SPARC Program Highlights
Who's Talking About SPARC?
Keep up with the latest news and views about neuromodulation, bioelectronic medicine, and the SPARC program:
BBC Science Focus (May 31, 2020)
Neurotech business report (July 2019)
Engadget (May 27, 2020)
Science News (January 2, 2019)
IEEE SPECTRUM (January 20, 2020)
Nature (September 8, 2016)
BBC FUTURES (December 16, 2019)
Prism (October 2015)
PNAS (December 3, 2019)
STAT (September 28, 2015)
Time (October 24, 2019)
SPARC Enters Phase 2
In Phase 2 of NIH Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program, SPARC is launching three new initiatives: SPARC-V, SPARC-O, and SPARC-X, which will improve understanding of the structure and function of the peripheral nervous system and advance new and open-source approaches to modifying nerve function. SPARC will continue to expand the data available on the SPARC.science website for scientists around the world to use.
See the full announcement on SPARC.science, and learn more about the Phase 2 initiatives and awardees here.
Winners announced for Phase 1 of the $9.8 million Neuromod Prize
The NIH Common Fund has announced eight Phase 1 winners of the Neuromod Prize, a $9.8 million competition to accelerate the development of targeted neuromodulation therapies. The first phase called on scientists, engineers, and clinicians to submit novel concepts and plans for development.
The eight winners were selected by a federal judging panel and each team was awarded $100,000 and an exclusive invitation to conduct proof-of-concept studies in the second phase of the competition, expected to begin later this year. The prizewinning ideas include various approaches to stimulate a range of targets, including the spinal cord, sacral, pelvic, and vagus nerves. These innovative solutions have the potential to reduce pain, restore function, and address a variety of health conditions – improving patient quality of life with limited side effects.
Phase 2 will invite the winning teams from Phase 1 to build on their submissions by conducting proof-of-concept studies. Up to four Phase 2 winners may be selected to advance to Phase 3. The competition will provide additional resources to help teams accelerate and develop their solutions.
Learn more about the Neuromod Prize in the Common Fund announcement and press releases from BIOS, Duke University, and University of Louisville.
$9.8 million Neuromod Prize to accelerate the development of targeted neuromodulation therapies
SPARC has launched the Neuromod Prize, a $9.8 million competition to accelerate the development of targeted neuromodulation therapies. The first phase calls on scientists, engineers, and clinicians to submit novel concepts and plans for development. With this competition, NIH hopes to bridge the gap between early-stage research and clinical use for solutions capable of targeting multiple autonomic functions through selective stimulation of the peripheral nervous system. The competition is open to U.S. participants, subject to eligibility requirements. Phase 1 participants will submit concept papers describing their proposed therapeutic approach and plan for conducting proof-of-concept studies, rationale for therapeutic use, and clinical impact. Submissions are due by April 28.
Learn more about the Neuromod Prize in the press release. Prospective participants can register to join the February 7 virtual information session.
The ASCENT of New Technology to Advance Bioelectronic Medicine
Peripheral nerves are spread throughout the body, sending signals from our limbs and organs back to the brain and spinal cord allowing us to feel stimuli, such as the warmth from the sun, and to move our limbs to accomplish our daily activities. Bioelectronic medicine sends similar electrical signals to nerves in our body to treat a wide variety of diseases, such as epilepsy, heart failure, rheumatoid arthritis, and obesity. However, more research is needed to discover how much electrical stimulation is needed, where to apply it, and how to best use this technology for each individual patient and condition. Researchers from the NIH Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program have created new digital technology to better understand the effects of nerve stimulation, as well as to aid in designing, building, and running next generation computational models to advance the field of bioelectronic medicine.
