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Gene Therapy Shows Promise Repairing Brain Tissue Damaged by Stroke

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Glial Gene Therapy
Caption: Neurons (red) converted from glial cells using a new NeuroD1-based gene therapy in mice. Credit: Chen Laboratory, Penn State, University Park

It’s a race against time when someone suffers a stroke caused by a blockage of a blood vessel supplying the brain. Unless clot-busting treatment is given within a few hours after symptoms appear, vast numbers of the brain’s neurons die, often leading to paralysis or other disabilities. It would be great to have a way to replace those lost neurons. Thanks to gene therapy, some encouraging strides are now being made.

In a recent study in Molecular Therapy, researchers reported that, in their mouse and rat models of ischemic stroke, gene therapy could actually convert the brain’s support cells into new, fully functional neurons [1]. Even better, after gaining the new neurons, the animals had improved motor and memory skills.

For the team led by Gong Chen, Penn State, University Park, the quest to replace lost neurons in the brain began about a decade ago. While searching for the right approach, Chen noticed other groups had learned to reprogram fibroblasts into stem cells and make replacement neural cells.

As innovative as this work was at the time, it was performed mostly in lab Petri dishes. Chen and his colleagues thought, why not reprogram cells already in the brain?

They turned their attention to the brain’s billions of supportive glial cells. Unlike neurons, glial cells divide and replicate. They also are known to survive and activate following a brain injury, remaining at the wound and ultimately forming a scar. This same process had also been observed in the brain following many types of injury, including stroke and neurodegenerative conditions such as Alzheimer’s disease.

To Chen’s NIH-supported team, it looked like glial cells might be a perfect target for gene therapies to replace lost neurons. As reported about five years ago, the researchers were on the right track [2].

The Chen team showed it was possible to reprogram glial cells in the brain into functional neurons. They succeeded using a genetically engineered retrovirus that delivered a single protein called NeuroD1. It’s a neural transcription factor that switches genes on and off in neural cells and helps to determine their cell fate. The newly generated neurons were also capable of integrating into brain circuits to repair damaged tissue.

There was one major hitch: the NeuroD1 retroviral vector only reprogrammed actively dividing glial cells. That suggested their strategy likely couldn’t generate the large numbers of new cells needed to repair damaged brain tissue following a stroke.

Fast-forward a couple of years, and improved adeno-associated viral vectors (AAV) have emerged as a major alternative to retroviruses for gene therapy applications. This was exactly the breakthrough that the Chen team needed. The AAVs can reprogram glial cells whether they are dividing or not.

In the new study, Chen’s team, led by post-doc Yu-Chen Chen, put this new gene therapy system to work, and the results are quite remarkable. In a mouse model of ischemic stroke, the researchers showed the treatment could regenerate about a third of the total lost neurons by preferentially targeting reactive, scar-forming glial cells. The conversion of those reactive glial cells into neurons also protected another third of the neurons from injury.

Studies in brain slices showed that the replacement neurons were fully functional and appeared to have made the needed neural connections in the brain. Importantly, their studies also showed that the NeuroD1 gene therapy led to marked improvements in the functional recovery of the mice after a stroke.

In fact, several tests of their ability to make fine movements with their forelimbs showed about a 60 percent improvement within 20 to 60 days of receiving the NeuroD1 therapy. Together with study collaborator and NIH grantee Gregory Quirk, University of Puerto Rico, San Juan, they went on to show similar improvements in the ability of rats to recover from stroke-related deficits in memory.

While further study is needed, the findings in rodents offer encouraging evidence that treatments to repair the brain after a stroke or other injury may be on the horizon. In the meantime, the best strategy for limiting the number of neurons lost due to stroke is to recognize the signs and get to a well-equipped hospital or call 911 right away if you or a loved one experience them. Those signs include: sudden numbness or weakness of one side of the body; confusion; difficulty speaking, seeing, or walking; and a sudden, severe headache with unknown causes. Getting treatment for this kind of “brain attack” within four hours of the onset of symptoms can make all the difference in recovery.

References:

[1] A NeuroD1 AAV-Based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Chen Y-C et al. Molecular Therapy. Published online September 6, 2019.

