Home | Pregnancy Timeline | News Alerts |News Archive May 6, 2014
Researchers have long speculated that one subset of GABA interneurons might
regulate movement by controlling the strength of sensory feedback signals from muscles.
Excitatory neurons carry information over a long range, and most GABA-releasing interneurons
exert their effects after synapse, by blocking excitation neurons on the receiving end.
How spinal neurons control precise movement
New research has made an important step towards understanding normal human motor function,with the potential for treating movement disorders from injury and disease.
Researchers have identified two types of nerve cells that enable the spinal cord to control skilled movement. The first covers long distance neurons, the second short distance neurons — that regulate long distance neurons. Both are needed for smooth movement of our limbs
"We take for granted many motor behaviors, such as catching a ball or flipping a coin, that in fact require considerable planning and precision. While such motor acts seem effortless, they depend on intricate and carefully orchestrated communication between neural networks which connect the brain to the spinal cord and muscles."
Thomas M. Jessell, PhD, senior author on both studies, isprofessor of Motor Neuron Disorders, Departments of Neuroscience, Biochemistry and Molecular Biophysics, Columbia University Medical Center's (CUMC's).
In order to move your hand to a desired target, your brain sends the spinal cord signals to activate motor neurons that control limb muscles. During subsequent movements, information from the limb is sent back to the brain and spinal cord, providing a feedback loop that supports control and adjustment of your hand's motor output.
"But feedback from muscles is not quick enough to permit the most rapid real-time adjustments of fine motor control, suggesting that there may be other, faster, systems at play." says Dr. Jessell.
Researchers suspected that one rapid feedback loop might come from interneurons - called propriospinal neurons (PNs) - and located in the cervical spinal cord.
Like many other neurons, PNs send signals to motor neurons to innervate arm muscles and trigger movement. But, motor neurons also have distinct branches that project away from the motor neurons and towards the cerebellum. Through a dual-branched loop, these neurons have the potential to carry internal copies of motor output signals up to the brain.
The nature of this internal feedback path and whether it has any impact on movement at all, is still not clear. "If PNs were indeed sending copies of outgoing motor commands to the brain, they could provide a conveniently rapid means of adjusting ongoing movements when things go awry," said Eiman Azim, PhD, a postdoctoral fellow in Dr. Jessell's lab and lead author of the first paper. "But without a way to selectively target the copy function of PNs, there was no way to test this theory."
The CUMC team, in collaboration with Bror Alstermark, PhD, a professor in integrative medical biology at Umeå University in Sweden, overcame this technical barrier by developing a genetic method for accessing and eliminating PNs in mice, abolishing both motor-directed and copy signals sent by the neurons. The researchers then quantified limb movements of the PN-deprived mice in three dimensions as the mice reached for food pellets. Now researchers found the mice's ability to reach for the target accurately was badly compromised. "Basically, their movements were uncoordinated," said Dr. Azim. "The PN-deprived mice consistently over- or under-reached."
But with both PN output signals gone, the precise role of the PN copy signal remained unclear. The researchers then turned to optogenetics—the use of light to control neuronal activity. They selectively activated the copy axonal branch alone, decalibrating this copy signal from the version sent to motor neurons. With the copy signal altered, the animals' ability to reach was severely compromised, indicating that the PN copy pathway is capable of influencing the outcome of goal-directed reaching movements.
The PN copy signal also works blazingly fast. It takes just 4 to 5 milliseconds for motor neuron activity to be altered after transmission of a PN copy signal.
"These reaching movements typically take 200 to 300 milliseconds, so the PN copy signal pathway appears well equipped to correct arm movements," said Dr. Azim.
The researchers think that this copy signal represents just one of many similar internal feedback pathways that the spinal cord and brain use to validate and correct movements throughout the body.
Are these findings relevant to human motor performance? Many of the pathways and circuits that influence reach and grasp in monkeys and humans are conserved in mice. "We need to learn more about these pathways before we can evaluate how their dysfunction contributes to deficits seen after spinal cord injury and neurodegenerative disease," said Dr. Azim.
In the second Nature 2 study, CUMC researchers examined how spinal circuits regulate sensory feedback from muscles to control movement.
The simplest form of this feedback involves a reflex pathway — such as the knee-jerk reflex — in which sensory endings in muscles convey signals to motor neurons through direct monosynaptic connections. Signals from motor neurons, in turn, cause muscles to contract, completing the reflex cycle.
Researchers have long wondered how the strength of this sensory signal might be regulated. Studies had shown that spinal interneurons — in particular those that release the neurotransmitter GABA, inhibiting neuronal activity — play a key role in this process. But most GABA-releasing interneurons exert their effects postsynaptically, by blocking the excitation of neurons on the receiving end of a synapse (the gap across which two neurons communicate).
"We knew that such neurons are unlikely to be responsible for fine-tuning the sensory signal," said lead author Andrew J. P. Fink, PhD, a former graduate student in Dr. Jessell's lab. "Postsynaptic inhibition affects the entire neuron, and motor neurons receive many different inputs. So a mechanism that shut down the motor neuron to all of its inputs would lack refinement."