This research team at Duke University, led by Dr. Nicole A. Pelot, has developed the Automated Simulations to Characterize Electrical Nerve Thresholds (ASCENT) pipeline, which builds 3D models of nerves using cuff electrodes to simulate individual neuron responses to electrical signals. This technology has been used to compare existing models of individual neurons, as well as new models of neurons in peripheral tissues of the body, that reproduce previously published laboratory experimental results using computational methods. The team at Duke University has used ASCENT technology in collaboration with researchers at the University of Wisconsin-Madison to reveal key pathways for side effects of vagus nerve stimulation, a bioelectronic medicine treatment used to treat epilepsy. These results can serve as a guide to avoid side effects of epilepsy treatment and increase the therapeutic effects of bioelectronic medicine in the treatment of this disease. The ASCENT pipeline has the potential to advance the field of bioelectronic medicine by streamlining the creation of new reproducible computational models of nerve stimulations that can be used to treat a variety of conditions, while factoring in the individuality of specific individuals and details of their unique nervous system makeup.
Learn more about this work on the SPARC Portal Community Spotlight page.
ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds): A pipeline for sample-specific computational modeling of electrical stimulation of peripheral nerves. Musselman E, Cariello J, Grill W, Pelot N. PLOS Computational Biology. 2021 August 26. DOI: 10.1371/journal.pcbi.1009285
A Knife to the Heart: Mapping the Intracardiac Nervous System
SPARC1 projects are mapping the innervation of organs and tissues, and identifying new targets for future neuromodulation therapies—treatments that directly alter nerve function
Cardiac function is tightly controlled to ensure the heart never skips a beat. At the center of this ability is the intracardiac nervous system (ICN), the heart’s own internal nervous system that helps regulate functions like rhythm and blood flow. The neurons that comprise the ICN are found in clusters within the heart, but their exact positions and functions have never been comprehensively mapped. The NIH Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program supports efforts to map nerve structures like the ICN so they can be targeted more specifically by neuromodulation therapies.
Now a team at SPARC awardee institution Thomas Jefferson University, led by Dr. James S. Schwaber, has illuminated the form and function of the rat ICN at single cell resolution within the whole heart. They used a technique called knife-edge scanning microscopy (KESM) along with single cell gene activity data to create a comprehensive map of the heart. As the name suggests, KESM collects images from deep within tissues by scanning along a knife-edge as it sequentially removes one layer of tissue at a time. The 3D structure is then rebuilt from the scanned images. In a parallel process, individual neurons are laser-cut out of the tissue, profiled for active genes, and then oriented to their correct position within the 3D map of the heart. The resulting data set reveals a high level of complexity and diversity of ICN neuron anatomy and function that will stimulate additional research, including identification of potential therapeutic targets, both surgical and neuromodulatory. The reproducible techniques used in this study can be applied to other organs and systems, opening up a new pipeline for high-resolution mapping of neurons within organ systems.
Read more about this work in these news reports: Science News, Engadget, STAT, BBC Science Focus, Interesting Engineering, Cardiovascular Business, News Medical, Report Door, Cosmos Magazine, Neuro Central, and Slash Gear.
The raw data supporting the study’s conclusions are available on the SPARC Portal.
A Comprehensive Integrated Anatomical and Molecular Atlas of Rat Intrinsic Cardiac Nervous System. Achanta S, Gorky J, Leung C, Moss A, Robbins S, Eisenman L, Chen J, Tappan S, Heal M, Farahani N, Huffman T, England S, Cheng ZJ, Vadigepalli R, Schwaber JS iScience. 2020 May 23.
Finding the Lanes on the Vagus Highway
SPARC2 projects are developing next generation tools and technologies to inform future neuromodulation therapies
The vagus nerve is a bioelectronic highway that carries two-way electrical signals between the brain and many other organs of the body. The “lanes” of this highway are composed of over a hundred thousand nerve fibers. The use of a device to initiate or modify electrical signals in the vagus nerve, called vagus nerve stimulation (VNS), is under study as a therapeutic strategy for a wide range of conditions, including heart failure and inflammatory diseases. This type of therapeutic approach to modify electrical activity in nerves is broadly called neuromodulation. Current VNS technology stimulates the entire nerve, hitting all the fibers in the hope of activating the right ones. The therapy could be improved by selective stimulation of specific fibers to induce the desired therapeutic response, while avoiding or minimizing side effects. To do this, we need more information about how the vagus nerve fibers are organized. The NIH Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program supports efforts to map these fibers so they can be targeted more specifically by neuromodulation therapies like VNS.