[2] In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. Cell Stem Cell. 2014 Feb 6;14(2):188-202.

Links:

Stroke (National Heart, Lung, and Blood Institute/NIH)

Gene Therapy (National Human Genome Research Institute/NIH)

Chen Lab (Penn State, University Park)

NIH Support: National Institute on Aging; National Institute of Mental Health


New Grants Explore Benefits of Music on Health

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It’s not every day you get to perform with one of the finest voices on the planet. What an honor it was to join renowned opera singer Renée Fleming back in May for a rendition of “How Can I Keep from Singing?” at the NIH’s J. Edward Rall Cultural Lecture. Yet our duet was so much more. Between the song’s timeless message and Renée’s matchless soprano, the music filled me with a profound sense of joy, like being briefly lifted outside myself into a place of beauty and well-being. How does that happen?

Indeed, the benefits of music for human health and well-being have long been recognized. But biomedical science still has a quite limited understanding of music’s mechanisms of action in the brain, as well as its potential to ease symptoms of an array of disorders including Parkinson’s disease, stroke, and post-traumatic stress disorder (PTSD). In a major step toward using rigorous science to realize music’s potential for improving human health, NIH has just awarded $20 million over five years to support the first research projects of the Sound Health initiative. Launched a couple of years ago, Sound Health is a partnership between NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts.

With support from 10 NIH institutes and centers, the Sound Health awardees will, among other things, study how music might improve the motor skills of people with Parkinson’s disease. Previous research has shown that the beat of a metronome can steady the gait of someone with Parkinson’s disease, but more research is needed to determine exactly why that happens.

Other fascinating areas to be explored by the Sound Health awardees include:

• Assessing how active music interventions, often called music therapies, affect multiple biomarkers that correlate with improvement in health status. The aim is to provide a more holistic understanding of how such interventions serve to ease cancer-related stress and possibly even improve immune function.

• Investigating the effects of music on the developing brain of infants as they learn to talk. Such work may be especially helpful for youngsters at high risk for speech and language disorders.

• Studying synchronization of musical rhythm as part of social development. This research will look at how this process is disrupted in children with autism spectrum disorder, possibly suggesting ways of developing music-based interventions to improve communication.

• Examining the memory-related impacts of repeated exposures to a certain song or musical phrase, including those “earworms” that get “stuck” in our heads. This work might tell us more about how music sometimes serves as a cue for retrieving associated memories, even in people whose memory skills are impaired by Alzheimer’s disease or other cognitive disorders.

• Tracing the developmental timeline—from childhood to adulthood—of how music shapes the brain. This will include studying how musical training at different points on that timeline may influence attention span, executive function, social/emotional functioning, and language skills.

We are fortunate to live in an exceptional time of discovery in neuroscience, as well as an extraordinary era of creativity in music. These Sound Health grants represent just the beginning of what I hope will be a long and productive partnership that brings these creative fields together. I am convinced that the power of science holds tremendous promise for improving the effectiveness of music-based interventions, and expanding their reach to improve the health and well-being of people suffering from a wide variety of conditions.

Links:

The Soprano and the Scientist: A Conversation About Music and Medicine, (National Public Radio, June 2, 2017)

NIH Workshop on Music and Health, January 2017

Sound Health (NIH)

NIH Support: National Center for Complementary and Integrative Health; National Eye Institute; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research; Office of Behavioral and Social Sciences Research; Office of the Director


The Amazing Brain: Making Up for Lost Vision

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Recently, I’ve highlighted just a few of the many amazing advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. And for our grand finale, I’d like to share a cool video that reveals how this revolutionary effort to map the human brain is opening up potential plans to help people with disabilities, such as vision loss, that were once unimaginable.

This video, produced by Jordi Chanovas and narrated by Stephen Macknik, State University of New York Downstate Health Sciences University, Brooklyn, outlines a new strategy aimed at restoring loss of central vision in people with age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older. The researchers’ ultimate goal is to give such people the ability to see the faces of their loved ones or possibly even read again.

In the innovative approach you see here, neuroscientists aren’t even trying to repair the part of the eye destroyed by AMD: the light-sensitive retina. Instead, they are attempting to recreate the light-recording function of the retina within the brain itself.

