The neurons in the brain are much more diverse than we thought

A team of researchers has developed the first method to identify different subtypes of neurons in the human brain. The research lays the foundations for "mapping" gene activity in the human brain and can help provide a better understanding of brain functions and disorders, including diseases such as Alzheimer's, Parkinson's, schizophrenia and depression

A team of researchers has developed the first method to identify different subtypes of neurons in the human brain. The research lays the foundations for "mapping" gene activity in the human brain and can help provide a better understanding of brain functions and disorders, including diseases such as Alzheimer's, Parkinson's, schizophrenia and depression.

The researchers identified 16 subtypes of cortical neurons by isolating and analyzing the nuclei and individual human brain cells. The outer layer of the brain that contains the nerve tissue responsible for cognitive functions including memory, attention and decision making. The team, led by researchers at the University of California, San Diego, The Scripps Research Institute (TSRI), and Illumina published their findings in the June 24 online issue of the journal Science.

"We provide a unified framework for looking at and comparing single neurons, which can help us discover how many unique types of neurons exist," said Kun Zhang, professor of bioengineering at the University of California, San Diego and lead author of the paper.

Researchers can use these different subtypes of neurons to build what Zhang calls a "reference map" of the human brain—an infrastructure that will make it possible to understand the differences between a healthy brain and a diseased brain.

"In the future, patients with brain disorders or defects will be able to be diagnosed and treated according to how they differ from the reference map. It's similar to what we did with the human genome map," Zhang said.

The new research reflects the growing understanding that individual brain cells are unique: they express different types of genes and perform different actions. To better understand this diversity, the researchers analyzed more than 3,200 human neurons in six Brodmann areas, areas of the cerebral cortex classified according to their neuronal functions and arrangement.

Through a joint interdisciplinary effort, the team developed a new method to isolate and sequence single cell nuclei. The researchers from TSRI, led by neuroscience professor Jerrold Chun, obtained the brain samples from deceased cadavers and focused on isolating the neuron nuclei. Zhang's lab worked with Fluidigm, a manufacturer of microfluidic chips that allow the study of single cells, to develop a protocol for identifying and quantifying the RNA molecules of neuronal nuclei. Scientists at San Diego-based Illumina prepared libraries of the resulting RNA sequences. Researchers, led by UC San Diego biochemistry professor Wang Wei, developed algorithms to identify 16 subtypes of nerve cells from the sequencing datasets.

The researchers deciphered which types of genes were "turned on" within each nucleus and discovered that different combinations of 16 subtypes of net nerve cells, clustered in layers in the cerebral cortex and Brodmann's areas, help explain why these areas look and function differently.

The neurons showed many differences in their transcription profiles - the patterns of genes that were actively expressed by these cells - revealing individual neurons with common characteristics but also unique to each type, which explain the differences in cell function.

"We're finding new ways to understand the basic building blocks of the brain," said Blue Lake, a postdoctoral researcher in Zhang's lab and co-author of the paper. "Our research opens the door to the observation of universal gene expression patterns and examines how to define cell types within healthy tissues, when the information will make it possible to identify what is abnormal in terms of disease or disorders."

In future studies, researchers aim to analyze neurons in other Brodmann areas of the brain and investigate which subneurons exist in other areas of the brain. They also plan to study neurons that will all be taken from a single deceased brain to study the neural diversity between individuals.

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