Detailed brain maps include neurons in the prefrontal cortex, as well as gene activity in immune and vascular cells.
Credit: PASIEKA/SPL/Getty
Largest Human Prefrontal Cortex Gene Map Reveals How Brain Cells Change With Age and Disease
Researchers have created the largest map to date of gene activity in the human prefrontal cortex1—brain regions that support planning, decision-making, and behavioral and emotional control. The landmark map provides unprecedented detail for studying neurodegenerative and psychiatric diseases, based on sequence data from more than 6 million individual cells taken from approximately 1,500 people.
The research was published today as part of a collection of eight studies, including three papers in Nature1–3.
“The scale of this project and the amount of work required to put it together is truly astonishing,” says Zhiqiao Miao, a computational biologist at China’s Guangzhou National Laboratory who was not involved in the work. “Single-cell studies of the human brain have traditionally been limited to relatively small numbers of individuals. Pushing us into a population-sized setting changes the kinds of questions we can ask.”
Why the prefrontal cortex matters
Panos Roussos, director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai in New York City and a co-author of all eight papers, says the study is the culmination of a large-scale effort that began in 2019. The PsychAD Consortium is an NIH-funded collaboration between multiple US institutions that aims to link genetic mutations, ageing, and disease to changes in specific brain cells.
Roussos says the group focused on the prefrontal cortex because it plays an important role in working memory and executive function—high-level processes involved in planning, concentration, and multitasking. Destruction of a specific subregion, called the dorsolateral prefrontal cortex, has been implicated in several psychiatric disorders and types of dementia.
To create the map, the team studied tissue from about 1,500 people whose brains were donated to science after death. The donors ranged from infants to 108 years old, had diverse ancestry, and included neurotypical controls and people diagnosed with Alzheimer’s disease, Lewy body dementia, Parkinson’s disease, vascular dementia, tauopathy, frontotemporal dementia, schizophrenia, or bipolar disorder.
More than 6 million brain cells analyzed
The researchers used single-cell RNA sequencing, a technique that identifies the RNA transcripts active within individual cells at the time of sampling. This allows scientists to examine the state and function of cells in detail.
Using this approach, the researchers recorded gene activity in more than 6.3 million individual brain cells, including neurons that carry electrical messages, immune cells, and blood-vessel cells.
“Studying the same area under different conditions allows for more consistent comparisons and helps link the results to existing genetic and molecular studies,” says Roussos. “This is an important window into brain disease, but additional disciplines are needed to understand the full picture.”
How the prefrontal cortex changes across the lifespan
In the first study1, researchers examined healthy brains collected from people younger than 1 year old to 97 years old to investigate how the human dorsolateral prefrontal cortex changes over the lifespan.
The team identified three distinct stages of cortical development: rapid remodeling early in life, stability through middle age after about age 24, and a second remodeling phase beginning around age 65.
Different cell types showed distinct patterns of gene activity. These included changes associated with early brain development and later-life changes involving cell types linked to immune activity, stress responses, and the brain’s daily circadian rhythm.
Source: www.nature.com