Single-cell analysis reveals diverse landscape of genetic changes in the brain after a sensory experience

February 8, 2018, Harvard Medical School
'brainbow' of cerebral cortex neurons labeled with different colors . Credit: Lichtman Lab, Harvard University.

"Nature and nurture is a convenient jingle of words, for it separates under two distinct heads the innumerable elements of which personality is composed. Nature is all that a man brings with himself into the world; nurture is every influence from without that affects him after his birth." - Francis Galton, cousin of Charles Darwin, 1874.

Is it nature or nurture that ultimately shapes a human? Are actions and behaviors a result of or environment? Variations of these questions have been explored by countless philosophers and scientists across millennia. Yet, as biologists continue to better understand the mechanisms that underlie , it is increasingly apparent that this long-debated dichotomy may be no dichotomy at all.

In a study published in Nature Neuroscience on Jan. 21, neuroscientists and systems biologists from Harvard Medical School reveal just how inexorably interwoven nature and nurture are in the mouse brain. Using novel technologies developed at HMS, the team looked at how a single sensory experience affects in the brain by analyzing more than 114,000 individual cells in the mouse visual cortex before and after exposure to light.

Their findings revealed a dramatic and diverse landscape of across all cell types, involving 611 different genes, many linked to neural connectivity and the brain's ability to rewire itself to learn and adapt.

The results offer insights into how bursts of neuronal activity that last only milliseconds trigger lasting changes in the brain, and open new fields of exploration for efforts to understand how the brain works.

"What we found is, in a sense, amazing. In response to visual stimulation, virtually every cell in the visual cortex is responding in a different way," said co-senior author Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and chair of the Department of Neurobiology at HMS.

"This in essence addresses the long-asked question about nature and nurture: Is it genes or environment? It's both, and this is how they come together," he said.

One out of many

Neuroscientists have known that stimuli—sensory experiences such as touch or sound, metabolic changes, injury and other environmental experiences—can trigger the activation of genetic programs within the brain.

Composed of a vast array of different cells, the brain depends on a complex orchestra of cellular functions to carry out its tasks. Scientists have long sought to understand how individual cells respond to various stimuli. However, due to technological limitations, previous genetic studies largely focused on mixed populations of cells, obscuring critical nuances in cellular behavior.

To build a more comprehensive picture, Greenberg teamed with co-corresponding author Bernardo Sabatini, the Alice and Rodman W. Moorhead III Professor of Neurobiology at HMS, and Allon Klein, assistant professor of systems biology at HMS.

Spearheaded by co-lead authors Sinisa Hrvatin, a postdoctoral fellow in the Greenberg lab, Daniel Hochbaum, a postdoctoral fellow in the Sabatini lab and M. Aurel Nagy, an MD-PhD student in the Greenberg lab, the researchers first housed mice in complete darkness to quiet the visual cortex, the area of the brain that controls vision.

They then exposed the mice to light and studied how it affected genes within the brain. Using technology developed by the Klein lab known as inDrops, they tracked which genes got turned on or off in tens of thousands of before and after light exposure.

The team found significant changes in gene expression after light exposure in all cell types in the visual cortex—both neurons and, unexpectedly, nonneuronal cells such as astrocytes, macrophages and muscle cells that line blood vessels in the brain.

Roughly 50 to 70 percent of excitatory neurons, for example, exhibited changes regardless of their location or function. Remarkably, the authors said, a large proportion of non-neuronal —almost half of all astrocytes, for example—also exhibited changes.

The team identified thousands of genes with altered expression patterns after , and 611 genes that had at least two-fold increases or decreases.

Many of these genes have been previously linked to structural remodeling in the brain, suggesting that virtually the entire , including the vasculature and muscle cell types, may undergo genetically controlled rewiring in response to a sensory experience.

There has been some controversy among neuroscientists over whether gene expression could functionally control plasticity or connectivity between neurons.

"I think our study strongly suggests that this is the case, and that each cell has a unique genetic program that's tailored to the function of a given cell within a neural circuit," Greenberg said.

Question goldmine

These findings open a wide range of avenues for further study, the authors said. For example, how genetic programs affect the function of specific cell types, how they vary early or later in life and how dysfunction in these programs might contribute to disease, all of which could help scientists learn more about the fundamental workings of the brain.

"Experience and environmental stimuli appear to almost constantly affect gene expression and function throughout the brain. This may help us to understand how processes such as learning and memory formation, which require long-term changes in the brain, arise from the short bursts of electrical activity through which neurons signal to each other," Greenberg said.

