Novel tool provides an unprecedented view of brain cell activity

To decipher the mysteries behind memory and learning, researchers from Johns Hopkins Medicine developed a system to trace millions of connections amongst brain cells in mice, simultaneously—when the animals’ whiskers are tweaked, a signal for learning.

3D Brain Synapses in Mice

Every green glowing area is one synapse in a living mouse’s brain. The image shows dense constellations of millions of synapses throughout the mouse cortex. Video Credit: Austin Graves, Johns Hopkins Medicine.

Scientists reveal that the novel tool provides an unparalleled view of brain cell activity in a synapse—a small space between two brain cells, where chemicals and molecules are transferred back and forth.

It was science fiction to be able to image nearly every synapse in the brain and watch a change in behavior.”

Richard Huganir PhD, Bloomberg Distinguished Professor, Neuroscience and Psychological and Brain Sciences, The Johns Hopkins University

Richard Huganir is also the director of the Department of Neuroscience at the Johns Hopkins University School of Medicine.

The research summary was published on October 18th, 2021, and the whole article was published on November 25th, 2021 in the eLife journal.

The scientists never assumed that it is possible to visualize brain activity on such a big scale. According to the, before the development of the tool, the capability to visualize brain cell activity was similar to gazing in the night sky with bare eyes and watching billions of stars.

It’s like we can see and track each of the stars at the same time.”

Austin Graves PhD, Instructor, Neuroscience, Johns Hopkin University School of Medicine

The space between brain cells, or neurons, is small and is less than a micron—about one-tenth of the width of a human hair. Inside these junctions between neurons is a highway of passing proteins and molecules—majorly calcium and sodium—transporting from one neuron to the next.

The neurotransmitters when passing across a synapse and land on a neuron, they activate an AMPA glutamate receptor—a protein present in the outer covering of the neuron.

These receptors are the functional machinery of language between neurons.”

Austin Graves PhD, Instructor, Neuroscience, Johns Hopkin University School of Medicine

Huganir and other researchers revealed that synapses and the receptors enclosed in them are major locations for learning in the brain. According to them, that is where memories are encoded.

To investigate the operation of the synapses, researchers customarily cultured samples of brain cells in the lab to screen for decreases or increases in proteins produced by the cells. They also analyzed subsets of neurons in different regions of the brain, however, researchers could not image synapses in the whole brain on such a massive scale earlier.

The researchers genetically engineered mice by introducing the GRIA1 gene into the DNA, producing a green glowing tag on all AMPA glutamate proteins. When neurons amp up their signaling, they produce more AMPA glutamate proteins.

This results in the green signal getting brighter. As AMPA glutamate receptors are found commonly, the scientists could identify most of the excitatory neurons—which send signals to other neurons instead of blocking them—in the mouse brain.

The scientists later tweaked a whisker on each mouse and employed high-powered microscopes to track the synapses that glowed green and also the brightness of the signal. They observed that around 600,000 glowing synapses and indications that the brightness of the green signal corresponded to the strength of the AMPA glutamate receptor’s response.

Huganir states the novel system produces amazing amounts of data. So, the scientists associated with computational scientists in the Johns Hopkins Department of Biomedical Engineering to create machine learning and artificial intelligence techniques to train and evaluate algorithms that instinctively identify all of the glowing synapses and how they change with time due to experience and learning.

The scientists state that the current research is a proof-of-principle study that demonstrates the abilities of the synaptic imaging tool. Other researchers were urged to use genetically engineered mice in their investigations.

The scientists also intend to use the tool to analyze learning and memory, other mouse behaviors, and to investigate how synapses alter under specific conditions like autism and Alzheimer’s Disease.

Source:
Journal reference:

Graves, A. R., et al. (2021) Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors. eLife. doi.org/10.7554/eLife.66809.

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