“Our dream was to invent a window into the brain so that we can see what’s happening inside when we think, plan, feel and remember,” says Professor May-Britt Moser, describing discussions with her long-term colleague Professor Edvard Moser as a young psychology student in the early 1990s Founding Director of the Center for Neural Computation and Co-Director of the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology (NTNU) and a Nobel laureate, she shared with her research partner Edvard Moser, co-director of the Kavli Institute for Systems Neuroscience.
Today, Leif Erikson the Mouse is the first step in making that dream come true. The mouse is equipped with a window on the head. At the top of the window are 2.4 grams of pure technological innovation. The portable “Mini2P” is perhaps best described as a tiny cortical observatory that records live images of neural landscapes like never seen before.
Reporting live from the brain
In the brain of Leif Erikson the mouse, thousands of neurons work together to solve a very specific task. This activity is visible when some cells start to glow. Shortly thereafter, other cells light up.
The Mini2P can record live from the brain area responsible for Leif’s navigation skills. At the same time, the sparkling brain cells that the researchers see on the screen enable the mouse to find its way across the floor, up a climbing tower, to the tower roof, where delicious vanilla cream biscuit crumbles await.
“If we want to understand complex behaviors, the animal must be able to move freely and behave in a way that is natural for it,” says Edvard Moser. “The Mini2P is the first tool that allows us to study neural network activity in naturally behaving animals at high resolution.”
Great inventions come in small packages
The basic mechanisms of Mini2P are not too different from a light microscope or the human eye. The smallest unit of light is called a photon. Mini2P uses two and two tiny light beams from a laser to stimulate and register neurons with high resolution and precision.
“In developing the Mini2P, we followed two rules that we were not willing to compromise on,” says Weijian Zong. Zong is the first author of a new article describing the technology and is a researcher at the Kavli Institute.
“The first rule was that any improvement in equipment must not affect the natural behavior of the animal. So we knew we had to lose weight to make the microscope and its cable as light and flexible as possible,” he said. “The second rule was that we cannot compromise on the performance of the microscope. If we want researchers to invest time in a new tool, the features of the miniscope have to be significantly better than its predecessors.”
One of the Mini2P’s several brilliantly engineered features is a tiny electrically tunable lens. By using static tension, Zong was able to manipulate the curvature of the lens without causing an increase in temperature. By changing the curvature of the lens, Mini2P is prompted to shift the plane of focus between the surface and deeper cell layers of the cortex, which also enables 3D structural recordings of brain tissue.
A gene borrowed from jellyfish makes brain cells glow when they chat with each other.
Using bioluminescence, researchers can see exactly which cells are participating in which segments of the conversation. You can also observe how ideas emerge from the neuronal conversation, which the mouse then stages “in the outside world”.
The researchers can also color-code the brain cells based on the genes they express and the brain areas they communicate with. In this way, researchers learn what types of brain cells need to work together to create different cognitive abilities.
Mini2P simultaneously records thousands of brain cells. It can follow the same brain cells for more than a month, keeping them in focus during even the most vigorous activity, like repeated jumps from a 9-inch tower. Mini2P can explore different areas and mental functions throughout the cortex of the brain.
The researchers tested Mini2P in several regions of the brain, such as the navigation system, the memory center and the visual area. Using a kind of patchwork quilting technique, it can map even larger neural landscapes, such as 10,000 brain cells in the visual cortex. All measurements were made while the mouse was moving freely and doing what it normally does. That was simply impossible before Mini2P.
Play off Mini2P against the next existing technologies
1-photon miniscopes have been around for a decade. You have several problems. The resolution is insufficient, imaging may be too slow, the focal plane cannot be shifted in the Z-axis, or they are unusable for most parts of the cortex with high activity and high cell density.
Mini2P enables acquisition of multiple planes along the Z-axis at scales ranging from cell substructures such as axonal branches to topographic maps of tens of thousands of cells. The current benchtop version of the two-photon microscope weighs half a ton and takes up most of the space. The tabletop microscope requires the mouse’s head to be held in place, which restricts the mouse’s natural movement. It also replaces the mouse’s access to the real world with virtual reality. This isn’t something a mouse would normally experience, which means its behavior probably isn’t natural either.
Mini2P, on the other hand, weighs 2.4 grams and features a super-flexible laser and light-gathering cable that allows the mouse to move freely and dynamically just as if it were wearing Mini2P on its head.
Mini2P is open source
“We believe that Mini2P is a game changer and we want to share it with neuroscientists and laboratories around the world,” says May-Britt Moser.
“The amount of research data collected from each individual record can also play a role in reducing the number of animals used in research,” she said. The new tool could also play an important role in understanding brain diseases.
“Alzheimer’s disease often begins with damage to the entorhinal cortex,” says Edvard Moser. “We know that Alzheimer’s causes deficits in the ability to navigate and in memory. These are brain functions that result from the joint cooperation of thousands of brain cells.”
“The Mini2P offers a way to monitor changes in dynamics between thousands of cells in freely moving mice, using mouse strains that are model organisms for studying Alzheimer’s disease,” he explains. “The ability to label different cell types may also allow us to identify which cells are susceptible to the early changes associated with Alzheimer’s disease,” said Edvard Moser.
Mini2P is an open source invention available from the Kavli Institute for Systems Neuroscience at NTNU in Trondheim. The blueprint, a shopping list, and how-to movies are available on GitHub. The institute will also offer workshops later in the year. Equip your lab with the Mini2P Brain Explorer here:
reference: Zong W, Obenhaus HA, Skytoen ER, et al. Large-area two-photon calcium imaging in freely moving mice. cell. 2022;0(0). doi:10.1016/j.cell.2022.02.017
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