One especially interesting area of inquiry, according to Greenberg, includes the regulatory elements that control the expression of genes in response to sensory experience. In a paper published earlier this year in Molecular Cell, he and his team explored the activity of the FOS/JUN protein complex, which is expressed across many different in the brain but appears to regulate unique programs in each different cell type.

Identifying the regulatory elements that control gene expression is critical because they may account for differences in brain function from one human to another, and may also underlie disorders such as autism, schizophrenia and bipolar disease, the researchers said.

"We're sitting on a goldmine of questions that can help us better understand how the works," Greenberg said. "And there is a whole field of exploration waiting to be tapped."

Explore further: Scientists use gene expression to understand how astrocytes change with age

More information: Sinisa Hrvatin et al, Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex, Nature Neuroscience (2017). DOI: 10.1038/s41593-017-0029-5

Related Stories

Scientists use gene expression to understand how astrocytes change with age

January 11, 2018
Potentially explaining why even healthy brains don't function well with age, Salk researchers have discovered that genes that are switched on early in brain development to sever connections between neurons as the brain fine-tunes, ...

Researchers map out genetic 'switches' behind human brain evolution

January 11, 2018
UCLA researchers have developed the first map of gene regulation in human neurogenesis, the process by which neural stem cells turn into brain cells and the cerebral cortex expands in size. The scientists identified factors ...

NeuroExpresso: Web app enables exploration of brain cell types

November 20, 2017
An online database of gene expression profiles for 36 major types of brain cells from 12 brain regions, based on mouse data from multiple laboratories, is reported in a new paper published in eNeuro. The tool is provided ...

Using genes to understand the brain's building blocks

January 4, 2016
Understanding the cellular building blocks of the brain, including the number and diversity of cell types, is a fundamental step toward understanding brain function. Researchers at the Allen Institute for Brain Science have ...

Researchers look to the fruit fly to understand the human brain

December 1, 2017
The human nervous system is like a complex circuit board. When wires cross or circuits malfunction, conditions such as schizophrenia or bipolar disorder can arise.

Scientists discover regional differences among chandelier cells

October 10, 2017
The brain is composed of distinct regions that differ in their functional roles and cellular architecture. For example, the hippocampus is an area well-known for its involvement in memory and its dysfunction in diseases such ...

Recommended for you

Children with brain tumors who undergo radiation less likely to recall recent events

August 20, 2018
Children with certain types of brain tumors who undergo radiation treatment are less likely to recall the specifics of events they experienced after radiation than to remember pre-treatment happenings, according to a Baylor ...

Female mice are immune to cognitive damage from space radiation

August 20, 2018
Humankind still dreams of breaking from the bounds of Earth's atmosphere and venturing to the moon, Mars and beyond. But once astronauts blast past the International Space Station, they become exposed to one of the many dangers ...

Researchers unravel why people with HIV suffer from more neurologic diseases

August 20, 2018
Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), which the HIV virus can cause, continue to be one of the world's greatest health problems.

Fluidically linked blood-brain barrier and Organ Chips offer new method for studying effects of drugs on the brain

August 20, 2018
The human brain, with its 100 billion neurons that control every thought, word, and action, is the most complex and delicate organ in the body. Because it needs extra protection from toxins and other harmful substances, the ...

Rogue proteins may underlie some ALS and frontotemporal dementia cases, says study

August 20, 2018
ALS—amyotrophic lateral sclerosis—is a neurodegenerative disease that attacks motor neurons in the brain and spinal cord, slowly robbing its victims of their ability to walk, talk, breathe and swallow. In a cruel twist, ...

Bilingual children who speak native language at home have higher intelligence

August 20, 2018
Children who regularly use their native language at home while growing up in a different country have higher IQs, a new study has shown.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

RobertKarlStonjek
not rated yet Feb 08, 2018
Nature-Nurture was always a flawed dichotomy when it comes to behavioural predisposition, in humans there are four influences, any one of which can dominate the course of the current behavioural episode:
1) Genetic predisposition and the Behavioural phenotype generally;
2a) the individual's interaction with the environment;
2b) the environment's interaction with the individual;
3) the culture a person adopts;
4) the current conditions.

I can be argued that adult individual's behaviour is influenced by all four sources of influence. For instance as the brain is derived from genetic predisposition, genetic inheritance always plays some role in behaviour mediated by the brain; moral considerations always play some role…

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.