UCLA scientists observed the activity of large numbers of neurons in the brains of rats while the animals navigated a virtual reality maze. [Mehta Lab/UCLA]

It has been long understood that the area of the brain called the hippocampus is important for memory, learning, and navigation. Scientists in a UCLA lab, led by neurophysicist Mayank Mehta, PhD, have now gained a deeper understanding of how the hippocampus works on a circuit level, with millions of neurons involved in its functioning. The UCLA researchers studied rats in a virtual reality maze, and while observing the activities of large numbers of individual neurons in each animal’s hippocampus, the scientists discovered neuronal responses that revealed a specific mechanism for navigation.

That knowledge, they suggested, could be an important step toward the development of treatments for neurological disorders such as Alzheimer’s disease, schizophrenia, and epilepsy, all of which are related to dysfunction in the hippocampus. The study could also help explain why people with damage to the hippocampus struggle not just with so-called spatial tasks, like finding their way home or locating a lost set of keys, but also with memory tasks, such as recalling what they had for lunch or whether they took their daily medication.

“The hippocampus is one of the first regions to be affected in memory-based diseases like Alzheimer’s,” said the study’s lead author, Jason Moore, PhD, a former UCLA postdoctoral scholar who is now at New York University. “So it is crucial to understand its functionality, flexibility, and limits.”

Mehta and colleagues reported on their rodent studies in Nature, in a paper titled, “Linking hippocampal multiplexed tuning, Hebbian plasticity, and navigation.”

Research in Mehta’s lab and elsewhere over the past 25 years has shown that changes in neurons’ activity—or neuroplasticity—occur via a process known as Hebbian learning. That process is mediated by a neurochemical called NMDA, which is a common target for drugs used to treat neurological disorders. In fact, Hebbian synaptic plasticity is one of what the team referred to in their paper as the “three major pillars of hippocampal function, together with spatial navigation and spatial selectivity. The hippocampus is also thought to be involved in episodic memory, but, the authors noted, “the precise link between these four functions is missing.”

For their newly reported study to further investigate neuronal activity in the hippocampus, the researchers used a type of virtual reality system that was developed in Mehta’s lab. “… we trained four adult rats to execute a virtual navigation task (VNT) similar to the Morris water maze, and measured hippocampal neural responses and their experience-dependent plasticity,” the team explained. This technology is intended to keep the animals comfortable and avoid causing dizziness and other symptoms that other VR systems can trigger.

The test rats were placed on a small treadmill inside a box with images of a maze projected onto the container’s walls. The rats were encouraged to run through the maze to find their reward, a drop of sugar water. In order to make it to the reward, rats needed to discern where they were in relation to the virtual objects around them, where they needed to go to receive their rewards, and how far away the destination was. “Virtual reality (VR) entirely removes nonspecific cues and human intervention and ensures navigation using only distal visual cues, which is a fundamental feature of cognitive mapping,” the investigators further noted. “The appetitive reinforcement, similar to most place cell experiments, allows rats to run many trials and removes stress experienced in the water maze that could impair synaptic plasticity.”

Several animals were tested over many sessions, enabling the researchers to observe how their neuronal responses changed as the rats learned to navigate the maze. “The trial-based structure of the task allows us to explore the neural encoding of sequences of behaviorally relevant events and measures, such as initiation and direction of movement, distance traveled, and the expected reward position,” they stated.

The scientists observed that hippocampal neurons encoded multiple aspects of the animal’s location—where it is in space, the angle of its body relative to its reward, and how far it has moved along its path—a phenomenon called multiplexing. That finding is significant because it had been widely thought that neurons in the hippocampus code only for position. “Remarkably, the same cell could multiplex and represent all three variables: allocentric space, angle, and path distance,” the team noted. “This supports the hypothesis that the hippocampus learns a schema, involving both spatial and nonspatial components, for accurate navigation.”

“We found that in the virtual maze, the neurons carry very little information about the rat’s position,” said Mehta, a UCLA professor of neurology, neurobiology, and physics. “Instead, most neurons encode for other aspects of navigation, such as distance traveled and which direction the body is heading.” As the team commented in their report, “Thus, not only the ensemble of neurons but also individual neurons could provide information about ‘what’ happened during the entire experience.”

The scientists also observed that as the rats gained experience in the maze, their neurons “remembered” the maze even more reliably and accurately. “The strength of neural activity and tuning strongly correlated with performance, with a temporal relationship indicating neural responses influencing behavior and vice versa … Remarkably, neuroplasticity was far greater in the virtual reality environment than in simpler, real-world mazes,” Mehta said. “Further, this boosted neuroplasticity was related to performance.”

Mehta added that the neuroplasticity observed in the rats is likely due to Hebbian learning across billions of synapses. That conclusion was further strengthened when the researchers injected the animals with substances to inhibit NMDA, which then impaired their performance in the maze.

In future studies, Mehta and his colleagues aim to conduct similar research on rats and on humans with memory impairment, to test whether virtual reality can be used for early diagnosis and to evaluate the effectiveness of medications. As they concluded in their paper, “These results open up the possibility of testing rodents and humans under nearly identical, noninvasive, and nonaversive conditions using VR to diagnose learning and memory disorders and achieve effective translation of treatments across species.”

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