Nature, Meet Nurture


Single-cell analysis reveals dramatic landscape of genetic changes in the brain after visual stimulation

A “brainbow” of cerebral cortex neurons labeled with different colors.

“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 genes 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 brain function, 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.

Using novel technologies developed at HMS, the team looked at how a single sensory experience affects gene expression 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 gene expression changes 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 individual cells 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, non-neuronal 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 cells—almost half of all astrocytes, for example—also exhibited changes.

The team identified thousands of genes with altered expression patterns after light exposure, 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 visual cortex, 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.

Goldmine of questions

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 cell types 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 brain works,” Greenberg said. “And there is a whole field of exploration waiting to be tapped.”

Study reveals rats show regret, a cognitive behavior once thought to be uniquely human.


Study reveals rats show regret, a cognitive behavior once thought to be uniquely human

New research from the Department of Neuroscience at the University of Minnesota reveals that rats show regret, a cognitive behavior once thought to be uniquely and fundamentally human.

 
Research findings were recently published in Nature Neuroscience.
To measure the cognitive behavior of regret, A. David Redish, Ph.D., a professor of neuroscience in the University of Minnesota Department of Neuroscience, and Adam Steiner, a graduate student in the Graduate Program in Neuroscience, who led the study, started from the definitions of regret that economists and psychologists have identified in the past.
“Regret is the recognition that you made a mistake, that if you had done something else, you would have been better off,” said Redish. “The difficult part of this study was separating regret from disappointment, which is when things aren’t as good as you would have hoped. The key to distinguishing between the two was letting the rats choose what to do.”
Redish and Steiner developed a new task that asked rats how long they were willing to wait for certain foods. “It’s like waiting in line at a restaurant,” said Redish. “If the line is too long at the Chinese food restaurant, then you give up and go to the Indian food restaurant across the street.”
In this task, which they named “Restaurant Row,” the rat is presented with a series of food options but has limited time at each “restaurant.”
Research findings show rats were willing to wait longer for certain flavors, implying they had individual preferences. Because they could measure the rats’ individual preferences, Steiner and Redish could measure good deals and bad deals. Sometimes, the rats skipped a good deal and found themselves facing a bad deal.
“In humans, a part of the brain called the orbitofrontal cortex is active during regret. We found in rats that recognized they had made a mistake, indicators in the orbitofrontal cortex represented the missed opportunity. Interestingly, the rat’s orbitofrontal cortex represented what the rat should have done, not the missed reward. This makes sense because you don’t regret the thing you didn’t get, you regret the thing you didn’t do,” said Redish.
Redish adds that results from Restaurant Row allow neuroscientists to ask additional questions to better understand why humans do things the way they do. By building upon this animal model of regret, Redish believes future research could help us understand how regret affects the decisions we make

Mice can ‘warn’ sons, grandsons of dangers via sperm .


Lab mice trained to fear a particular smell can transfer the impulse to their unborn sons and grandsons through a mechanism in their sperm, a study reveals.

The research claims to provide evidence for the concept of animals “inheriting” a memory of their ancestors’ traumas, and responding as if they had lived the events themselves.

It is the latest find in the study of epigenetics, in which environmental factors are said to cause genes to start behaving differently without any change to their underlying DNA encoding.

“Knowing how ancestral experiences influence descendant generations will allow us to understand more about the development of neuropsychiatric disorders that have a transgenerational basis,” says study co-author Brian Dias of the Emory University School of Medicine in Atlanta, Georgia.

And it may one day lead to therapies that can soften the memory “inheritance”.

For the study, Dias and co-author Kerry Ressler trained mice, using foot shocks, to fear an odour that resembles cherry blossoms.

Later, they tested the extent to which the animals’ offspring startled when exposed to the same smell. The younger generation had not even been conceived when their fathers underwent the training, and had never smelt the odour before the experiment.

The offspring of trained mice were “able to detect and respond to far less amounts of odour… suggesting they are more sensitive” to it, says Ressler co-author of the study published in the journal Nature Neuroscience.

