Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

Kathren L. Fink, Francesc López-Giráldez, In-Jung Kim, Stephen M. Strittmatter, William B.J. Cafferty Open Access
DOI: http://dx.doi.org/10.1016/j.celrep.2017.02.058

Highlights
•Mechanisms driving functional plasticity of intact CNS circuits are unknown
•Retrograde spinal tracing reveals CST neurons undergoing functional plasticity
•Transcriptional profiling of these neurons reveals pro-axon growth targets
•Molecular modulation of the identified LPA-LPPR1 axis enhances plasticity post-SCI

Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

See the Full Article at Cell.com

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U.S. Capitol Police arrest people in wheelchairs inside the Capitol Rotunda over Trumpcare Health Bill

A U.S. Capitol Police spokeswoman says 54 people, many in wheelchairs, were arrested Wednesday in the Capitol Rotunda as they protested the health care bill being considered in the House.

Spokeswoman Eva Malecki says the 41 women and 13 men arrested were charged under District of Columbia law that makes it illegal for someone to obstruct passage through a public building and continue to do so after being instructed by police to cease. Eva Malecki, says arrests were made and additional details will be provided later.

Chanting “Rather go to jail than die without Medicaid,” the protesters were led out individually or in pairs by members of the U.S. Capitol Police.

One of the protesters being led out says she is part of ADAPT, an organization that promotes rights for people with disabilities.

One protester is displaying a sign that says “Medicaid = Life 4 Disabled.”

The GOP-led bill would limit future federal financing for Medicaid.

VIDEO LINK:

ABC NEWS WIRE LINK:

Posted in Advocacy | 1 Comment

What Budget Cuts Might Mean for US Science

A look at the historical effects of downsized research funding suggests that the Trump administration’s proposed budget could hit early-career scientists the hardest.

By Diana Kwon | March 21, 2017

The Trump administration’s proposed federal budget has already evoked significant backlash from scientists and science advocacy organizations across the United States. The FY2018 budget proposal, released by the White House last week, includes massive cuts to agencies that fund research, including the National Institutes of Health (NIH) and the Environmental Protection Agency (EPA).

Despite the alarm surrounding the news of proposed science funding cuts, experts stressed that the budget request is unlikely to pass as is. “This is the president’s proposal . . . this is a statement from the White House about what they would like to see,” Rush Holt, CEO of the American Association for the Advancement of Science (AAAS), told The Scientist. “It’s Congress that makes the appropriations.”

Congress has traditionally shown bipartisan support for biomedical research, said Elias Zerhouni, who was director of the NIH from 2002 until 2008. “I used to say that ‘Disease knows no party affiliation’ and ‘Disease knows no politics,’ and frankly, that’s my experience, so I’m hopeful that the damage will not be as great as what is being proposed.”

Read the full article in The Scientist: HERE

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CITC LTD and partners on personalized stem cell therapies for injury and diseases of the CNS

CITC Ltd has recently concluded a non-esclusive license agreement with Provendis GmbH, a technology transfer agency of 27 universities of North Rhine-Westphalia, including the University of Bonn, for a manufacturing technology of autologous induced neural stem cells (iNSC) from adult cells that are harvested from simple skin biopsy or from other somatic sources.

Directly reprogrammed autologous iNSCs are seen as a powerful and safe tool to treat patients with neurological illnesses and injuries, that may occur while they age.

In line with CITC ltd’s governing mission, this license agreement helps develop further our unique portfolio of technologies and Intellectual Property in the field of molecular diagnostics, nano-medicine, and advanced therapies, and to establish a translational path toward clinical use in humans, subject to successful clinical trials.

See the Full Article HERE

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Nerve growth At The Extremeties

Researchers have found a genetic signature located exclusively in the nerve cells that supply, or innervate, the muscles of an organism’s outermost extremities: the hands and feet. This signature, observed in both mice and chicks, involves the coordinated activity of multiple genes, and is fundamentally distinct from cells innervating nearby anatomical regions, such as more proximal muscles in the limb. The findings suggest that the evolution of the extremities may be related to the emergence of fine motor control, such as grasping — one of biology’s most essential adaptations.

