A very cool paper has just been published in the top tier journal Nature Neuroscience
, titled “Identification of a cellular node for motor control pathways
.” It’s rather complicated on the molecular biology level but it is really about identifying circuits in the spinal cord that automate certain motor activities and behaviors. The work is relevant to spinal cord injury because targeting these cellular networks, or what the paper calls motor synergy encoders (MSE), has the potential to activate significant movement in paralyzed muscles.
The work comes by way of the Sam Pfaff
group at the Salk Institute in San Diego -- one of seven labs in the Reeve International Research Consortium on Spinal Cord Injury
. The paper demonstrates two key features of this network of scientists: collaboration and development of scientific talent. It combines skills and ideas between labs in the spirit of cross-lab mutuality. The work was mainly done by lead author Ariel Levine, M.D., Ph.D., a young post-doc for Pfaff and an Associate in the Consortium. Said she, “I don’t think I could have done this project in any other context than in the Consortium.”
Levine hopes to follow in the footsteps of numerous Consortium Associates who have gone on to start their own labs; she plans to expand her studies of spinal circuitry.
Besides Levine and Pfaff, authors of the paper include Christopher Hinckley, Kathryn Hilde, Shawn Driscoll, Tiffany Poon and Jessica Montgomery. All are Salk scientists.
Scientists have been looking at what they call motor synergies for a long time. Indeed, Levine cites work by the great neurophysiologist Sir Charles Sherrington dating to 1906 (“The Integrative Action of the Nervous System”). Sherrington was interested in reflexes and wondered, as did others for the next century, why animals could move even if their brains were removed. Of course he didn’t have the trendy new tools the scientists have nowadays, including a couple that Levine took advantage of: a rabies virus vector to trace microscopic nerve pathways and optical-generated evoked potentials to measure activity in these nerves.
“The idea has been around for a long time,” said Levine. “It is very appealing that the spinal cord holds programs for certain kinds of movements that the body may do all the time – such as locomotion, reaching for an object, or pulling a hurt limb towards the body.”
From the paper:
Common movements, such as reaching and grasping an object or stepping, involve complex neural calculations to select the appropriate muscles and precisely control the timing of their contractions to achieve the desired outcome. This motor coordination involves many regions in the central nervous system (CNS), including the motor cortex, red nucleus, basal ganglia, brainstem, cerebellum, peripheral sensory system and spinal neurons. These neural pathways ultimately converge onto motorneuron pools that are each dedicated to controlling a single muscle of the body. Given the number of muscles and possible joint positions of the body that can vary at each moment, the efficiency and reliability of common movements are remarkable.
To simplify the motor-control tasks of the CNS, neural plans for compound movements that invoke multiple joints or body regions are thought to be fractionated into a series of subroutines or ‘synergies’ that bind together useful combinations of motorneuron activation. These synergies may then be flexibly recruited into multiple types of movement, such as voluntary and reflexive behaviors.
So where do these spinal networks or motor synergy programs live? Until now that hasn’t been certain. But Levine et al
have found a group of cells deep in the dorsal horn of the spinal cord that seem to hold the program. “We call them encoder cells,” she said. “Functional studies of these MSE neurons revealed an orderly circuit organization; we speculate this helps to simplify the selection of the appropriate programs.”
You might wonder if this encoder cell is anything like the cells that form the central pattern generator (CPG), the source of spinal cord automaticity that we have come to know as the basis for spinal cord memory and activation when stimulated. Says Levine, similar, yes. But not the same. She explains that CPG networks are important motor pathways typically involved in rhythmic activity for major behaviors such as locomotion and breathing. An encoder cell network is poised to be involved in a wider variety of behaviors, including the movement involved in withdrawal from pain, or of the motion of bringing a cup to one’s lip, but also for behaviors such as locomotion.
“The encoder cells are more efficient and reliable, and we see them operating as a network to produce multiple patterns of non-rhythmic motor activity. In addition, these motor synergy encoders cells are different from what we know about the CPG in that they are direct targets of the motor cortex in the brain, and thus may have a bigger role in voluntary movement.”
Levine said that the main distinctions between MSE and CPG cells relates to the synaptic inputs (MSE are direct targets of the motor cortex -- this has not been demonstrated for CPG neurons) and to the increased reliability of MSE evoked motor responses compared with responses evoked from putative CPG neurons.
It appears, then, that the CPG and the MSE cells act together to shape motor activity. Levine speculates that it may be possible, as these spinal networks are further understood and mapped, to refine the signals that activate movement, and directly control the stimulation by way of the MSE nodes.
What they did:
Using newborn mice, Levine and her colleagues at the Pfaff lab began by searching for projecting neurons with strong direct connections to motorneurons. “We used a monosynaptic circuit–tracing strategy that limits the spread of trans-synaptic rabies virus to only first-order premotor neurons. This approach is based on co-infecting motorneurons with genetically modified rabies virus (Rab?G) and adeno-associated virus (AAV) encoding glycoprotein (AAV:G).”
The viruses were co-injected into a range of muscles that control joint movements of the hindlimb and forelimb. To see if the rabies-labeled neurons were able to drive motor synergies for multi-joint movements, they directly stimulated them using light-activated channelrhodopsin 2 (a photoreceptive protein). They measured electrical activity from deep in the spinal cord to the leg, and yes, the optical stimulation produced motorneuron electrical activity.
Says the paper:
...these findings reveal a population of spinal neurons that have four key features related to motor synergies. First, these neurons represent a major source of the direct synaptic input to motorneurons. Second, they extend axons intersegmentally and therefore are well-suited to bind spatially segregated but functionally related motor pools. Third, these cells are located in the deep dorsal horn, the region from which electrical stimulation of the spinal cord can best evoke motor synergies. Finally, direct stimulation of these cells is a sufficient and reliable means to activate multiple motor groups. Accordingly, we considered that these cells are candidates to be motor synergy encoders, and we designated them MSE neurons.
Levine notes that since her putative MSE neurons receive inputs from both sensory and cortical pathways, “they may represent the underlying cellular network for controlling motor programs common to reflex and voluntary motor behaviors.”
She speculates that MSE neurons may have first arisen in very simple animals lacking a motor cortex (e.g., brain). As the cortex evolved, it may have “co-opted” the MSE circuits in order to simplify complex multi-joint movements. Again, from the paper:
In spinal cord injury, spinal neuronal networks are effectively isolated from descending input, and volitional movement of the body is lost below the injury level. If motor synergies are autonomously encoded in spinal MSE neuron networks, perhaps in the same way evolution may have coopted this circuitry, it may be useful to target MSE cells for therapeutic intervention in order to facilitate purposeful movements in patients with spinal cord injury.