July 1, 2024
Remembering where we’ve been is fundamental both to our ability to function and to our personal identity. That alone might be enough motivation to want to know how the brain forms memories of places, but for neuroscientists an even deeper motivation is that the process illustrates multiple mechanisms of “plasticity,” which is a term for the many ways neurons change the strength of their connections with other neurons to represent memories in circuits. With a new fellowship award from the Klingenstein Philanthropies and the Simons Foundation Assistant Professor Linlin Fan will launch research to advance understanding of how the brain employs plasticity to learn places.
“The overall goal is to understand how inhibitory synaptic plasticity manifests in behaving mammals during learning and memory,” said Fan, an investigator in The Picower Institute for Learning and Memory and a faculty member in MIT’s Department of Brain and Cognitive Sciences.
The study may have medical implications as well. Because the dynamic involves a critical role for endocannabinoids, a brain chemical that can modulate the neurotransmitter release of neurons, the research could also shed light on epilepsy and on marijuana use, Fan said. Epileptic seizures are believed to increase endocannabinoid release, which could affect plasticity processes that depend on its levels. Meanwhile, marijuana use supplies the brain with external cannabinoids that could compete with the natural cannabinoid dynamics necessary for place memory plasticity.
A mysterious mechanism
The plasticity hypothesized to be at play in place memory formation is fundamental, but it’s not necessarily simple. In a 2023 study in Cell, Fan led a study showing that a “place cell” in the hippocampus region of the mouse brain could be compelled to represent a memory of a specific location if scientists artificially activated the cell when the mouse reached that location in a virtual maze. To do so, Fan and her colleagues used “optogenetics,” a technology that genetically engineers neurons to be controlled with pulses of visible light. Using innovative imaging techniques that Fan devised, she simultaneously employed that technique alongside the use of a genetically encoded voltage indicator (GEVI) that glows based on the level of a neuron’s electrical activity. The study demonstrated the mechanisms of behavioral-timescale plasticity of place cell learning of locations.
But excitatory plasticity is not all there is to the story. There is mounting evidence that the place cell also must suppress inhibitory input from another kind of neuron to improve its tuning to a favored location. Earlier this year Fan and her colleagues published a study in Science to investigate this mysterious part of the process, called “depolarization-induced suppression of inhibition” (DSI). They showed that when a place cell receives the excitation that tunes it to a location, it emits an endocannabinoid signal that is received by inhibitory neurons that normally tamp down the place cell’s electrical activity. Using Fan’s optical methods, they further showed that a cell was able to suppress incoming inhibition when it was receiving excitation (as in the Cell study), but not when it wasn’t. In another experiment they showed that if they knocked out the inhibitory cells’ endocannabinoid receptors then the place cells did a poorer job of representing the favored location.
Improving understanding
Taken together the results in Science provided an important set of associations suggesting that when place cells are being excited to refine their tuning to a specific location they use endocannabinoid signaling to modulate the incoming inhibition. In the new project funded by the Klingenstein-Simons award, Fan said, she wants to more deeply study the role of this inhibitory plasticity in learning and memory.
For instance, Fan said she plans to conduct experiments to test whether behavioral timescale plasticity (for instance, the process that occurred when they artificially imprinted a place memory cell in 2023 Cell paper) recruits DSI.
“We hypothesize that this depolarization induced suppression of inhibition may promote cellular excitability and open a time window for excitatory synaptic plasticity to occur,” Fan said.
To get at whether endocannabinoids have a causal role in modulating inhibition, Fan will knock out the inhibitory cells’ endocannabinoid receptors and measure whether the place cells fail to show the same implementation of plasticity they can achieve when cannabinoid signaling is not disrupted. She’ll also measure the effect on plasticity when she optogenetically suppresses or excites the inhibitory cells.
Fan’s use of multiple simultaneous optical methods (optogenetics, GEVIs and an endocannabinoid reporter) is new in the field, so she said she felt encouraged that the Klingenstein-Simons Fellowship i Neuroscience program was willing to support her approach.
“I’m very grateful to these organizations for supporting our work,” Fan said. “Not a lot of other people are doing this type of work, both developing new technology but also using it to discover new biology.”
