(Image caption: Dendrite of an amygdala principal neuron with dendritic spines (white). Inhibitory synaptic contacts are shown in red. Credit: © MPI f. Brain Research/ J. Letzkus)

Learning brakes in the brain

A brain capable of learning is important for survival: only those who learn can endure in the natural world. When it learns, the brain stores new information by changing the strength of the junctions that connect its nerve cells. This process is referred to as synaptic plasticity. Scientists at the Max-Planck Institute for Brain Research in Frankfurt, working with researchers from Basel, have demonstrated for the first time that inhibitory neurons need to be at least partly blocked during learning. This disinhibition is a bit like taking the foot off the brake in a car: if the inhibitory neurons are less active, learning is accelerated.

Learning is often a matter of timing: different stimuli become strongly associated if they occur in close succession. The Max Planck scientists made use of this phenomenon in conditioning experiments in which mice learned to react to a tone. For this learning effect to occur, the synapses of the so-called principal neurons in the amygdala need to become more sensitive. The researchers concentrated on two types of inhibitory neurons which produce the proteins parvalbumin and somatostatin and inhibit the principal neurons of the amygdala.

The results obtained by the Max Planck researchers show that both cell types are inhibited during different phases of the learning process. This disinhibition enhances the activation of the principal neurons. Moreover, the scientists were able to control the learning behaviour of the mice through the use of optogenetics. In these experiments, they equipped both types of inhibitory neurons in the amygdala with light-sensitive ion channels, allowing them to use light to switch the neurons on or off as required. “When we prevent disinhibition, the mice learn less well. In contrast, enhancing the disinhibition leads to intensified learning”, says Johannes Letzkus from the Max Planck Institute for Brain Research. Next, the scientists aim to identify the nerve pathways which are involved in disinhibition.

Studies Identify Spinal Cord Neurons that Control Skilled Limb Movement

Researchers have identified two types of neurons that enable the spinal cord to control skilled forelimb movement. The first is a group of excitatory interneurons that are needed to make accurate and precise movements; the second is a group of inhibitory interneurons necessary for achieving smooth movement of the limbs. The findings are important steps toward understanding normal human motor function and potentially treating movement disorders that arise from injury or disease.

“We take for granted many motor behaviors, such as catching a ball or flipping a coin, that in fact require considerable planning and precision,” said Columbia University Medical Center’s (CUMC’s) Thomas M. Jessell, PhD, a senior author of both studies, which were published separately in recent issues of Nature (1, 2). “While such motor acts seem effortless, they depend on intricate and carefully orchestrated communication between neural networks that connect the brain to the spinal cord and muscles.”

To move one’s hand to a desired target, the brain sends the spinal cord signals, which activate the motor neurons that control limb muscles. During subsequent movements, information from the limb is conveyed back to the brain and spinal cord, providing a feedback system that can support the control and adjustment of motor output.

“But feedback from muscles is not quick enough to permit the most rapid real-time adjustments of fine motor control,” said Dr. Jessell, “suggesting that there may be other, faster, systems at play.” Dr. Jessell is the 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, all at Columbia.

Researchers had suspected that one rapid form of feedback might derive from a group of interneurons in the cervical spinal cord called propriospinal neurons (PNs). Like many other neurons, PNs send signals to motor neurons that innervate arm muscles and trigger movement. But this subset of neurons also has a distinct output branch that projects away from motor neurons towards the cerebellum. Through this dual-branched anatomy, these neurons have the potential to carry internal copies of motor output signals up to the brain.

However, the nature of this internal feedback pathway and whether it has any impact on movement have not been 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. When the researchers quantified the limb movements of the PN-deprived mice in three dimensions as they reached for food pellets, they found that 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 study, CUMC researchers examined how spinal circuits regulate sensory feedback from muscles to control movement. The simplest form of this feedback system involves a reflex pathway (such as the knee-jerk reflex), in which sensory endings in muscles convey signals to the motor system through direct monosynaptic connections with motor neurons. 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.”

Researchers have long speculated that one subset of GABAergic interneurons might regulate movement by controlling the strength of sensory feedback signals from muscles. “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 and his colleagues identified a way to access this subset of interneurons genetically in mice and then devised approaches to manipulate their function in a selective manner. In one experiment, they activated presynaptic inhibitory interneurons optogenetically, decreasing the strength of sensory-motor transmission. They also ablated these interneurons by making them selectively sensitive to a lethal toxin, abolishing their control over sensory feedback strength. Without sensory feedback regulation, forelimb movements were dominated by severe oscillatory tremors, drastically diminishing motor accuracy.

This finding, along with parallel modeling studies, indicates that presynaptic inhibitory neurons normally adjust 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.

Dynorphin Acts as a Neuromodulator to Inhibit Itch in the Dorsal Horn of the Spinal Cord

Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.

Full Article

Transplanting interneurons: Getting the right mix

Despite early optimistic studies, the promise of curing neurological conditions using transplants remains unfulfilled. While researchers have exhaustively cataloged different types of cells in the brain, and also the largely biochemical issues underlying common diseases, neural repair shops are still a ways off. Fortunately, significant progress is being made towards identifying the broader operant principles that might bear on any one disease work-around. A review just published in Science focuses on recent work on transplanting interneurons—a diverse family of cells united by their mutual love of inhibition and their local loyalty. The UCLA-based authors, reach the conclusion that the fate of transplanted neurons ultimately depends less on the influences of the new host environment, and more on the early upbringing of the cells within the donor embryo.