A SPARC-supported research team led by Dr. Warren Grill at Duke University is building simulations that predict which fiber lanes on the vagus nerve highway will be activated by different patterns of electrical pulses. To work well, these models need to be fed anatomical data such as size, number, and location of the fibers within the vagus nerves in humans and in appropriate animal models. In a newly published study, lead author Megan Settell and colleagues from Dr. Kip Ludwig’s group at the University of Wisconsin-Madison, along with Dr. Warren Grill’s group at Duke, used careful dissection, labeling, and analysis to chart the different lanes of fibers along the vagus nerve highway in pigs. They even identified areas along the vagus nerve highway that may contribute to unwanted side effects when electrodes are placed there. Their findings are helping improve predictive VNS simulations that may pave the way to new devices, placement strategies, or stimulation protocols, adding up to more effective VNS therapies in the future.
Read more about this work in a news article from the University of Wisconsin-Madison.
Functional vagotopy in the cervical vagus nerve of the domestic pig: Implications for the study of vagus nerve stimulation. Settell M, Pelot NA, Knudsen BE, Dingle AM, McConico AL, Nicolai EN, Trevathan JK, Ezzell JA, Ross EK, Gustafson KJ, Shoffstall A, Williams JC, Zeng W, Poore SO, Populin LC, Suminski A, Grill WM, Ludwig K. J Neural Eng. 2020 Feb 27.
A Change of Heart? Uncovering Sex Differences in Cardiac Neurochemistry
SPARC1 projects are mapping the innervation of organs and tissues, and identifying new targets for future neuromodulation therapies
Although cardiovascular disease is a leading cause of death in women in the US, most research studies have only focused on male animals. One team of researchers in the NIH Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) program is helping to change this by including female animals in their cardiovascular research studies.
The team at SPARC awardee institution Oregon Health & Science University, led by Dr. Beth Habecker, generated data from both female and male rats to help map cardiac neurochemistry—the chemical signals produced by nerves to influence heart function—across different tissues. They measured gene expression levels (measurements of molecules encoded by genes) in the stellate ganglion nerve cells that send electrical signals to the heart, and the levels of neurotransmitters (chemical signals transmitted by nerves) within the heart. Establishing these baseline values was critical to understanding how female and male hearts were different, and how they were the same.
The researchers discovered a number of differences between females and males. For example, stellate ganglia in female rats had lower expression of a gene that helps decrease heart rate and blood pressure. Surprisingly, female hearts had higher levels of the neurotransmitter norepinephrine than male hearts, despite identical levels of the molecules that control production of norepinephrine in female and male stellate ganglia. Norepinephrine increases heart rate and blood pressure, and higher levels in female hearts could contribute to development of cardiovascular disease, which is increasingly understood to differ between women and men. These findings highlight the continued need to include both sexes in research studies, and to carefully analyze both the target organs and the nerves that carry signals to-and-from them to develop a more complete understanding of health and disease.
Learn more about the NIH Policy on Sex as a Biological Variable.
Sex differences in sympathetic gene expression and cardiac neurochemistry in Wistar Kyoto rats. Bayles RG, Tran J, Olivas A, Woodward WR, Fei SS, Gao L, Habecker BA. PLoS One. 2019 Jun 13.
Safety First: Developing Tools and Biomarkers to Prevent Nerve Injury
SPARC2 projects are developing next generation tools and technologies to detect and monitor nerve structure changes in real-time
Bioelectronic medicine, the use of therapeutic devices to modulate electrical activity in nerves and improve organ function, has the potential to treat a wide variety of diseases and conditions, such as heart arrhythmias, gastrointestinal disorders, and type II diabetes. The nerves that connect the brain and spinal cord to organs in the body are composed of long cable-like bundles of fibers called axons, wrapped in a supportive layer of connective tissue that contains blood vessels essential for nerve health and function. As with any therapeutic, safety is enhanced by understanding and reducing potential unintended effects, including tissue damage to stimulated nerves.
