Mechanistic steps of a novel type of synaptic plasticity

A long-standing question in neuroscience is how the brains of mammals, including humans, adapt to external environments, information, and experiences
.
In a paradigm shift study published in the journal Nature, researchers at the Jan and Dan Duncan Institute for Neurological Research (Duncan NRI) at Children's Hospital Texas and Baylor College of Medicine have identified a new mechanistic step of synaptic plasticity called behavioral timescale synaptic plasticity (BTSP).

。 The study, led by Baylor University professor Jeffrey Magee, Ph.
D.
, who is also a researcher at the Howard Hughes Medical Institute and the Duncan NRI, sheds light on how the entorhinal cortex (EC) sends guiding signals to the hippocampus, a brain region critical for spatial navigation, memory encoding, and consolidation, and directs it to specifically reorganize the location and activity of specific subpopulations of its neurons to achieve changing behaviors
that respond to changing environmental and spatial cues.

Neurons communicate
with each other through connections called synapses.
Synaptic plasticity refers to the ability of these neuronal connections to become stronger or weaker adaptable over time as a direct response
to changes in the external environment.
Our neurons' ability to respond quickly and accurately to external cues is essential for our survival and growth, and is the neurochemical basis
of learning and memory.

Animal brain activity and behavior quickly adapt to spatial changes

To determine the mechanism by which mammalian brains have adaptive learning capabilities, Dr.
Christine Grienberger, a postdoctoral researcher in Magee's lab and lead author of the study, measured the activity of a group of location-specific cells, specialized hippocampal neurons that build and update "maps"
of the external environment.
She mounted a high-powered microscope on the brains of these mice and measured the activity of
these cells as the mice ran on a linear treadmill.

At the initial stage, mice adapt to this experimental setup and change the position of
the reward (sugar water) at each turn.
"At this stage, the rats continue to run at the same speed while continuously licking the runway
.
This means that the location cells in these mice form a uniform tiling pattern," said Dr.
Greenberg, who is currently an assistant professor
at Brandeis University.

In the next stage, she fixes the reward to a specific location on the track, along with some visual cues to determine the direction of the mouse and measure the activity of the same set of
neurons.
"I found that changing the reward position changed the behavior
of these animals.
Now, the rats briefly slow down in front of the reward site to taste the sugar water
.
More interestingly, this change in behavior was accompanied by an increase
in the density and activity of cells at locations around the reward site.
This suggests that changes in spatial cues can lead to adaptive reorganization and activity of hippocampal neurons," Dr.
Greenberg added
.

This experimental paradigm allowed researchers to explore how changes in spatial cues shape mammalian brains, triggering new adaptive behaviors
.

For more than 70 years, Herb's theory — popularly summed up as "neurons signal together, connect together" — has strangely dominated neuroscientists' ideas
about how synapses get stronger or weaker over time.
While this well-researched theory is the basis for several advances in neuroscience, it also has some limitations
.
In 2017, researchers in Magee's lab discovered a new, powerful type of synaptic plasticity—behavioral timescale synaptic plasticity (BTSP), which overcame these limitations and provided a model that best simulates the timescale
of events we learn or remember in real life.

Using the new experimental paradigm, Dr.
Greenberg observed that in the second stage, after the reward position is fixed, the previously silent position cell neurons suddenly acquire a large position field
within a single circle.
This finding is consistent
with non-Hegelian forms of synaptic plasticity and learning.
Further experiments confirmed that the observed adaptive changes in hippocampal location cells and the behavior of these mice were indeed due to BTSP
.

The endotorhinal cortex indicates how hippocampal location cells respond to spatial changes

Based on their previous research, Magee's team knew that BTSP involved a guideline/supervisory signal that wasn't necessarily located inside or near
the activated target neuron (in this case, hippocampal location cells).
To determine the source of this guiding signal, they studied axon projections
from a nearby brain region called the entorhinal cortex (EC).
The entorhinal cortex innervates the nerves of the hippocampus, acting as a conduit
between the hippocampus and the neocortical regions that control the higher executive/decision-making processes.

"We found that when we specifically inhibited a subset of the EC axons that innervate CA1 hippocampal neurons, it prevented the development of CA1 reward overperformance in the brain," Dr.
Magee said
.

Based on several lines of investigation, they concluded that the entorhinal cortex provides a relatively constant target indication signal that guides the position and activity of cells at the hippocampal body mass group, which in turn influences animal behavior
.

"The discovery that one part of the brain (the endoolfactory complex) can direct another brain region (the hippocampus) to change the location and activity of its neurons (locating cells) is an extraordinary discovery in the field of neuroscience," Dr.
Magee added
.
"It completely changes our view of how learning-dependent changes occur in the brain, revealing new areas of possibilities that will change and guide how we deal with neurological and neurodegenerative diseases
in the future.
"

The study was funded
by the Howard Hughes Medical Institute, the Cullen Foundation, and the Jane and Dan Duncan Institute of Neurology at Texas Children's Hospital.