Read more

CC to the brain: How neurons control fine motor behavior of the arm

Motor commands issued by the brain to activate arm muscles take two different routes. As the research group led by Professor Silvia Arber at the Basel University Biozentrum and the Friedrich Miescher Institute for Biomedical Research has now discovered, many neurons in the spinal cord send their instructions not only towards the musculature, but at the same time also back to the brain via an exquisitely organized network. This dual information stream provides the neural basis for accurate control of arm and hand movements. These findings have now been published in “Cell”.

Movement is a fundamental capability of humans and animals, involving the highly complex interplay of brain, nerves and muscles. Movements of our arms and hands, in particular, call for extremely precise coordination. The brain sends a constant stream of commands via the spinal cord to our muscles to execute a wide variety of movements. This stream of information from the brain reaches interneurons in the spinal cord, which then transmit the commands via further circuits to motor neurons innervating muscles. The research group led by Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research has now elucidated the organization of a second information pathway taken by these commands.

cc to the brain: one command – two directions

The scientists showed that many interneurons in the mouse spinal cord not only transmit their signals via motor neurons to the target muscle, but also simultaneously send a copy of this information back to the brain. Chiara Pivetta, first author of the publication, explains: “The motor command to the muscle is sent in two different directions – in one direction, to trigger the desired muscular contraction and in the other, to inform the brain that the command has actually been passed on to the musculature.” In analogy to e‑mail transmission, the information is thus not only sent to the recipient but also to the original requester.

Information to brainstem nucleus segregated by function

What happens to the information sent by spinal interneurons to the brain? As Arber’s group discovered, this input is segregated by function and spatially organized within a brainstem nucleus. Information from different types of interneurons thus flows to different areas of the nucleus. For example, spinal information that will influence left-right coordination of a movement is collected at a different site than information affecting the speed of a movement.

Fine motor skills supported by dual information stream

Arber comments: “From one millisecond to the next, this extremely precise feedback ensures that commands are correctly transmitted and that – via the signals sent back to the brain from the spinal cord – the resulting movement is immediately coordinated with the brain and adjusted.” Interestingly, the scientists only observed this kind of information flow to the brain for arm, but not for leg control. “What this shows,” says Arber, “is that this information pathway is most likely important for fine motor skills. Compared to the leg, movements of our arm and especially our hands have to be far more precise. Evidently, our body can only ensure this level of accuracy in motor control with constant feedback of information.”

In further studies, Silvia Arber’s group now plans to investigate what happens if the flow of information back to the brain is disrupted in specific ways. Since some interneurons facilitate and others inhibit movement, such studies could provide additional insights into the functionality of circuits controlling movement.

Signal found to enhance survival of new brain cells

A specialized type of brain cell that tamps down stem cell activity ironically, perhaps, encourages the survival of the stem cells’ progeny, Johns Hopkins researchers report. Understanding how these new brain cells “decide” whether to live or die and how to behave is of special interest because changes in their activity are linked to neurodegenerative diseases such as Alzheimer’s, mental illness and aging.

"We’ve identified a critical mechanism for keeping newborn neurons, or new brain cells, alive," says Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine’s Institute for Cell Engineering’s Stem Cell Program. "Not only can this help us understand the underlying causes of some diseases, it may also be a step toward overcoming barriers to therapeutic cell transplantation."

Working with a group led by Guo-li Ming, M.D., Ph.D., a professor of neurology in the Institute for Cell Engineering, and other collaborators, Song’s research team first reported last year that brain cells known as parvalbumin-expressing interneurons instruct nearby stem cells not to divide by releasing a chemical signal called GABA.

In their new study, as reported Nov. 10 online in Nature Neuroscience, Song and Ming wanted to find out how GABA from surrounding neurons affects the newborn neurons that stem cells produce. Many of these newborn neurons naturally die soon after their “birth,” Song says; if they do survive, the new cells migrate to a permanent home in the brain and forge connections called synapses with other cells.

To learn whether GABA is a factor in the newborn neurons’ survival and behavior, the research team tagged newborn neurons from mouse brains with a fluorescent protein, then watched their response to GABA. “We didn’t expect these immature neurons to form synapses, so we were surprised to see that they had built synapses from surrounding interneurons and that GABA was getting to them that way,” Song says. In the earlier study, the team had found that GABA was getting to the synapse-less stem cells by a less direct route, drifting across the spaces between cells.

To confirm the finding, the team engineered the interneurons to be either stimulated or suppressed by light. When stimulated, the cells would indeed activate nearby newborn neurons, the researchers found. They next tried the light-stimulation trick in live mice, and found that when the specialized interneurons were stimulated and gave off more GABA, the mice’s newborn neurons survived in greater numbers than otherwise. This was in contrast to the response of the stem cells, which go dormant when they detect GABA.

"This appears to be a very efficient system for tuning the brain’s response to its environment," says Song. "When you have a high level of brain activity, you need more newborn neurons, and when you don’t have high activity, you don’t need newborn neurons, but you need to prepare yourself by keeping the stem cells active. It’s all regulated by the same signal."

Song notes that parvalbumin-expressing interneurons have been found by others to behave abnormally in neurodegenerative diseases such as Alzheimer’s and mental illnesses such as schizophrenia. “Now we want to see what the role of these interneurons is in the newborn neurons’ next steps: migrating to the right place and integrating into the existing circuitry,” he says. “That may be the key to their role in disease.” The team is also interested in investigating whether the GABA mechanism can be used to help keep transplanted cells alive without affecting other brain processes as a side effect.