A team at SPARC awardee institution Massachusetts General Hospital, led by Dr. Benjamin Vakoc, worked with scientists in the medical device laboratories at the Food and Drug Administration (FDA) to develop a novel approach for predicting and preventing nerve injury caused by electrical stimulation in real time. In order to capture a clear image of tissue damage, they created a custom 3D-printed device to simultaneously stimulate the nerve while also stabilizing it to prevent blurry images caused by breathing and muscle movement. They used optical coherence tomography (OCT), an imaging approach that measures the quantity and direction of light deflected and reflected by tissue, to monitor blood flow and blood vessel size during electrical stimulation of the sciatic nerve. They then compared OCT observations during stimulation with established analyses of nerve function and tissue structure to correlate the changes with nerve injury. This approach points to new real-time biomarkers that could be used to calibrate bioelectronic medicine therapies in order to predict and prevent nerve injury.
Toward optical coherence tomography angiography-based biomarkers to assess the safety of peripheral nerve electrostimulation. Vasudevan S, Vo J, Shafer B, Nam, Ahhyun S, Vakoc B, Hammer D. J Neural Eng. 2019 Jun.
Don’t Sweat It: Harnessing the Power of Brown Fat to Burn Calories
SPARC1 projects are mapping the innervation of organs and tissues, identifying new targets for future neuromodulation therapies
What if you could burn extra calories without breaking a sweat? It may sound counterintuitive, but a specific type of fat – called brown fat – has the potential to do just that. Brown fat is abundant in infants, where it helps regulate body temperature by converting energy stored in fat and sugar into heat. For decades scientists thought that brown fat didn’t have an active role later in life, but that view has changed in recent years with the discovery of brown fat deposits in adults that are activated by drops in temperature. When faced with cold temperatures, the nervous system sends electrical signals that tell brown fat cells to burn more calories, which helps raise the body’s core temperature to a more comfortable level. If scientists could figure out a way to regulate the intricate network of nerves that send these signals in order to harness brown fat’s calorie-burning potential this knowledge could be applied in a variety of ways – from treatments for health conditions related to energy regulation, such as diabetes, to enhancing the healthy effects of exercise.
To do this, we would need to know more about the locations of the nerves by finding a way to see through brown fat to map the neurons that innervate it. A team at SPARC awardee institution Louisiana State University, led by Dr. Heike Münzberg, used a combination of mouse genetics and fluorescent tracers to light up the neurons. They then made them visible using a recently developed chemical process for “clearing” the intact tissue containing the nerves. This process enables high-resolution imaging and 3D reconstruction of the specific neurons that innervate brown fat, without disturbing their location in the tissue. Improved understanding of brown fat innervation patterns could lead to neuromodulation strategies to precisely control the metabolic activity of brown fat by regulating the nerves’ electrical signals. These new tissue-clearing and circuit-tracing methods are being used to visualize and map innervation of other organs and tissues, bringing us closer to identifying precise targets for neuromodulation therapies that could be used to treat a variety of diseases and conditions.
Sympathetic innervation of the interscapular brown adipose tissue in mouse. François M, Torres H, Huesing C, Zhang R1, Saurage C, Lee N, Qualls-Creekmore E, Yu S, Morrison CD, Burk D, Berthoud HR, Münzberg H. Ann N Y Acad Sci. 2019 Jun 11.
Clear and Light-Hearted Way to Visualize Brain-Heart Neural Connections
Does your heart race when you are exercising and slow down when you are sleeping? Hopefully, it does because precise control of heart rate changes like these can influence medical outcomes, making the neural connections between your brain and heart important targets for devices that modulate the neural pathways running throughout your body (the autonomic nervous system). Historically, the variability in clinical trial results hampered being able to prove the therapeutic efficacy of neuromodulation devices for patients at risk of heart failure. One possible reason is that identifying specific neural connections can be difficult—like finding which wire amongst thousands of wires connects your TV to the cable box. If we improve upon current tools, adding cell-type specificity to existing maps of neural structures and electrical signaling, then we can empower clinicians and device developers to design more specific neuromodulation strategies and decrease treatment variability.
