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Cold Spring Harbor lab part of team mapping mouse brains

Dr. Pavel Osten pulls up data input and

Dr. Pavel Osten pulls up data input and output of cell detection in a mouse brain in his lab at the Cold Spring Harbor Laboratory in Cold Spring Harbor on Wednesday, Oct. 11, 2017. Credit: Randee Daddona

A first-of-its kind mapping of the mouse brain has revealed unexpected gender differences and suggests the possibility that similar variances ultimately may be found in research of the more complex, 3-pound human brain.

Neuroscientists at Cold Spring Harbor Laboratory, working with a team of collaborators in this country and abroad, have completed a quantitative whole-brain map — or qBrain — which is an imaging and analytic technology.

It allowed scientists to examine cell populations known as inhibitory neurons, brain cells that play a critical role in regulating responses to stimuli. Those cells also have been implicated in mental health conditions such as autism and schizophrenia.

“Neurons come in all shapes and sizes,” said Dr. Pavel Osten, an associate professor at the lab and the investigation’s lead scientist, who added that the project allowed him and a team of colleagues to peer into the brains of mice and learn new lessons about the organ’s functions.

Key to the research was tracking neurons throughout the brain — even its most primitive regions, sometimes called the lizard brain. The qBrain technique allowed researchers to visualize those cells as they never had been seen before.

“We can map their distribution in three dimensions across the entire mouse brain,” Osten said.

The study, published this month in the journal Cell, is a proof of concept that specific brain cells now can be imaged and literally counted to produce the first cell-specific 3-D brain maps.

In all, Osten and his collaborators at Cold Spring Harbor Laboratory and beyond examined hundreds of distinct regions and drew a new conclusion. “Among the 600 regions, we found 11 that are different between males and females and they were all in the lizard brain,” Osten said of the area responsible for innate behaviors, such as social responses, parenting and aggression.

Whether such differences exist in comparable regions of the human brain is the subject of an upcoming study, Osten said.

The brain-mapping technology was developed by Osten and Pennsylvania State University College of Medicine collaborator Yongsoo Kim, previously a researcher at the Cold Spring Harbor lab.

The scientists found differences between male and female mice because the new technique allowed them to take a census of cell types. Female mice, despite a smaller overall brain size compared with that of males, had a greater abundance of regulatory neurons in the key regions, Osten said.

Neurons throughout the brain and the rest of the central nervous system generally can be divided into two major cell types: excitatory and inhibitory neurons, according to Kim and the Penn State part of the team.

Excitatory neurons, they said, are the main carriers of information, much like an accelerator in a car, while inhibitory neurons control the activity of excitatory neurons — like a car’s brake. The female mice had more “brakes” that controlled primitive responses, which include sexual behavior.

The new research also helps illuminate how the mammalian brain can make sense out of all of the information flowing through it. The human brain has a bewildering circuitry of 100 billion connections.

“This provides new anatomical evidence to explain how high-cognitive brain regions can basically compute all the information that’s coming from the sensory brain regions and make sense out of the external world,” Kim said.

Osten said one purpose of the qBrain study is to develop a resource for other scientists who can use the findings to enhance their brain-region research.

The animal brain — regardless of species — is a complex “Lego puzzle,” Osten said, noting that it will take time to understand the organ’s complexity, especially with respect to the types and number of neurons in specific regions.

“If you want to understand how brain circuits work,” Osten said, “you first need to know how many pieces there are, of what types, and how are they distributed.”