"These particular neurons are known to work presynaptically, by forming direct connections with the terminals of sensory neurons and suppressing the release of sensory neurotransmitter," said Dr. Fink. For technical reasons, the function of these interneurons, if any, in motor behavior has remained elusive.
Dr. Fink in one experiment, activated presynaptic inhibitory interneurons by decreasing the strength of sensory-motor transmission. His team also made the same interneurons selectively sensitive to a lethal toxin, abolishing their control over sensory feedback strength. Without sensory feedback regulation, forelimb movements were dominated by severe vibrating tremors, drastically diminishing motor accuracy.
This finding, along with parallel studies, indicates that presynaptic inhibitory neurons normally adjust for the "gain" of sensory feedback at synapses with motor neurons and are therefore crucial for the smooth execution of movement.
Understanding how these basic microcircuits regulate sensory input and motor output may, in the long run, provide insight into ways to combat the movement instability and tremor seen in many neurological disorders.
"These two studies shed new light on how discrete classes of spinal interneurons empower the nervous system to direct motor behaviors in ways that match the particular task at hand," said Dr. Jessell.
1 The first paper, published in the April 17 issue of Nature, is titled: Skilled reaching relies on a V2a propriospinal internal copy circuit
Authors are Eiman Azim (CUMC), Juan Jiang (Umeå University, Umeå, Sweden), Bror Alstermark (Umeå University), and Thomas M. Jessell (CUMC).
The study was supported by grants from the Helen Hay Whitney Foundation, Howard Hughes Medical Institute, Umeå University, the Swedish Research Council, the National Institutes of Health (NS033245), the G. Harold and Leila Y. Mathers Foundation, and Project A.L.S.
The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.
2 The second paper, published in the May 1 issue, is titled: Presynaptic inhibition of spinal sensory feedback ensures smooth movement
The authors are Andrew J. P. Fink (CUMC), Katherine R. Croce (CUMC), Z. Josh Huang (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York), L. F. Abbott (CUMC), Thomas M. Jessell (CUMC), and Eiman Azim (CUMC).
The precision of skilled movement depends on sensory feedback and its refinement by local inhibitory microcircuits. One specialized set of spinal GABAergic interneurons forms axo–axonic contacts with the central terminals of sensory afferents, exerting presynaptic inhibitory control over sensory–motor transmission. The inability to achieve selective access to the GABAergic neurons responsible for this unorthodox inhibitory mechanism has left unresolved the contribution of presynaptic inhibition to motor behaviour. We used Gad2 as a genetic entry point to manipulate the interneurons that contact sensory terminals, and show that activation of these interneurons in mice elicits the defining physiological characteristics of presynaptic inhibition. Selective genetic ablation of Gad2-expressing interneurons severely perturbs goal-directed reaching movements, uncovering a pronounced and stereotypic forelimb motor oscillation, the core features of which are captured by modelling the consequences of sensory feedback at high gain. Our findings define the neural substrate of a genetically hardwired gain control system crucial for the smooth execution of movement.
Thomas M. Jessell, PhD, senior author of both studies appearing in the journal Nature, Claire Tow Professor of Motor Neuron Disorders in the Departments of Neuroscience and of Biochemistry and Molecular Biophysics, co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute, co-director of the Kavli Institute for Brain Science, and a Howard Hughes Medical Institute investigator, Columbia University Medical Center's (CUMC's).
The study was supported by grants from Howard Hughes Medical Institute, the National Institutes of Health (MH078844, MH093338, and NS033245), the G. Harold and Leila Y. Mathers Foundation, the Gatsby Charitable Foundation, the Swartz Foundation, the Helen Hay Whitney Foundation, and Project A.L.S.
The authors declare no financial or other conflicts of interests.
The Department of Neuroscience at Columbia University Medical Center
CUMC's Department of Neuroscience, whose faculty includes two Nobel laureates, focuses on fundamental aspects of neural circuit development, organization, and function, using cutting-edge biophysical, cellular imaging, and molecular genetic approaches. Its faculty have backgrounds in a range of fields, including molecular and cell biology, systems neuroscience, theoretical neuroscience, and biophysics.
The Mortimer B. Zuckerman Mind Brain Behavior Institute
Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute is an interdisciplinary center for scholars across the university, created on a scope and scale to explore the human brain and behavior at levels of inquiry from cells to society. The institute's leadership, which includes two Nobel Prize-winning neuroscientists, and many of its principal investigators will be based at the 450,000-square-foot Jerome L. Greene Science Center, now rising on the university's new Manhattanville campus. In combining Columbia's preeminence in neuroscience with its strengths in the biological and physical sciences, social sciences, arts, and humanities, the institute provides a common intellectual forum for research communities from Columbia University Medical Center, the Faculty of Arts and Sciences, the School of Engineering and Applied Science, and professional schools on both the Morningside Heights and Washington Heights campuses. Their collective mission is to further our understanding of the human condition and to find cures for disease.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.eduor columbiadoctors.org.
Return to top of page