They did not react the same way to other odours, and compared to the offspring of non-trained mice, their reaction to the cherry blossom whiff was about 200 percent stronger, he says.

The scientists then looked at a gene (M71) that governs the functioning of an odour receptor in the nose that responds specifically to the cherry blossom smell.

Epigenetic marks

The gene, inherited through the sperm of trained mice, had undergone no change to its DNA encoding, the team found.

But the gene did carry epigenetic marks that could alter its behaviour and cause it to be “expressed more” in descendants, says Dias.

This in turn caused a physical change in the brains of the trained mice, their sons and grandsons, who all had a larger glomerulus – a section in the olfactory (smell) unit of the brain.

“This happens because there are more M71 neurons in the nose sending more axons” into the brain, says Dias.

Similar changes in the brain were seen even in offspring conceived with artificial insemination from the sperm of cherry blossom-fearing fathers.

The sons of trained mouse fathers also had the altered gene expression in their sperm.

“Such information transfer would be an efficient way for parents to ‘inform’ their offspring about the importance of specific environmental features that they are likely to encounter in their future environments,” says Ressler.

Happening in humans?

Commenting on the findings, British geneticist Marcus Pembrey says they could be useful in the study of phobias, anxiety and post-traumatic stress disorders.

“It is high time public health researchers took human transgenerational responses seriously,” he said in a statement issued by the Science Media Centre.

Focal point sperm cell entering a human egg depicting conception of child birth.

“I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach.”

Wolf Reik, epigenetics head at the Babraham Institute in England, says such results were “encouraging” as they suggested that transgenerational inheritance does exist, but cannot yet be extrapolated to humans.

 

‘Memories’ pass between generations


Generations of a family

Behaviour can be affected by events in previous generations which have been passed on through a form of genetic memory, animal studies suggest.

Experiments showed that a traumatic event could affect the DNA in sperm and alter the brains and behaviour of subsequent generations.

A Nature Neuroscience study shows mice trained to avoid a smell passed their aversion on to their “grandchildren”.

Experts said the results were important for phobia and anxiety research.

The animals were trained to fear a smell similar to cherry blossom.

The team at the Emory University School of Medicine, in the US, then looked at what was happening inside the sperm.

They showed a section of DNA responsible for sensitivity to the cherry blossom scent was made more active in the mice’s sperm.

Both the mice’s offspring, and their offspring, were “extremely sensitive” to cherry blossom and would avoid the scent, despite never having experiencing it in their lives.

Changes in brain structure were also found.

“The experiences of a parent, even before conceiving, markedly influence both structure and function in the nervous system of subsequent generations,” the report concluded.

Family affair

The findings provide evidence of “transgenerational epigenetic inheritance” – that the environment can affect an individual’s genetics, which can in turn be passed on.

One of the researchers Dr Brian Dias told the BBC: “This might be one mechanism that descendants show imprints of their ancestor.

“There is absolutely no doubt that what happens to the sperm and egg will affect subsequent generations.”

Prof Marcus Pembrey, from University College London, said the findings were “highly relevant to phobias, anxiety and post-traumatic stress disorders” and provided “compelling evidence” that a form of memory could be passed between generations.

He commented: “It is high time public health researchers took human transgenerational responses seriously.

“I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach.”

In the smell-aversion study, is it thought that either some of the odour ends up in the bloodstream which affected sperm production or that a signal from the brain was sent to the sperm to alter DNA.

Get Off the Pot.


Researchers demonstrate the successful treatment of marijuana abuse in rats and monkeys.

A drug that increases levels of a naturally occurring chemical may help marijuana users kick the habit, according to new research published this week (October 13) in Nature Neuroscience. In rats, the drug, called Ro 61-8048, boosted brain levels of kynurenic acid dosed with THC, marijuana’s active ingredient, which subsequently diminished dopamine-driven neural activity associated with pleasure. In monkeys, the same treatment reduced voluntary use of THC by 80 percent.