The study, led by neuroscientists at Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute and New York University, was published in the journal Neuron.

“The emergence of hands, feet and digits — about 400 million years ago — represented a turning point in evolution; it helped the first land animals perform a variety of fine motor skills, like grasping, which eventually gave rise to the complex motor abilities that we humans use every day — from typing on a keyboard to painting a work of art,” said Thomas M. Jessell, PhD, the paper’s senior author and codirector of Columbia’s Zuckerman Institute. “But while fine motor control has proven critical for survival for hundreds of millions of years, little was known about how the nerve cells that extend to the tips of our fingers and toes make these skills possible.”

For this study, the researchers focused on motor neurons, the class of nerve cells that guide movement. Motor neurons achieve this by innervating specific muscles, and then relaying signals from the brain about how those muscles should move. The motor neurons that guide movement of the digits are called digit-innervating motor neurons.

“When we began this research, we were simply looking to compare key molecular features — namely gene activity — in motor neurons that supply different muscles in the leg,” said Alana Mendelsohn, an MD/PhD candidate at Columbia and the paper’s first author. “Instead, it soon became clear that the pattern of gene activity in the digit-innervating motor neurons in the foot was strikingly different compared to activity of motor neurons that innervate the more proximal muscles of the limb.”

Specifically, Mendelsohn observed that the motor neurons that supply both the hands and the feet did not produce a molecule called retinoic acid.

“One of the hallmark features of motor neurons is that they require retinoic acid for their growth and development,” said Mendelsohn. “But for some reason digit-innervating motor neurons weren’t producing it.”

Read the Full Article at Cell Science from Technology Networks LINK

Posted in Chronic Spinal Cord Injury Research, Gene Therapy, Regenerative Medicine, Spinal Research, Stem Cell Research | Leave a comment

Noradrenergic pathways and epidural electrical stimulation synergistically modulate proprioceptive feedback circuits in order to restore locomotion after SCI

Abstract
Several interventions exploiting chemical and electrical neuromodulation therapies have been designed to engage spinal sensorimotor circuits in order to facilitate the recovery of standing and walking after spinal cord injury. However, the mechanisms through which electrical and chemical stimulation modulate spinal circuits remain poorly understood. To study these mechanisms, we investigated the circuit-level interactions between noradrenergic receptor modulation and epidural electrical stimulation during standing and walking after a complete spinal cord injury. Previous work suggested that epidural electrical stimulation facilitates motor control through the modulation of proprioceptive feedback circuits. Using genetic deletion experiments and calcium imaging, we confirmed that epidural electrical stimulation promotes locomotion through the activation of proprioceptive feedback circuits. Anatomical experiments in genetically modified mice revealed that noradrenergic receptors are prominently expressed on these circuits. In turn, pharmacological testing in rats and genetic deletion in mice showed that the manipulation of noradrenergic pathways strongly modulated the gain in proprioceptive feedback circuits, which abolished or augmented the effects of epidural electrical stimulation. This electrochemical stimulation strategy restored robust locomotion in paralyzed animals. Our findings provide new insights into the mechanisms through which electrochemical neuromodulation therapies facilitate motor control after injury, and provide a framework to refine these interventions for clinical applications.

Authors
*K. BARTHOLDI1, Q. BARRAUD1, E. FORMENTO1, A. ROWALD1, P. MUSIENKO2, M. CAPOGROSSO1, G. COURTINE1;
1EPFL, Lausanne, Switzerland; 2Pavlov Inst. of Physiol., Saint Petersburg, Russian Federation
Disclosures
K. Bartholdi: None. Q. Barraud: None. E. Formento: None. A. Rowald: None. P. Musienko: None. M. Capogrosso: None. G. Courtine: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Technology Review LINK

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Paul Knoepfler Stem Blog “The Niche” providing weekly Q & A.

The Niche LINK:

Segment 1.

Where is the stem cell field now and where the heck is it heading? There are hundreds of questions.