To this end, SPARC awardee Kalyanam Shivkumar and his collaborators are clearing a way for other researchers — literally. Dr. Shivkumar’s team made mouse hearts transparent, a critical step in an innovative multi-stage approach that ultimately allowed them to create 3D visualizations of the neural connections that impact heart rate. After using structure-preserving clearing methods to make mouse hearts easy to see through, they used genetically engineered viruses to “tag” and fluorescently trace specific neurons as a way to build 3D visualizations of the intricate circuits that receive input from nerve structures like the spinal cord and the vagus nerve (image from publication shown). They also showed that similar genetic techniques could be used to make only certain neuron types responsive to light, which could enable more specifically targeted neuromodulation in the future. This is crucial to improving the efficacy of neuromodulation devices because better targets mean new ways to treat heart disease!
Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies. Rajendran, P.S., Challis, R.C., Fowlkes, C.C., Hanna, P., Tompkins, J.D., Jordan, M.C., Hiyari, S., Gabris-Weber, B.A., Greenbaum, A., Chan, K.Y., Deverman, B.E., Münzberg H., Ardell J.L., Salama G., Gradinaru V., and Shivkumar K. Nature communications (2019) 565(7739), 361.
Modeling the Future of Treatment
Computational modeling, using computers to simulate the behavior of complex systems through mathematics, physics and/or computer science, is increasingly important to therapeutic development. It allows for the exploration of possibilities in a shorter period of time than studies focused on humans or animals or even isolated cells. Several SPARC awardees are making strides in this area; here we highlight two that are working to improve the understanding of how current and future therapies interact with the heart.
Dr. Colleen E. Clancy’s team used computational modeling to look for structural nooks and crannies where novel heart medications and anesthetic drugs might interact with the heart’s tiny electrical “gates”, or channels. These channels control how and which charged particles enter heart cells and can be sites of action, or “targets” for therapeutics. The model shows how drug molecules might interact in 4D with the structures of the heart’s channels (see video simulations in movie 1 & movie 2). This innovative approach essentially ‘digitally screened’ the drugs, revealing it requires two drug molecules to properly bind to the channel as well as identifying additional three-dimensional pathways that drug molecules can take to get to their binding sites. This has important implications for the design of drugs for heart conditions and could help push the field toward smarter designs for new drug therapies before they are tested in animals or humans.
In another SPARC-supported computational modeling effort, Dr. Elenora Grandi’s team studied the importance of a different type of electrical channel in heart function. Working from a recent finding that this channel could be involved in heart disease, they simulated the effects of reducing its activity. In the simulation, this resulted in an increase in the duration of electrophysiological patterns that are associated with potentially dangerous abnormal heart rhythms such as atrial fibrillation. This is additional evidence that the balance of specific electrical activities is critical to healthy heart function. New approaches for managing abnormal heart rhythms could involve maintaining this balance with drugs or devices.
To improve neuromodulation therapies targeting the heart, we will need to understand the specific effects of nerve or spinal cord stimulation on the channel proteins studied by Clancy, Grandi, and others. Each of these studies is impactful in its own right; however, the SPARC program seeks to amplify the impact of this type of research by addressing data and model interoperability. As an example, these two studies both involve heart channels; yet without a shared vocabulary or common framework, the output of one study cannot be used as an input to another without manual curation and reformatting. Such gaps are routine across biomedical science and create delays in making findings useful and translational. Through its Data and Resource Center, the SPARC program is supporting the development of such a common framework, allowing maps and simulations to integrate diverse anatomical and physiological results from many different groups. The resulting resources, whose development you can track at http://sparc.science and MAP-core (a SPARC resource, building interactive visualizations of nerve-organ anatomy and function; see figure), will allow for the generation of new therapeutic hypotheses that leverage a broader multidisciplinary range of biomedical research than in the past.
Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel. Nguyen, P. T., DeMarco, K. R., Vorobyov, I., Clancy, C. E., & & Yarov-Yarovoy, V. . Proceedings of the National Academy of Sciences (2019) 116(8), 2945-2954.
Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium. Ni, H., Zhang, H., Grandi, E., Narayan, S. M., & & Giles, W. R. American Journal of Physiology-Heart and Circulatory Physiology (2018) 316(3), H527-H542.
K+ Channel Isoforms Regulate Human Atrial Arrhythmogenesis. Haibo Ni, Henggui Zhang, Elenora Grandi, Sanjiv M. Narayan, and Wayne R. Giles. AJP-Heart and Circulatory Podcasts.
In the News:
Atomic-scale simulation of antiarrhythmic drug interaction with cardiac cells, Phys.org
What's the Matter Bladder?
Overactive bladder is a condition that affects millions of people and causes a frequent need to urinate, incontinence, and an increase in bladder voiding. A common treatment uses low levels of electricity to stimulate nerves controlling the bladder. Unfortunately, it’s not precise and can lead to off-target effects and pain. SPARC program awardee Dr. Aaron Mickle developed an innovative approach to this problem by creating a miniature implanted device that can sense and control bladder function in rats. This self-adjusting coordination of devices, that manipulate nerves to control organs, is called a closed-loop system.
Instead of activating nerves using electricity, Dr. Mickle and his team used a technique called optogenetics where genetically modified rat nerve cells could be activated using light. In rats, Mickle’s team inserted a stretch sensor that measured changes in bladder expansion over time. The sensor was connected to LEDs. Both were connected by wires to a flexible base-station device implanted in the abdomen. The bladder-stretch sensor communicated data to the base station, which wirelessly transmitted this information to an external device that recorded and monitored bladder function. Rats received the molecule cyclophosamide, which leads to frequent bladder emptying. When the external device detected this abnormal bladder function (i.e. signs of overactive bladder), it transmitted a wireless signal causing light-driven inhibition of nerves affecting bladder emptying—preventing abnormal frequency of urination.
Although the animal model of overactive bladder shows promise for this technology, questions remain about whether this approach could be used in humans or to treat other diseases. Additionally, the body’s long-term response to the stretchable sensor is unknown and there are other concerns about possible tissue damage or unintended adhesion to the tissue that affect the device’s function. However, if it ultimately proves fruitful, this work could correct organ dysfunction and manage pain.
A wireless closed-loop system for optogenetic peripheral neuromodulation. Mickle, A. D., Won, S. M., Noh, K. N., Yoon, J., Meacham, K. W., Xue, Y., Mcllvried, A. L., Copits, B. A., Samineni, V. K., Crawford, K. E., Kim, D. H., Srivastava, P., Kim, B. H., Min, S., Shiuan, Y., Yun, Y., Payne, M. A., Zhang, J., Jang, H., Li, Y., Lai, H. H., Huang, Y., Park, S., Gereau IV, R. W., & Rogers, J. A. Nature (2019) 565(7739), 361.
In the News:
Implanted device enables responsive bladder control, Nature
Shocking Nerves to Treat Gut Disorders
The gut, or gastrointestinal tract, is an organ system responsible for the digestion of food. Several human diseases and conditions, including gastroparesis, obesity, and reflux disease, are associated with impaired regulation of gut function. Along with pharmaceutical, surgical, and dietary interventions, which are not always successful in treating these disorders, researchers have begun to explore electrical stimulation of the vagus nerve to precisely control gastrointestinal function. For this treatment strategy to work, scientists must understand the function of vagal nerve signals carried between the central nervous system and the gut.