“The really interesting finding is that when we looked at behavior, simply increasing kynurenic acid levels totally blocked the abuse potential and the chance of relapse,” coauthor Robert Schwarcz, a neuroscientist at the University of Maryland, told Smithsonian.com. “It’s a totally new approach to affecting THC function.”

Though marijuana may not have serious long-term consequences, and may even hold potential in treating various medical maladies, it is commonly used as a recreational drug, and some people who abuse it show signs of addiction to the substance. This addiction is believed to stem from THC’s ability to activate the pleasure circuitry of the brain, increasing levels of dopamine and eliciting feelings of happiness. Kynurenic acid can also mediate dopamine-regulated brain activity, and was thus a top target of Schwarcz and his colleagues as they looked for ways to inhibit THC’s euphoric effects.

Indeed, dosing rats with Ro 61-8048 caused kynurenic acid levels to rise, after which THC no longer elicited the dopamine-driven brain activity in the reward centers of the brain, including the nucleus accumbens. It seemed that kynurenic acid was literally blocking the brain’s dopamine receptors, thereby decreasing the pleasurable feelings normally elicited by THC. As a result of the treatment, both rats and monkeys with the ability to self-dose with THC reduced their drug intake by about 80 percent.

“Currently, we’re doing some experiments with nicotine abuse, and there’s some very interesting preliminary data indicating it may work the same way,” Schwarcz told Smithsonian.com.

MS damage repair treatment looked at by Edinburgh researchers.


New treatments that could help slow the progression of multiple sclerosis could be a step closer due to research by Edinburgh University.

In MS patients the protective layer around nerve cells in the brain, known as myelin, is broken down.

Scientists have discovered that immune cells, known as macrophages, help trigger the regeneration of myelin.

The researchers hope their work could eventually lead to the development of new drugs.

The sheath around nerves cells, made of myelin, is destroyed in MS, leaving the nerves struggling to pass on messages.

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This leads to problems with mobility, balance and vision. There is no cure but current treatments concentrate on limiting the damage to myelin.

‘Stripped away’

Now the team at Edinburgh University has found that the immune cells, known as macrophages, can release a compound called activin-A, which activates production of more myelin.

Dr Veronique Miron, from the Medical Research Council Centre for Regenerative Medicine at the university, said: “In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.

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We look forward to seeing this research develop further”

Dr Susan Kohlhaas MS Society

“Approved therapies for multiple sclerosis work by reducing the initial myelin injury – they do not promote myelin regeneration.

“This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.”

The study, which looked at myelin regeneration in human tissue samples and in mice, was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.

The findings are published in Nature Neuroscience.

Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.

Dr Susan Kohlhaas, head of biomedical research at the MS Society, said: “We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin.

“We look forward to seeing this research develop further.”

Source:BBC

 

 

 

 

Arc protein ‘could be key to memory loss’, says study.


Scientists have discovered more about the role of an important brain protein which is instrumental in translating learning into long-term memories.

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Writing in Nature Neuroscience, they said further research into the Arc protein’s role could help in finding new ways to fight neurological diseases.

The same protein may also be a factor in autism, the study said.

Recent research found Arc lacking in the brains of Alzheimer’s patients.

Dr Steve Finkbeiner, professor of neurology and physiology at the University of California, who led the research at Gladstone Institutes, said lab work showed that the role of the Arc protein was crucial.

“Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” he said.

Further experiments revealed that Arc acted as a “master regulator” of the neurons during the process of long-term memory formation.

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Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.”

Dr Finkbeiner

The study explained that during memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories.

The authors found that it was Arc that directed this process, from inside the nucleus.

Dr Finkbeiner said people who lack the protein could have memory problems.

“Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.

“It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.”

The study says that dysfunctions in Arc production and transport could also be a vital player in autism.

The genetic disorder Fragile X syndrome, for example, which is a common cause of both mental disabilities and autism, directly affects the production of Arc in neurons.

The Californian research team said they hoped further research into the Arc protein’s role in human health and disease would provide even deeper insights into these disorders and lay the groundwork for new therapeutic strategies to fight them.

Source: BBC