Readers often email me questions or leave them as comments. It’s not unusual to get questions about CRISPR as well.

As time permits, I’m hoping once or twice a month on Sundays to post a video answering some reader questions. Here’s today’s February 26th edition, focused on stem cells.

Posted in Regenerative Medicine, Spinal Research, Stem Cell Research, Uncategorized | Tagged | Leave a comment

Electrical neuromodulation of the cervical spinal cord facilitates forelimb skilled function recovery in spinal cord injured rats

Abstract: Enabling motor control by epidural electrical stimulation of the spinal cord is a promising therapeutic technique for the recovery of motor function after a spinal cord injury (SCI). Although epidural electrical stimulation has resulted in improvement in hindlimb motor function, it is unknown whether it has any therapeutic benefit for improving forelimb fine motor function after a cervical SCI. We tested whether trains of pulses delivered at spinal cord segments C6 and C8 would facilitate the recovery of forelimb fine motor control after a cervical SCI in rats. Rats were trained to reach and grasp sugar pellets. Immediately after a dorsal funiculus crush at C4, the rats showed significant deficits in forelimb fine motor control. The rats were tested to reach and grasp with and without cervical epidural stimulation for 10 weeks post-injury. To determine the best stimulation parameters to activate the cervical spinal networks involved in forelimb motor function, monopolar and bipolar currents were delivered at varying frequencies (20, 40, and 60 Hz) concomitant with the reaching and grasping task. We found that cervical epidural stimulation increased reaching and grasping success rates compared to the no stimulation condition. Bipolar stimulation (C6– C8 + and C6 + C8–) produced the largest spinal motor-evoked potentials (sMEPs) and resulted in higher reaching and grasping success rates compared with monopolar stimulation (C6– Ref + and C8– Ref +). Forelimb performance was similar when tested at stimulation frequencies of 20, 40, and 60 Hz. We also found that the EMG activity in most forelimb muscles as well as the co-activation between flexor and extensor muscles increased post-injury. With epidural stimulation, however, this trend was reversed indicating that cervical epidural spinal cord stimulation has therapeutic potential for rehabilitation after a cervical SCI.

Monzurul Alama, 1, Guillermo Garcia-Aliasa, 1, Benita Jina, Jonathan Keyesa, Hui Zhonga, Roland R. Roya, b, Yury Gerasimenkoa, c, d, Daniel C. Lue, V. Reggie Edgertona, b, f, g, ,
a Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States
b Brain Research Institute, University of California, Los Angeles, CA 90095, United States
c Pavlov Institute of Physiology, St. Petersburg 199034, Russia
d Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420006, Russia
e Departments of Neurosurgery, University of California, Los Angeles, CA 90095, United States
f Departments of Neurobiology, University of California, Los Angeles, CA 90095, United States
g Departments of Neuroscience, University of California, Los Angeles, CA 90095, United States

Link

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Assessment of the combined effects of chondroitinase and autologous Schwann cells on hand function after cervical SCI in primates

Abstract
Introduction: Chondroitinase ABC and Schwann cells have been shown independently to promote functional recovery in rodents after contusive injury. Autologous human Schwann cells ahSC are being tested in Phase 1 clinical trials for sub-acute and chronic SCI. Recognizing the necessity of combination strategies, we are exploring the acute injection of a lentiviral transfer vector carrying a mammalian compatible engineered chABC gene (LV-chABC), with or without sub-acute aSC transplantation, in primates following unilateral C3/4 SCI. Here, we present the preliminary evaluation of the hand and arm recovery up to six months post-injury and treatment. Methods: Seven young adult male primates (Macaca fascicularis) received a right-sided hemi-contusion using the Miami Large Animal Impactor. They were randomized into: Injury only controls (n=2), Injury + 2 hours post-injury perilesional injection of LV-chABC (n=3), and Injury + LV-chABC injection + aSC transplant 14 days post-SCI (n=2). Animals were acclimatized to be comfortable within a primate chair and also provided with cage objects to promote grasp practice. They were trained to retrieve food pellets from a modified Brinkman board consisting of 20 cross-shaped slots suited to the monkeys’ fingers. The board was presented in the horizontal and vertical planes (relative to the floor) to test arm and shoulder strength, wrist rotation and thenar opposition. Both hands were exposed to the tasks equally during the pre and post injury phases.
Results: Significant differences in retrieval time and retrieval quality were found between the left (control) and right (injured) hand in each animal and between the 3 groups as of 6 months post-injury. LV-chABC injected animals showed the most rapid recovery. Additionally observed differences include the rate to reach hand function plateau and the variety of strategies developed to perform the task.
Conclusions: Animals continue to survive. The tests discriminate recovery of fine dexterity of finger movements from adaptation strategies. Deficits and recovery of combined upper and lower extremity gait coupling are assessed with treadmill kinematics.

