Stories about: neuroscience

Sensing light without sight: The visual system’s ‘third eye’

ipRGCs provide non-image vision, responding to light independently of rods and cones
Intrinsically photosensitive retinal ganglion cells, rich in melanopsin, respond to light independently of rods and cones. (Courtesy Elliott Milner, PhD)

Michael Tri H. Do, PhD, is an investigator in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and an assistant professor of neurology at Harvard Medical School.

Light affects us even without impinging on our awareness. In 1995, Charles Czeisler and colleagues at Harvard Medical School described people who lacked visual perception due to retinal degeneration, but nevertheless responded to light subconsciously — despite being blind, their melatonin level was suppressed, and they appeared to synchronize their circadian clock with the solar day. Across the pond at Oxford, Russell Foster and colleagues were finding the same in mice, and learned that these responses began in the eye.

These discoveries spurred an intense research effort that continues to this day. What system confers subconscious sight, and how does it differ from the system that generates visual experience?

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Mutations accumulate in our brain cells as we age. Do they explain cognitive loss?

the aging brain - do DNA mutations in neurons account for cognitive loss?

Scientists have long wondered whether somatic, or non-inherited, mutations play a role in aging and brain degeneration. But until recently, there was no good technology to test this idea.

Enter whole-genome sequencing of individual neurons. This fairly new technique has shown that our brain cells have a great deal of DNA diversity, making neurons somewhat like snowflakes. In a study published online today in Science, the same single-neuron technique provides strong evidence that our brains acquire genetic mutations over time.

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What’s trending in neurological drug development?

Advanced MRI scans of the brain showing neural network connections
Credit: Boston Children’s Hospital

Momentum has been growing in the field of neuroscience in our ability to understand and treat various disorders affecting the brain, central nervous system, neuromuscular network and more. So what are the key ways that researchers and drug industry collaborators are discovering new therapies for preventing or reversing neurological disease?

Experts weighed in recently to offer their insights.

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How do we sense moonlight? Daylight? There’s a cell for that

environmental light sensing must span a wide spectrum of light intensities

To run our circadian clocks, regulate sleep and control hormone levels, we rely on light-sensing neurons known as M1 ganglion cell photoreceptors. Separate from the retina’s rods and cones, M1 cells specialize in “non-image” vision and function even in people who are blind.

Reporting in today’s Cell, neuroscientists at Boston Children’s Hospital describe an unexpected system that M1 cells use to sense changing amounts of environmental illumination. They found that the cells divvy up the job, with particular neurons tuned to different ranges of light intensity.

“As the earth turns, the level of illumination ranges across many orders of magnitude, from starlight to full daylight,” says Michael Do, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, senior author on the paper. “How do you build a sensory system that covers such a broad range? It seems like a straightforward problem, but the solution we found was a lot more complex than expected.”

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A new inlet to treating neurological disease

Image of brains showing red tracer dye, indicating passage of molecules through the blood-brain barrier
These brain images tell a story about the blood-brain barrier: At left, the brain before injection of red tracer dye. At center, an injection of tracer dye shows only a small amount of molecules can infiltrate the blood brain barrier. At right, a new approach for crossing the blood-brain barrier increases the tracer’s penetration into brain tissue.

The blood-brain barrier was designed by nature to protect the brain and central nervous system (CNS) from toxins and other would-be invaders in the body’s circulating blood. Made up of tightly-packed cells, the barrier allows nutrients to pass into the CNS and waste products from the brain to be flushed out, while blocking entry of harmful substances.

A dysfunctional blood-brain barrier can contribute to CNS diseases including Alzheimer’s and multiple sclerosis (MS). But, ironically, the same blood-brain barrier can keep out drugs intended to treat CNS disease. Scientists have long been seeking ways to overcome this obstacle.

Now, Timothy Hla, PhD, and members of his laboratory in the Boston Children’s Hospital Vascular Biology Program have found a way to selectively control openings in the blood brain barrier to allow passage of small drug molecules.

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Zinc chelation: A better way to regenerate the optic nerve?

optic nerve zinc chelation

For more than two decades, researchers have tried to regenerate the injured optic nerve using different growth factors and/or agents that overcome natural growth inhibition. They’ve had partial success, sometimes even restoring rudimentary elements of vision in mouse models.

But at best, these methods get only about 1 percent of the injured nerve fibers to regenerate and reconnect the retina to the brain. That’s because most of the damaged cells, known as retinal ganglion cells (RGCs), eventually die, says Larry Benowitz, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Benowitz and colleagues now show a surprising new approach that gets RGCs to live longer and regenerate robustly: using chelating agents to bind up zinc that’s released as a result of the injury.

