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A new platform for genetically engineered laboratory animals is allowing neuroscientists to ask – and answer – new kinds of questions about the brain.
5 min read
Nearly 50 of these “lines” of mice, each with a different genetic modification, are described in a study published today in the journal Cell.
That publication is the fruit of more than a decade worth of work, said Hongkui Zeng, Ph.D., Executive Director of Structured Science at the Allen Institute for Brain Science and senior author on the study.
Zeng has been working on developing genetic tools for neuroscience research at the Allen Institute since 2007, but what makes many of the new types of transgenic mice described in the current study special is the region of the genome that is used, Zeng said. That region is called TIGRE, and it’s what is known as “permissive,” meaning when genetic researchers like Zeng and her colleagues insert genes in this specific location, they can get consistently high levels of the protein product made from those genes, or expression of those genes, in many different cell types within the brain..
That’s important because there are certain types of brain cells that researchers just haven’t been able to visualize or manipulate with other currently available genetic tools, said Tanya Daigle, Ph.D., Senior Scientist at the Allen Institute for Brain Science and an author on the study. Some of the mice are now genetically engineered with fluorescent proteins or other molecular tools that are only produced in certain cell types in the brain, allowing scientists to sort out specific brain cells that previously were hard to distinguish from the background of the rest of the brain.
“There are huge populations of cells that were essentially untargetable,” Daigle said. “Now we can target them.”
For example, when scientists want to know what individual neurons do in the brain, they first need to know where those neurons are – all the parts of them. That’s a tougher challenge than it would appear, for neurons send long, thin tendrils known as axons through the brain to make connections to other cells.
Tracing those axons in their entirety can help scientists better understand how different cells in the brain communicate information to each other, but to date it’s been difficult to pick out these delicate threads individually under the microscope. Techniques exist to fluorescently label neurons, but the labeling is typically either so dense that researchers can’t tell which axons come from which cells, or they only label one cell in an entire brain, making tracing multiple individual cells an even more laborious process, said Julie Harris, Ph.D., Associate Director of Neuroanatomy at the Allen Institute for Brain Science.
Now, some of the newly created animal lines are allowing Harris and her team to trace certain axons in the mouse brain, offering a more detailed view of the brain’s connections. In one example presented at a 2017 conference, they traced a single neuron whose axon wrapped around the animal’s entire brain. More recently, neuroanatomist Yun Wang, Ph.D., and others on the team have been piecing together many more neurons, up to 70 separate individual cells of a single type and their axons.
Understanding how the brain makes connections at this level will let Harris and her colleagues start to answer questions like: “What can a single neuron do? And is there a logic to what they do?” she said.
The sheer brightness of the fluorescent proteins in the genetically modified animals Daigle, Zeng and their colleagues engineered is helping make that possible, Harris said.
The engineered animals allow more than just visualization, though. For example, some of the mouse lines let scientists switch cells on and off in the brain to study how they work. The 49 lines in the current study represent about half the different engineered mouse types Zeng’s team has developed, nearly all of which are available for researchers to order through the nonprofit Jackson Laboratory.
Of the approximately 100 mouse lines the team has engineered, about half are what is known as “reporter” lines, which express the engineered gene that allows researchers to conduct an experiment, such as recording the activities of cells in a living brain. The other half are “driver” lines, which tell specific cells in the brain to activate the reporter gene. Scientists can mix and match reporters and drivers to create the type of animal for their specific experiment.
Zeng and her team are already working on the next iteration of the TIGRE mouse lines, some of which will use two different fluorescent proteins in one animal to visualize even rarer brain cell types. It’s all part of the quest to better understand how the brain is organized, Zeng said.
“There are organizing principles for the brain. We think one of those is cell types,” she said. “If we want to understand how these cell types function, we need to have tools to label them and tweak them.”
Other authors on the study include Linda Madisen, Travis Hage, Matthew Valley, Ulf Knoblich, Rylan Larsen, Marc Takeno, Lawrence Huang, Hong Gu, Rachael Larsen, Maya Mills, Alice Bosma-Moody, La’ Akea Siverts, Miranda Walker, Lucas Graybuck, Zizhen Yao, Olivia Fong, Thuc Nghi Nguyen, Emma Garren, Garreck H. Lenz, Julie Pendergraft, James Harrington, Karla Hirokawa, Philip Nicovich, Medea McGraw, Douglas Ollerenshaw, Kimberly Smith, Christopher Baker, Jonathan Ting, Susan Sunkin, Jérôme Lecoq, Gabe Murphy, Nuno da Costa, Jack Waters, Lu Li and Bosiljka Tasic of the Allen Institute for Brain Science; Mariya Chavarha and Michael Lin of Stanford University School of Medicine; and Edward Boyden of the Massachusetts Institute of Technology.
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