How is that possible? Normally, the retina streams visual information continuously to the brain’s primary visual cortex, which receives the information and processes it into the vision that allows you to read these words. In folks with AMD-related vision loss, even though many cells in the center of the retina have stopped streaming, the primary visual cortex remains fully functional to receive and process visual information.

About five years ago, Macknik and his collaborator Susana Martinez-Conde, also at Downstate, wondered whether it might be possible to circumvent the eyes and stream an alternative source of visual information to the brain’s primary visual cortex, thereby restoring vision in people with AMD. They sketched out some possibilities and settled on an innovative system that they call OBServ.

Among the vital components of this experimental system are tiny, implantable neuro-prosthetic recording devices. Created in the Macknik and Martinez-Conde labs, this 1-centimeter device is powered by induction coils similar to those in the cochlear implants used to help people with profound hearing loss. The researchers propose to surgically implant two of these devices in the rear of the brain, where they will orchestrate the visual process.

For technical reasons, the restoration of central vision will likely be partial, with the window of vision spanning only about the size of one-third of an adult thumbnail held at arm’s length. But researchers think that would be enough central vision for people with AMD to regain some of their lost independence.

As demonstrated in this video from the BRAIN Initiative’s “Show Us Your Brain!” contest, here’s how researchers envision the system would ultimately work:

• A person with vision loss puts on a specially designed set of glasses. Each lens contains two cameras: one to record visual information in the person’s field of vision; the other to track that person’s eye movements enabled by residual peripheral vision.
• The eyeglass cameras wirelessly stream the visual information they have recorded to two neuro-prosthetic devices implanted in the rear of the brain.
• The neuro-prosthetic devices process and project this information onto a specific set of excitatory neurons in the brain’s hard-wired visual pathway. Researchers have previously used genetic engineering to turn these neurons into surrogate photoreceptor cells, which function much like those in the eye’s retina.
• The surrogate photoreceptor cells in the brain relay visual information to the primary visual cortex for processing.
• All the while, the neuro-prosthetic devices perform quality control of the visual signals, calibrating them to optimize their contrast and clarity.

While this might sound like the stuff of science-fiction (and this actual application still lies several years in the future), the OBServ project is now actually conceivable thanks to decades of advances in the fields of neuroscience, vision, bioengineering, and bioinformatics research. All this hard work has made the primary visual cortex, with its switchboard-like wiring system, among the brain’s best-understood regions.

OBServ also has implications that extend far beyond vision loss. This project provides hope that once other parts of the brain are fully mapped, it may be possible to design equally innovative systems to help make life easier for people with other disabilities and conditions.

Links:

Age-Related Macular Degeneration (National Eye Institute/NIH)

Macknik Lab (SUNY Downstate Health Sciences University, Brooklyn)

Martinez-Conde Laboratory (SUNY Downstate Health Sciences University)

Show Us Your Brain! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: BRAIN Initiative


The Amazing Brain: Mapping Brain Circuits in Vivid Color

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Hop aboard as we fly up, down, left, and right through the information highways of the human brain! This captivating and eye-catching video was one of the winners of the 2019 “Show us Your Brain!” contest sponsored by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

The video travels through several portions of the brain’s white matter—bundles of fiber that carry nerve signals between the brain and the body, as well as within the brain itself. Fiber colors indicate directionality: left-right fibers (red), front-back fibers (green), and top-bottom fibers (blue).

Looking from the back, we start our journey deep within the brain in the limbic system, the area that helps control emotion, learning, and memory. About three seconds in, visual fibers pop into view extending from the eyes to various brain areas into the occipital lobe (one of four major brain lobes) in the back of the brain.

About two seconds later, flying over top as the brain starts rotating, we see various fiber bundles spray upward throughout the cerebral cortex, communicating information related to language processing, short-term memory, and other functions. About halfway through the video, several green bundles emerge arching across the brain’s midline. These bundles, called the corpus callosum, house the fibers enabling communication between left and right sides of the brain. Finally, the video closes as we see many different fiber bundles lighting up all over, enabling communication between different cortical and subcortical portions of the brain through association and projection pathways.

