Stories about: FM Kirby Neurobiology Center

Can rare pain syndromes point the way to new analgesics?

analgesic drug discovery could reduce prescription opioid use
Boston Children’s Hospital and Amgen will collaborate to discover and accelerate non-addicting pain drugs.

As the opioid epidemic deepens and drug overdoses increase, effective non-addicting painkillers are desperately needed. Efforts to discover new pain pathways to target with new drugs have thus far had little success. Other promising research is investigating triggerable local delivery systems for non-opioid nerve blockers, but it’s still in the early stages.

A new collaboration between Boston Children’s Hospital and the biopharmaceutical company Amgen is aimed at accelerating new pain treatments. Announced yesterday, it will revolve around patients with rare, perplexing pain syndromes. The scientists hope that the genetic variants they find in these patients will shed new light on pain biology and lead to new ways of controlling pain. 

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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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Novel therapeutic cocktail could restore fine motor skills after spinal cord injury and stroke

CST axons sprout from intact to injured side
Therapeutic mixture induces sprouting of axons from healthy (L) into the injured (R) side of the spinal cord.

Neuron cells have long finger-like structures, called axons, that extend outward to conduct impulses and transmit information to other neurons and muscle fibers. After spinal cord injury or stroke, axons originating in the brain’s cortex and along the spinal cord become damaged, disrupting motor skills. Now, reported today in Neuron, a team of scientists at Boston Children’s Hospital has developed a method to promote axon regrowth after injury.

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Optic nerve regeneration: One approach doesn’t fit all

alpha retinal ganglion cells optic nerve regeneration
Alpha-type retinal ganglion cells (RGCs) in part of an intact mouse retina. The cell axons lead to the optic nerve head (top right) and then exit into the optic nerve. The alpha RGCs are killed by the transcription factor SOX11 despite its pro-regenerative effect on other types of RGCs. (Fengfeng Bei)

Getting a damaged optic nerve to regenerate is vital to restoring vision in people blinded through nerve trauma or disease. A variety of growth-promoting factors have been shown to help the optic nerve’s retinal ganglion cells regenerate their axons, but we are still far from restoring vision. A new study published yesterday in Neuron underscores the complexity of the problem.

A research team led by Fengfeng Bei, PhD, of Brigham and Women’s Hospital, Zhigang He, PhD, and Michael Norsworthy, PhD, of Boston Children’s Hospital, and Giovanni Coppola, MD, of UCLA conducted a screen for transcription factors that regulate the early differentiation of RGCs, when axon growth is initiated. While one factor, SOX11, appeared to be critical in helping certain kinds of RGCs regenerate their axons, it simultaneously killed another type — alpha-RGCS (above)— when tested in a mouse model.

At least 30 types of retinal ganglion cell message the brain via the optic nerve. “The goal will be to regenerate as many subtypes of neurons as possible,” says Bei. “Our results here suggest that different subtypes of neurons may respond differently to the same factors.”

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To address chronic pain, you need to address sleep

chronic pain
Acute or chronic sleep loss exacerbates pain, finds a study that kept mice awake for long periods by entertaining them.

The ongoing opioid epidemic underscores the dire need for new pain medications that aren’t addicting. New research published today in Nature Medicine suggests a possible avenue of relief for people with chronic pain: simply getting more sleep, or, failing that, taking medications to promote wakefulness.

In an unusually rigorous mouse study, either approach relieved pain better than ibuprofen or even morphine. The findings reveal an unexpected role for alertness in setting pain sensitivity.

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Impaired recycling of mitochondria in autism?

mitochondria in autism tuberous sclerosis

A study of tuberous sclerosis, a syndrome associated with autism, suggests a new treatment approach that could extend to other forms of autism.

The genetic disorder tuberous sclerosis complex (TSC) causes autism in about half of the children affected. Because its genetics are well defined, TSC offers a window into the cellular and network-level perturbations in the brain that lead to autism. A study published today by Cell Reports cracks the window open further, in an intriguing new way. It documents a defect in a basic housekeeping system cells use to recycle and renew their mitochondria.

Mitochondria are the organelles responsible for energy production and metabolism in cells. As they age or get damaged, cells digest them through a process known as autophagy (“self-eating”), clearing the way for healthy replacements. (Just this month, research on autophagy earned the Nobel Prize in Physiology or Medicine.)

Mustafa Sahin, MD, PhD, Darius Ebrahimi-Fakhari, MD, PhD, and Afshin Saffari, in Boston Children’s Hospital’s F.M. Kirby Neurobiology Center now report that autophagy goes awry in brain cells affected by TSC. But they also found that two existing medications restored autophagy: the epilepsy drug carbamazepine and drugs known as mTOR inhibitors. The findings may hold relevance not just for TSC but possibly for other forms of autism and some other neurologic disorders.

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News Notes: Pediatric science roundup

A quick look at recent research Vector finds noteworthy.

Tracking infants’ microbiomes

cute microbes-shutterstock_317080235-croppedMicrobiome studies are blooming as rapidly as bacteria in an immunocompromised host. But few studies have been done in children, whose microbiomes are actively forming and vulnerable to outside influences. Two studies in Science Translational Medicine on June 15 tracked infants’ gut microbiomes prospectively over time. The first, led by researchers at the Broad Institute and Massachusetts General Hospital, analyzed DNA from monthly stool samples from 39 Finnish infants, starting at 2 months of age. Over the next three years, 20 of the children received at least one course of antibiotics. Those who were repeatedly dosed had fewer “good” bacteria, including microbes important in training the immune system. Overall, their microbiomes were less diverse and less stable, and their gut microbes had more antibiotic resistance genes, some of which lingered even after antibiotic treatment. Delivery mode (cesarean vs. vaginal) also affected microbial diversity. A second study at NYU Langone Medical Center tracked 43 U.S. infants for two years and similarly found disturbances in microbiome development associated with antibiotic treatment, delivery by cesarean section and formula feeding versus breastfeeding.

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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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CDKL5: Understanding rare epilepsies, patient by patient, neuron by neuron

CDKL5 epilepsy
Haley with her parents and neurologist Heather Olson (right)

Nine-year-old Haley Hilt has had intractable seizures all her life. Though she cannot speak, she communicates volumes with her eyes. Using a tablet she controls with her gaze, she can tell her parents when her head hurts and has shown that she knows her letters, numbers and shapes.

Haley is one of a growing group of children who are advancing the science around CDKL5 epilepsy, Haley’s newly recognized genetic disorder. When Boston Children’s Hospital geneticist Joan Stoler, MD, diagnosed Haley in 2009, there were perhaps 100 cases known in the world; today, there are estimated to be a few thousand. Haley’s neurologist, Heather Olson, MD, leads a CDKL5 Center of Excellence at the hospital that is bringing the condition into better view.

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Genetic analysis backs a neuroimmune view of schizophrenia: Complement gone amok

schizophrenia C4
C4 (in green) located at the synapses of human neurons. (Courtesy Heather de Rivera, McCarroll lab)

A deep genetic analysis, involving nearly 65,000 people, finds a surprising risk factor for schizophrenia: variation in an immune molecule best known for its role in containing infection, known as complement component 4 or C4.

The findings, published this week in Nature, also support the emerging idea that schizophrenia is a disease of synaptic pruning, and could lead to much-needed new approaches to this elusive, devastating illness.

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