Authors
*A. Y. FLORES1, A. J. SANTAMARIA1, R. DE NEGRI1, F. D. BENAVIDES1, N. D. JAMES4, Y. NUNEZ-GOMEZ2, J. P. SOLANO2, J. VERHAAGEN5,6, E. J. BRADBURY4, J. D. GUEST1,3;
1Miami Project to Cure Paralysis, 2Pediatric Critical Care, 3Neurolog. Surgery, Univ. of Miami, Miller Sch. of Med., Miami, FL; 4The Wolfson Ctr. for Age-Related Dis., King’s Col., London, United Kingdom; 5Lab. for Neuroregeneration, Netherlands Inst. for Neurosci., Amsterdam, Netherlands; 6Ctr. for Neurogenomics and Cognition research, Vrije Univ. Amsterdam, Amsterdam, Netherlands
Disclosures
A.Y. Flores: None. A.J. Santamaria: None. R. de Negri: None. F.D. Benavides: None. N.D. James: None. Y. Nunez-Gomez: None. J.P. Solano: None. J. Verhaagen: None. E.J. Bradbury: None. J.D. Guest: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Rehabilitation, Spinal Research, Stem Cell Research

Selective late I-wave stimulation enhances voluntary motor output after SCI

Abstract
Targeted stimulation of the corticospinal tract has been shown to improve voluntary motor output in humans with spinal cord injury (SCI; Bunday and Perez, 2012). Here, we used a novel protocol that targeted late synaptic inputs into corticospinal neurons in humans with and without incomplete cervical chronic SCI. We used 180 paired transcranial magnetic stimulation (TMS) pulses over the hand representation of the primary motor cortex at interstimulus intervals of 4.3 ms (targeting I3-wave circuits; iTMS protocol) and 3.5 ms (targeting no I-wave interval; control protocol) at 0.1 Hz for a total of 30 min. Motor evoked potentials (MEPs) in an intrinsic finger muscle where measured at rest before, immediately after, and up to 30 min after the stimulation with the coil oriented to induce currents in the brain in the posterior-anterior (PA) and anterior-posterior (AP) direction to preferentially activate early and late synaptic inputs to corticospinal neurons, respectively. We found that MEPs size increased in the AP but not in the PA direction after the iTMS protocol for up to 30 min after the stimulation in control (by ~175%) and SCI (by ~142%) participants. No changes in MEP size were observed after the control protocol when tested with the coil either in the PA or AP direction in both groups. Notably, EMG and force outcomes during index finger abduction increased after the iTMS protocol in control (EMG by ~135%; force by ~129%) and SCI (EMG by ~130%; force by ~127%) participants. No changes were observed after the control protocol. SCI subjects needed ~15% less time to complete the nine-hold-peg-test after the iTMS protocol compared to baseline. Thus, we propose that targeting late synaptic inputs into corticospinal neurons might represent a novel strategy for enhancing corticospinal drive and voluntary motor output after human SCI.

Authors
J. LONG, P. FEDERICO, *S. LEHMANN, M. A. PEREZ;
Dept. of Neurolog. Surgery, The Miami Project to Cure Paralysis, Univ. of Miami, Miami, FL
Disclosures
J. Long: None. P. Federico: None. S. Lehmann: None. M.A. Perez: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research