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New study reveals how Fos helps form and stabilise spatial memories in the hippocampus

Written by Miyako Rogers, Science Writer

In a new study published in Nature, researchers show the role of transcription factor Fos in shaping and stabilising spatial memories in the hippocampus. Using a virtual reality-based spatial learning task, transgenic mice and a genetic loss of function approach, researchers showed how Fos-expression affects the formation and stability of spatial maps in the brain.

The role of Fos in memory

In the hippocampus, there are two major types of memory stored: Contextual memory and spatial memory. Contextual memory involves remembering the circumstances related to an event, whether that be where they happened, what happened, etc, and is encoded by engram cells, a type of neuron. Spatial memory, responsible for spatial information that allows us to plan a route, or recall locations, is encoded by place cells, another type of neuron.

Fos is a transcription factor, and the role of Fos in engram cells has been studied extensively. Previous studies have shown that expression of Fos occurs during encoding of a memory, and activation can trigger memory recall. However, little is known about the relationship between engram cells and place cells, or the role of Fos in the encoding of spatial memory.

This same team of researchers published a study in 2021 that showed Fos orchestrates neural plasticity in the CA1 hippocampal region, the region of the brain involved in spatial memory and learning. They also showed that Fos expression is required for spatial learning in mice performing a Morris water maze, a behavioural test for spatial learning. While these results suggest Fos may be involved in encoding spatial memory, it remained to be determined whether Fos has an active role in regulating place cell function during spatial learning.

Showing Fos encodes spatial maps

To tackle this question, researchers developed a behavioural test and imaging approach to study Fos expression and place cell function. To do so, they developed a spatial learning task in virtual reality. Mice ran on an air-supported ball and traversed a linear 2-metre-long track that was repeated in a circular topology and received rewards by licking a spout within a 20-cm reward zone (Figure 1a). To measure Fos expression, they used transgenic mice in which eGFP was under the control of the Fos promoter. To measure the activity of neurons in the CA1 hippocampus region, they expressed a calcium indicator and used two-photon imaging.

Figure 1 ¦ a) Schematic of virtual reality spatial learning task. b) Example behaviour of learning versus expert performance showing improvement. c) Average learning curve of mice selectively licking target.

Researchers found that during the VR task there was increased Fos expression and observed differences in the spiking patterns between neurons that expressed high levels of Fos versus neurons that expressed low levels of Fos. They also observed robust place-coding in neurons with high levels of Fos; in other words, Fos-high neurons were more likely to be place cells and had higher spatial information than Fos-low neurons. They then used a probabilistic classifier to predict the mouse’s current location based on the activity of Fos-high neurons and Fos-low neurons and found that the accuracy of predictions was significantly higher in Fos-high neurons.

To further define a causal role for Fos in spatial memory, researchers used a genetic loss of function approach. They found in the mice where Fos was knocked out, there was a significant decrease in reliability, spatial selectivity, and the stability of spatial maps across different days.

Future implications

The results from this study demonstrate that Fos-expression contributes to the formation of spatial maps in the hippocampus and influence their stability over time. Neurons in which Fos-expression was high, encoded accurate, stable, and spatially uniform maps, and knock-out studies suggest that Fos plays a causal role in shaping these patterns. Therefore, Fos-expression may link together 2 key aspects of memory in the hippocampus: Namely contextual memory and spatial memory. Further investigations are needed to elucidate the mechanisms involved, but this study opens up new avenues for research and is the first to highlight the role of Fos in spatial memory.

More on these topics

Brain / Gene Editing / Memory / neuroscience