These studies, too, were done in mice. If the findings hold up in human studies, they could spell hope for people with optic nerve injury due to trauma, glaucoma or other causes, and possibly even spinal cord injury.

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Science Seen: Worms give a clue to how the nervous system stays organized

nervous system tiling
Courtesy Candice Yip

To the eye, nervous systems look like a tangled mess of neurons and their tree-like branches known as dendrites, but it’s really organized chaos. How the system finds order has intrigued but eluded scientists. In the worm C. elegans, Max Heiman, PhD and graduate student Candice Yip found an elegant system to help explain how neurons each maintain their own space.

Normally, worms have just one neuron of a certain type on either side of their bodies. Yip did a “forward genetic screen” — mutating genes at random to find factors important for neuron wiring. One mutation caused the worm to grow not one set of neurons but five. By engineering the neurons to make a color-changing signal — as shown above — Yip showed that these extra neurons didn’t overlap with each other, but instead carved out discrete territories — a phenomenon known as tiling. How?

Acting on a hunch, Yip and Heiman, of Harvard Medical School and Boston Children’s Hospital’s Division of Genetics and Genomics, showed that C. elegans, faced with an increase in neurons, pressed a molecule called netrin into service to enforce boundaries between them. Netrin is better known for helping nerve fibers navigate to their destinations. When Yip took netrin out of action, the dendrites from the five neurons crossed the invisible borders and grew entangled.

The findings, published today in Cell Reports, could provide insight into neuropsychiatric diseases, believes Heiman, also part of Boston Children’s F.M. Kirby Neurobiology Center. “It’s fundamental to neuropsychiatric disease to make sure brain wiring goes right,” he says. “This is also story about how new features evolve, and how you can form something as complicated as a nervous system. There are pathways that bring everything into order.”

Read more in this feature from Harvard Medical School and learn more about Heiman’s research.

 

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DNA diversity in the brain: Somatic mutations reveal a neuron’s history

neurons somatic mutations
Neurons are more like snowflakes–no two alike–than anyone realized.

Walt Whitman’s famous line, “I am large, I contain multitudes,” has gained a new level of biological relevance in neuroscience.

As we grow, our brain cells develop different genomes from one another, according to new research from Harvard Medical School and Boston Children’s Hospital. The study, published last week in Science, provides the most definitive evidence yet that somatic (post-conception) mutations exist in significant numbers in the brains of healthy people—about 1,500 in each of the neurons they sampled.

The finding confirms previous suspicions and lays the foundation for exploring the role of these non-inherited mutations in human development and disease. Already, the researchers have found evidence that the mutations occur more often in the genes a neuron uses most. And they been able to trace brain-cell lineages based on mutation patterns.

“This work is a proof of principle that if we had unlimited resources, we could actually decode the whole pattern of development of the human brain,” says co-senior investigator Christopher Walsh, MD, PhD, the HMS Bullard Professor of Pediatrics and Neurology and chief of the Division of Genetics and Genomics at Boston Children’s. “These mutations are durable memory for where a cell came from and what it has been up to. I believe this method will also tell us a lot about healthy and unhealthy aging as well as what makes our brains different from those of other animals.”

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Beth Stevens: A transformative thinker in neuroscience

When 2015 MacArthur “genius” grant winner Beth Stevens, PhD, began studying the role of glia in the brain in the 1990s, these cells—“glue” from the Greek—weren’t given much thought. Traditionally, glia were thought to merely protect and support neurons, the brain’s real players.

But Stevens, from the Department of Neurology and the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, has made the case that glia are key actors in the brain, not just caretakers. Her work—at the interface between the nervous and immune systems—is helping transform how neurologic disorders like autism, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and schizophrenia are viewed.

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Early adversity and the brain: Bangladeshi children may provide lessons

neuroimaging adversity Bangladesh
Children from the neighborhood around the neuroimaging lab

Dhaka, Bangladesh, is a megacity, one of the world’s fastest growing. By 2025, the U.N. predicts, Dhaka will be home to more than 20 million people as rural migrants swell its population. Many residents live in extreme poverty, crowded into dense, hot, chaotic slums with open sewers and corrugated housing.

While traditional global health programs have focused on curbing infectious disease, low-resource settings like Dhaka are also coming to be seen as “living laboratories” for investigating how adversity affects children’s brain development. Last year, the Bill & Melinda Gates Foundation awarded a two-year, $2.5 million grant to Charles Nelson, PhD, to bring the first fully equipped neuroimaging facility to Bangladesh.

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