Getting a grip on hand function: Discovering key spinal cord circuits

Professor and neurosurgeon Dr. Rob Brownstone and postdoctoral fellow Dr. Tuan Bui have identified the spinal cord circuit that controls the hands’ ability to grasp.

The world’s leading neuroscience journal, Neuron, published the breakthrough finding in its latest issue.

The researchers have found that a certain population of neurons in the spinal cord — called the dI3 interneurons — assess information from sensory neurons in the hands and then send the appropriate signals to motor neurons in the spinal cord, and hence to the muscles, to control the hands’ grip.

Importance of hand-grip control

“This circuit allows us to subtly and unconsciously adjust our grasp so we apply the right amount of force to whatever we’re holding,” says Dr. Brownstone, a professor in the Department of Medical Neurosciences and the Division of Neurosurgery. “This mechanism is disrupted in spinal cord injuries, which can completely eliminate the ability to grasp, and in neurodegenerative diseases like Alzheimer’s disease, which can lead to an uncontrollable reflexive grasp such that people grab and can’t let go of what they touch.”

Impaired hand function has a devastating effect on people’s independence and ability to function in daily life. As Dr. Brownstone points out, people with quadriplegia ranked hand function as their number-one priority, when asked in a 2004 survey which function they would most want to recover if they could. They rated hand function well above trunk stability, walking, sexual function, bladder and bowel control, and normal sensation.

An unexpected finding

Drs. Brownstone and Bui were testing a spinal cord circuit for its role in the rhythmic pattern of walking, when they found it controlled hand grip instead. “The mice with this circuit disrupted were walking just fine, but I found it was unusually easy to remove them from their cages,” recounts Dr. Bui. “Mice will usually grab onto the cage wires when you go take them out, so this really got us thinking.”

While Dr. Bui was pondering the meaning of this unexpected observation in the lab, Dr. Brownstone was in his neurosurgery clinic, assessing a patient who was unable to control her grasp. “When she took my hand, she was unable to let go,” he recalls. “I had to peel her fingers off one by one to release my hand.”

As they compared notes, Drs. Brownstone and Dr. Bui quickly realized they had come across the circuit that controls hand grasp. Struck by the implications of their observations, they embarked on a series of experiments — with collaborators, including Dr. Tom Jessell at Columbia University in New York City — which validated the finding.

A path to future treatments

Now that the researchers have identified the specific spinal cord circuit that controls hand grip, they can go on to find targets for potential treatments for impaired hand function. “It’s possible that a neurotransmitter or other agent could be delivered to the spinal cord to correct the faulty circuit,” notes Dr. Brownstone. “It could be a complex strategy, but understanding is always the first step.”

Dr. Brownstone is a Tier 1 Canada Research Chair in spinal cord circuits. His research is also supported through grants from the Canadian Institutes of Health Research. Dr. Bui is a key member of Dr. Brownstone’s research team in the Motor Control Lab at Dalhousie University, where they are identifying the neural circuits that control our ability to walk and move in coordinated ways. Their ultimate goal is to identify targets for therapies to restore lost motor function and control in people with spinal cord injuries and other neurological diseases.

Study finds that hot and cold senses interact

A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.

“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as  direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.

The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.

Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.

The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.

This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals  that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”

TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.

Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.

Rats’ brains are more like ours than scientists previously thought

Neuroscientists face a multitude of challenges in their efforts to better understand the human brain. If not for model organisms such as the rat, they might never know what really goes on inside our heads.

The brain is a phenomenal processor that in a year’s time can generate roughly 300,000 petabytes of data — 30,000 times the amount generated by the Large Hadron Collider. Trying to decipher its signals is a daunting prospect.

But particularly for individuals who have lost a limb or been partially or fully paralyzed, such research has potentially life-changing results because it can enable such biotechnological advances as the development of a brain-computer interface for controlling prosthetic limbs.

