenberg’s lab studies the fos gene, which codes for a transcription factor protein that regulates the expression of other genes. In previous research, Greenberg and colleagues have shown that fos is expressed within minutes of a neuron activating, making it a useful marker of neuronal activity in the brain. They also demonstrated that fos mediates different types of neuronal plasticity, including navigation and memory formation. However, the relationship between fos and placing the cells in the hippocampus was not known.

Investigators wondered if fos may be involved in how mice form spatial maps as they navigate their environment.

To find out, the team used a technique developed in Harvey’s lab that places mice in a virtual reality maze: A mouse runs over a ball as it watches a large surround screen that displays a spatial navigation task. such as solving a maze to find a reward. As the mouse runs over the ball and performs the task, the researchers record neural activity and changes in fos expression in the hippocampus.

In what Greenberg called “a technical tour de force”, Pettit conducted a series of complicated experiments to unravel the link between fos and place the cells. The team found that within hours of a mouse performing a navigational task, neurons with high fos expression were more likely to form precise place fields—groups of place cells that signal spatial position—than those with low fos expression. Moreover, neurons with high fos expression had place fields that were more reliable over time in indicating spatial position when the mouse repeated the task on subsequent days.

“This tells us that at every instant while the mouse is navigating, the neurons that induce fos have very strong information about the spatial position of the mouse, which is the key variable needed to solve and memorize the task,” Pettit explained.

When the researchers eliminated fos in a subset of hippocampal neurons, they observed that these cells had less accurate spatial maps of the environment than neighboring neurons with fos expression. In addition, cards in cells without fos were less stable over time and, therefore, were less reliable as memories of the environment.

fos appears to be important for maintaining the stability and accuracy of place cells and representing a spatial map in the brain over time,” Greenberg said.

“There have been many studies on fos and there have been many studies of place cells, but this is one of the first papers that directly connects the two,” Harvey added, “it opens up many exciting new directions to study these mechanisms.”

For example, Greenberg would like to delve into the specific molecules and cells that are involved as fos helps the brain form and maintain stable spatial maps over time. He also wants to understand the different roles fos can play when memories of spatial maps are transferred from the hippocampus to other regions of the brain. Along the same lines, Harvey is interested in whether fos is part of the process by which memories of spatial maps are solidified during sleep.

Although the study was done in mice, the researchers noted that much of the system is conserved across all species, including humans. If the findings can be confirmed in humans, they could help scientists understand how our brains form spatial maps and what happens when we lose this ability due to injury or disease.

Beyond the science, the researchers pointed out that the research represents an unusual partnership between a lab that studies cellular and molecular mechanisms and another that focuses on animal behavior and neural circuitry.

“Our two labs are about as far apart in terms of what we do in the department, but we came together to study how molecules interact with the neural circuits that control learning, memory and behavior,” Greenberg said.

“It was a natural and exciting collaboration to learn that fos plays a role in spatial memories and spatial navigation,” Harvey agreed. “It’s hard to be an expert in all these different levels of neurobiology, but by working together, the two labs were able to bridge the gap.

Funding was provided by the National Institutes of Health (DP1 grants MH125776, R01 NS089521, R01 NS028829), Stuart HQ & Victoria Quan Fellowship, HMS Department of Neurobiology graduate fellowship, and Harvard Aramont Fellowship Fund for Emerging Science Research. The Greenberg Laboratory is supported by the Allen Discovery Centers.