A SPARC program-funded research team at Purdue University is studying the effect of vagus nerve stimulation on emptying the stomach as food moves into the small intestine (gastric emptying) in rats. They observe the process of gastric emptying using a technique called Magnetic Resonance Imaging (MRI). They found that selective electrical stimulation of the vagus nerve significantly increased gastric emptying through relaxation of the pyloric sphincter, a valve-like band of muscle that separates the stomach from the small intestine, which allows movement of food out of the stomach. These findings suggest that electrical stimulation of the vagus nerve could be used to improve gut function to treat gastric emptying disorders like gastroparesis. In addition, their MRI protocol describes a new non-invasive method to assess the effectiveness of many different types of therapies on gastrointestinal function.
Vagus nerve stimulation promotes gastric emptying by increasing pyloric opening measured with magnetic resonance imaging. Lu KH, Cao J, Oleson S, Ward MP, Phillips RJ, Powley TL, and Liu Z. October 2018. Wiley Publishers: Neurogastroenterology & Motility. e13380.
In the News:
MRI tool watches how electrical stimulation could cure digestive disorders, Purdue University News
Exploring Unexplained Bowel Pain
Understanding the causes of inflammatory bowel disease is difficult because the associated abdominal pain can occur without any obvious changes to the structure of the colon or signs of inflammation. Because pain sensations can be carried by sensory neurons, one factor in the generation of abdominal pain could be abnormal sensory neuron activity, which can be influenced by secretions from cells called “epithelial cells” that line the interior of the colon. Understanding interactions between colon epithelial cells and sensory neurons could help us understand and treat abdominal pain. To study the interactions between the types of cells, a SPARC-funded team led by investigators Dr. Brian Davis and Dr. Kathryn Albers used genetically modified mice that contain blue light-activated colon epithelial cells to examine signaling between colon epithelial cells and neurons. These mouse colon epithelial cells could be specifically stimulated by blue light without any physical or chemical stimulation, allowing the study of their effects apart from other factors. Stimulating the epithelial cells caused activity in the pain-sensing neurons and behavioral responses similar to those that result from pain-inducing physical stimulation of the colon. Further study found that firing of neurons was likely triggered by release of a molecule called ATP from the colon epithelial cells. The results indicate that the activity of the colon epithelial cells alone, without any physical or chemical stimulation, could lead to abdominal pain through activation of the pain-sensing neurons. This study advances the understanding of how colon sensory neuron activity is regulated and could aid in development of new treatment strategies for inflammatory bowel disease.
Reference: Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses. Makadia, PA, Naijar, SA, Saloman, JL, Adelman, P, Feng, B, Margiotta, J, Albers, KM, Davis, BM. June 2018. J Neurosci. 38(25): 5788-5798.
The Fat in Our Bones
You probably think of your bones as providing structure and support to your body and protecting your organs, but they have many other functions as well. The soft spongy area inside most bones, called the bone marrow, produces blood cells and stores energy in the form of fat and therefore plays an important role in bone health. The fat cells found in the bone marrow (bone marrow adipocytes) are very different from fat cells found in other parts of the body. Bone marrow adipocytes are also more difficult to study because they are found in small compartments inside of bones. SPARC program awardee Dr. Erica Scheller and her research team published a study in the journal Bone with some of the most detailed images ever acquired of bone marrow adipocytes. The images show that the bone marrow adipocytes interact with other components of their environment such as blood- and bone-forming cells and blood vessels. Of special interest to the SPARC program, a subset of the adipocytes were found to contact nerve cells. The results indicate that bone marrow adipocytes could send signaling molecules to nearby blood- and bone-forming cells and that nerves may coordinate the interactions between bone marrow adipocytes and these cells. This indicates that it could someday be possible to control or modulate bone formation and other bone processes by electrical stimulation of specific nerves. This could potentially lead to new treatments for conditions such as bone fragility, which occur more frequently in groups like the elderly and those with diabetes.
Reference: Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy. Robles, H, Park, S, Joens, MS, Fitzpatrick, JAJ, Craft, CS, and Scheller, E. Jan 2018. Bone. Doi: 10.1016/j.bone.2018.01.020.