Such devices require a detailed understanding of the motor cortex, a part of the brain that is crucial in issuing the neural commands that execute behavioral movements. A recent paper published in the journal Frontiers in Neural Circuits by Jared Smith and Kevin Alloway, researchers at the Penn State Center for Neural Engineering and affiliates of the Huck Institutes of the Life Sciences, details their discovery of a parallel between the motor cortices of rats and humans that signifies a greater relevance of the rat model to studies of the human brain than scientists had previously known.

"The motor cortex in primates is subdivided into multiple regions, each of which receives unique inputs that allow it to perform a specific motor function," said Alloway, professor of neural and behavioral sciences. "In the rat brain, the motor cortex is small and it appeared that all of it received the same type of input. We know now that sensory inputs to the rat motor cortex terminate in a small region of the motor cortex that is distinct from the larger region that issues the motor commands. Our work demonstrates that the rat motor cortex is parcellated into distinct subregions that perform specific functions, and this result appears to be similar to what is seen in the primate brain."

"You have to take into account the animal’s natural behaviors to best understand how its brain is structured for sensory and motor processing," said Jared Smith, graduate student in the Huck Institutes’ neuroscience program and the first author of the paper. "For primates like us, that means a strong reliance on visual information from the eyes, but for rats it’s more about the somatosensory inputs from their whiskers."

In fact, nearly a third of the rat’s sensorimotor cortex is devoted to processing whisker-related information, even though the whiskers’ occupy only one-third of one percent of the rat’s total body surface. In humans, nearly 40 percent of the entire cortex is devoted to processing visual information even though the eyes occupy a very tiny portion of our body’s surface.

To understand the structure and function of the rat motor cortex, Smith and Alloway conducted a series of experiments focused on the medial agranular region, which responds to whisker stimulation and elicits whisker movements when stimulated.

"Our research," said Smith, "was conducted in two stages to investigate the functional organization of the brain: first tracing the neuronal connectivity, and then measuring how the circuits behave in terms of their electrophysiology. Just like in any electrical circuit, the first thing you need to do is trace the wires to see how the different components are connected. Then you can use this information to make sense of the activity going on at any particular node. In the end, you can step back and see how all the circuits work together to achieve something more complex, such as motor control."

"We discovered different sensory input regions that were distinct from the region that issued the motor commands to move the whiskers," said Alloway. "In this respect, we were fortunate to have Patrick Drew [assistant professor of engineering science and mechanics and neurosurgery at Penn State] help us analyze the EMG signals produced by microstimulation because this showed that the sensory input region was significantly less effective in evoking whisker movements."

As a result of Smith and Alloway’s discovery, previously published data on the rat motor cortex can be revisited with a new degree of specificity, and more similarities between the brains and neural processes of rats and humans may eventually come to light, perhaps even informing studies of other model organisms. This discovery is also likely to advance the study of the human brain.

"This study opens up avenues for studying some very complex neural processes in rodents that are more like our own than we had previously thought," said Smith. "The tools now available for studying activity in the rodent brain are improving at a remarkable pace, and the findings are even more interesting as we discover just how similar these mammalian relatives are to us. This is a very exciting time in neuroscience."

Cell death in retina helps tune our internal clocks

With every sunrise and sunset, our eyes make note of the light as it waxes and wanes, a process that is critical to aligning our circadian rhythms to match the solar day so we are alert during the day and restful at night. Watching the sun come and go sounds like a peaceful process, but Johns Hopkins scientists have discovered that behind the scenes, millions of specialized cells in our eyes are fighting for their lives to help the retina set the stage to keep our internal clocks ticking.

In a study that appeared in a recent issue of Neuron, a team led by biologist Samer Hattar has found that there is a kind of turf war going on behind our eyeballs, where intrinsically photosensitive retinal ganglion cells (ipRGCs) are jockeying for the best position to receive information from rod and cone cells about light levels. By studying these specialized cells in mice, Hattar and his team found that the cells actually kill each other to seize more space and find the best position to do their job.