Dynamic maps like these are created using a 3D imaging technique called diffusion MRI tractography [1]. The technique tracks subtle pathways of water movement in the brain, and allows researchers to model the physical properties (connectional anatomy) that underlie the brain’s electrical properties (neuronal signaling). Postdoctoral researcher Ryan Cabeen and Arthur Toga, director of the University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, used the method to study how white matter changes in developing and aging brains, as well as in brains affected by neurodegenerative or neurological disorders.

Scientific animator Jim Stanis produced the video with Cabeen and Toga. The team first created a population-averaged brain using high-quality diffusion MRI datasets from the Human Connectome Project ,and then used sophisticated computational tools to delineate each bundle manually .

The tractography technique lets scientists visualize and quantitatively analyze the brain’s wiring patterns, complementing our understanding of how the brain functions. Such methods are especially useful to learn about the organization of deep-brain areas that remain out of reach for scientists using current tools and imaging techniques.

Reference:

[1] Kernel regression estimation of fiber orientation mixtures in diffusion MRI. Cabeen RP, Bastin ME, Laidlaw DH. Neuroimage. 2016 Feb 15;127:158-172.

Links:

Arthur Toga (USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles)

Ryan Cabeen (USC Mark and Mary Stevens Neuroimaging and Informatics Institute)

qitwiki—Information about the Quantitative Imaging Toolkit (USC)

Human Connectome Project (USC)

Show Us Your Brain Contest! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health


The Amazing Brain: Shining a Spotlight on Individual Neurons

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A major aim of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is to develop new technologies that allow us to look at the brain in many different ways on many different scales. So, I’m especially pleased to highlight this winner of the initiative’s recent “Show Us Your Brain!” contest.

Here you get a close-up look at pyramidal neurons located in the hippocampus, a region of the mammalian brain involved in memory. While this tiny sample of mouse brain is densely packed with many pyramidal neurons, researchers used new ExLLSM technology to zero in on just three. This super-resolution, 3D view reveals the intricacies of each cell’s structure and branching patterns.

The group that created this award-winning visual includes the labs of X. William Yang at the University of California, Los Angeles, and Kwanghun Chung at the Massachusetts Institute of Technology, Cambridge. Chung’s team also produced another quite different “Show Us Your Brain!” winner, a colorful video featuring hundreds of neural cells and connections in a part of the brain essential to movement.

Pyramidal neurons in the hippocampus come in many different varieties. Some important differences in their functional roles may be related to differences in their physical shapes, in ways that aren’t yet well understood. So, BRAIN-supported researchers are now applying a variety of new tools and approaches in a more detailed effort to identify and characterize these neurons and their subtypes.

The video featured here took advantage of Chung’s new method for preserving brain tissue samples [1]. Another secret to its powerful imagery was a novel suite of mouse models developed in the Yang lab. With some sophisticated genetics, these models make it possible to label, at random, just 1 to 5 percent of a given neuronal cell type, illuminating their full morphology in the brain [2]. The result was this unprecedented view of three pyramidal neurons in exquisite 3D detail.

Ultimately, the goal of these and other BRAIN Initiative researchers is to produce a dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. I look forward to their continued progress, which promises to revolutionize our understanding of how the human brain functions in both health and disease.

References:

[1] Protection of tissue physicochemical properties using polyfunctional crosslinkers. Park YG, Sohn CH, Chen R, McCue M, Yun DH, Drummond GT, Ku T, Evans NB, Oak HC, Trieu W, Choi H, Jin X, Lilascharoen V, Wang J, Truttmann MC, Qi HW, Ploegh HL, Golub TR, Chen SC, Frosch MP, Kulik HJ, Lim BK, Chung K. Nat Biotechnol. 2018 Dec 17.

[2] Genetically-directed Sparse Neuronal Labeling in BAC Transgenic Mice through Mononucleotide Repeat Frameshift. Lu XH, Yang XW. Sci Rep. 2017 Mar 8;7:43915.

Links:

Chung Lab (Massachusetts Institute of Technology, Cambridge)

Yang Lab (University of California, Los Angeles)

Show Us Your Brain! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Biomedical Imaging and Bioengineering


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