Click on the image to view a video of bone marrow innervation in Bone:
Getting the Gut Moving
The enteric nervous system (ENS) regulates stretching and contraction of muscles in the gastrointestinal tract (gut motility), which is critical for digestion. Gastrointestinal disorders resulting from irregular gut motility affect more than a quarter of the world’s population. One method of treating irregular organ function is neurostimulation, in which targeted electrical current is used to stimulate the ENS. However, this method has seen limited success for gastrointestinal disorders, because we don’t understand how electrical stimulation affects the ENS and gut motility. Current computational models that simulate the effects of electrical stimulation of the ENS are incomplete, which makes predicting the effects of different ENS stimulation patterns difficult in living organisms.
In a study funded by the NIH Common Fund SPARC Program, investigators Warren Grill and Xiling Shen developed a computational model of the ENS and used this model to assess neurostimulation strategies for regulating gut motility. The neuromechanical model included a network of parts involved in gut motility - enteric neurons, smooth muscle fibers, and interstitial cells of Cajal (ICCs, cells that act as electrical pacemakers and promote smooth muscle contraction during digestion). The team simulated intestinal tract motility by passing a virtual pellet that stimulates sensory neurons and responds to smooth muscle contractions through the ENS computer model. They found that simulated current pulses at a frequency of 0.5 Hz were more effective at regulating the pacemaker frequency of ICCs, and accelerating gut motility, than higher pulse frequencies that are more commonly used. They validated this model in experiments with rats, in which bead propulsion through the gut was measured during electrical stimulation of the colon and found to behave as predicted from the simulation. The results of this study have implications for the neurostimulation treatment of gastrointestinal disorders resulting from reduced gut motility.
Reference: Electrical stimulation of gut motility guided by an in silico model. Barth, BB, Henriquez, CS, Grill, WM, and Shen, X. Dec 2017. J. Neural Eng. 14(6): 066010.
Viruses Engineered for Good
One method of treating genetic diseases is to transfer new genes to cells affected by the disease. One tool scientists use to transfer genes is viruses, which interact with cells through an external covering, and then inject their DNA into the cells. Scientists take advantage of this ability by replacing virus DNA with DNA that encodes the genes they wish to deliver. In addition to treating diseases, this technique can be used to label cells with fluorescent colors in order to visualize them and identify their connections in the body. Using viruses to transfer genes to cells of the nervous system is difficult because neurons (nerve cells) are widely spread throughout the body, and reaching some neurons requires passage of the virus through the blood brain barrier, a selective layer that blocks the passage of many substances from reaching the brain and spinal cord tissue.
In a study led by NIH Common Fund SPARC program-funded investigator Viviana Gradinaru, a research team engineered viruses to efficiently deliver genes to neurons throughout the body of a mouse after injection into the bloodstream. They modified the external covering of existing viruses for more efficient gene delivery to neurons. They engineered one virus to pass the blood brain barrier and transfer genes to neurons in the brain and spinal cord (the central nervous system), and another virus to reach and transfer genes to neurons spread throughout the body (in the peripheral nervous system), including the heart. The engineered viruses are highly efficient at gene delivery at low doses, can be designed for their delivered genes to be turned on only in certain cell types, and are able to precisely label cells with fluorescent colors for visualization. The viruses can be further customized and potentially used for future non-invasive treatments of neurological disorders, as well as for multi-color labeling of neurons for generation of neuron circuit maps. Neuron maps showing connections between neurons and organs could aid in development of treatments for a variety of human diseases by altering the activity of specific neurons through a process called neuromodulation.
Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Chan, KY, Jang, MJ, Yoo, BB, Greenbaum, A, Ravi, N, Wu, WL, Sanchez-Guardado, L, Lois, C, Manmanian, SK, Deverman, BE, and Gradinaru, V. June 2017. Nat Neurosci. 20(8): 1172-1179.
In the News:
Novel viral vectors deliver useful cargo to neurons throughout the brain and body, ScienceDaily
Gene Therapy Vectors Come to Grips with Nervous System, Root and Branch, Genetic Engineering and Biotechnology News
This page last reviewed on October 26, 2022