Understanding this fight could one day lead to victories against several conditions, including autism and some psychiatric disorders, where neural circuits influence our behavior. The results could help scientists have a better idea about how the circuits behind our eyes assemble to influence our physiological functions, said Hattar, an associate professor of biology in the Krieger School of Arts and Sciences.

“In a nutshell, death in our retina plays a vital role in assembling the retinal circuits that influence crucial physiological functions such as circadian rhythms and sleep-wake cycles,” Hattar said. “Once we have a greater understanding of the circuit formation underlying all of our neuronal abilities, this could be applied to any neurological function.”

Hattar and his team determined that the killing among rival ipRGCs is justifiable homicide: Without this cell death, circadian blindness overcame the mice, who could no longer distinguish day from night. Hattar’s team studied mice that were genetically modified to prevent cell death by removing the Bax protein, an essential factor for cell death to occur. They discovered that if cell death is prevented, ipRGCs distribution is highly affected, leading the surplus cells to bunch up and form ineffectual, ugly clumps incapable of receiving light information from rods and cones for the alignment of circadian rhythms. To detect this, the researchers used wheel running activity measurements in mice that lacked the Bax protein as well as the melanopsin protein which allows ipRGCs to respond only through rods and cones and compared it to animals where only the Bax gene was deleted.

What the authors uncovered was exciting: When death is prevented, the ability of rods and cones to signal light to our internal clocks is highly impaired. This shows that cell death plays an essential role in setting the circuitry that allows the retinal rods and cones to influence our circadian rhythms and sleep.

(Image: Advanced Retinal Institute, Inc.)

Reshaping the brain: scientists reprogram neurons after birth

The cerebral cortex—the gray matter that forms the outer layers of the mammalian cerebrum and cerebellum—is divided into six different layers based on the presence of specialized neurons, and we’ve known that since the early 1900s. Denis Jabaudon is interested in using the tools of modern biology to understand the genetic mechanisms that establish and maintain those layers. Over the past few years, his lab has published papers implicating various genes in the generation of specific neuronal subtypes.

Now they have gone a step further. They have developed a new electrochemical method to transfer genes into specific types of neurons—they call it iontoporation. Using it, they have transformed one type of neuron in a mature brain into a different type entirely.

Although Jabaudon and others have made some headway in working out how the different neurons arise, they still don’t know how plastic they are—if they can change fates after they started differentiating down one particular path. In the context of brain injury, it would be useful to know if certain neural circuits could be reprogrammed and repaired by having the neurons that are already present change fates to adapt to the damage. But this has been challenging to determine, because changing the fate of specific neurons in the latter stages of differentiation has been technically difficult.

Layer 4 mouse spiny neurons have round bodies, with many short dendrites (connections with other cells) that stay within their layer of the brain. They receive sensory signals from the thalamus. Layer 5B output neurons are pyramidal in shape, with a prominent dendrite that extends all the way to layer 1.

Fezf2 is a transcription factor that regulates the activity of other genes. It is expressed throughout the L5B neuron’s entire life, and it is necessary and sufficient for turning early cortical cells into L5B neurons.

When Jabaudon’s colleagues iontoporated Fezf2 into L4 neurons the day after mice were born, a week after the neurons had established their identity, it completely transformed them. You guessed it: the L4 neurons walked, talked, looked, and quacked just like L5B neurons. They looked like L5B’s and began transmitting signals to other nerves just as these cells did. Most significantly, however, they rearranged their intracortical inputs, meaning that they now received signals from layer 2/3 neurons instead of from the thalamus.

The researchers tried their iontoporation as late as ten days after the mice were born, and found that the neurons become less amenable to reprogramming with time, but some features were still malleable for a week after the mice were born—two weeks after the neurons originated.

The authors hope to further explore the molecular mechanisms responsible for the emergence and patterning of different cortical areas during brain development and their plasticity after injury. They hope that one day, reprogramming existing neurons could be a means of nervous system repair.