Newly understood circuits add finesse to nerve signals

An unusual kind of circuit fine-tunes the brain’s control over movement and incoming sensory information, and without relying on conventional nerve pathways, according to a study published this week in the journal Neuron.

Researchers at the University of Alabama at Birmingham (UAB) discovered new details of a mechanism operating in the cerebellum, the brain region that processes nerve signals coming in from the spinal cord and cortex.

“Our results explain a second layer of nerve signal transmission that depends, not on whether a nerve cell is wired into a defined signaling pathway circuit, but instead on how close it is to the pathway,” said Jacques Wadiche, Ph.D., assistant professor in the Department of Neurobiology within the UAB School of Medicine, investigator in the Evelyn McKnight Brain Institute at UAB and senior study author. “It has become clear that this kind of nerve circuit is intimately linked with autism and certain movement disorders, and we hope the mechanisms detailed here contribute to the design of new treatments.”

Beyond nerve pathways

Nerve cells are known to occur in defined pathways that transmit messages in one direction. This pathway-specific view of nerve signaling has been reinforced by high-tech imaging studies yielding detailed connectivity maps. Along these lines, the Obama Administration will soon ask Congress for $100 million in research funding to further improve such maps.

Within nerve pathways, each nerve cell sends an electric pulse down an extension of itself called an axon until it reaches a synapse, a gap between itself and the next cell in line. When it reaches an axon’s end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap, where they either cause the downstream nerve cell to “fire” and pass on the message, or stop the message. In this way, each synapse between nerve cells in a pathway “decides” whether or not a message continues on.

In recent years, studies have found that neurotransmitters also spill into tissue surrounding axons in a type signaling not restricted to synaptic connections. With the term itself implying a mess, “spillover” was thought to degrade the capacity of nerve cells to precisely pass on signals.

The current study adds to recent evidence arguing that spillover may instead enhance message transmission, with the results revolving around three nerve cell types in the cerebellum: climbing fibers, Purkinje cells and interneurons.

Climbing fibers, which carry information from the brainstem into the cerebellum, play key roles in motor timing and sensory processing. Within these fibers, nerve cells release the excitatory neurotransmitter glutamate into synapses that then strive to pass messages deeper into the cerebellum. Purkinje cells are paired with climbing fibers and intent on inhibiting their signals.

When excited by glutamate from climbing fibers at one end, Purkinje cells release another neurotransmitter called GABA at their downstream synapse to stop the message. An excitatory signal triggers an inhibitory one as a counter-balance, a form of feedback critical to the function of the central nervous system. Lack of inhibition, for instance, causes circuits to seize, seizures and the death of Purkinje cells, the latter of which has been linked by post mortem studies to a higher incidence of autism spectrum disorders.

Previously, researchers thought that incoming signals from climbing fibers caused a single, strong response in the cerebellum: the activation of Purkinje cells that released GABA. The current study argues that such signals also trigger the firing of interneurons, nearby inhibitory middlemen that connect sets of nerve cells.

Interneurons within, and outside of, the glutamate spill zone around climbing fibers may have different effects on the other interneurons and Purkinje cells they connect to, according to the current finding. The interactions either inhibit or excite many Purkinje cells surrounding an active climbing fiber and refine its messages in a feedback system more sophisticated than once thought.

Glutamate has its effect by fitting into AMPA and NMDA receptor proteins, like a key into a lock, on the surfaces of nerve cells it signals to. The consensus has been that glutamate receptors occur only within synapses. Finding them on nerve cells outside of synapse-defined pathways represents “a fundamental shift in understanding,” said Wadiche, and may result in longer-lasting inhibition within key signaling pathways.

“A 2007 study published in Nature Neuroscience found that many climbing fibers signal to interneurons in the outer layer of the cerebellum outside nerve pathways and exclusively through glutamate spillover,” said Luke Coddington, a graduate student in Wadiche’s lab and study author. “Our team built on that observation to show how spillover affects the function of interneurons, Purkinje cells, and ultimately, the entire cerebellum. Spillover-mediated signaling recruits local microcircuits to extend the reach and finesse of climbing fiber signaling.”

Mapping blank spots in the cheeseboard maze

IST Austria Professor Jozsef Csicsvari together with collaborators succeeds in uncovering processes in which the formation of spatial memory is manifested in a map representation • Researchers investigate timescale of map formation • Inhibitory interneurons possibly involved in selection of map

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O’Neill, postdoc in Csicsvari’s group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called “place cells”. A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations “flicker”, with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection – helping one map dominate and take over during learning, so that the relevant information is encoded.

Breaking down the Parkinson’s pathway

The key hallmark of Parkinson’s disease is a slowdown of movement caused by a cutoff in the supply of dopamine to the brain region responsible for coordinating movement. While scientists have understood this general process for many years, the exact details of how this happens are still murky.

“We know the neurotransmitter, we know roughly the pathways in the brain that are being affected, but when you come right down to it and ask what exactly is the sequence of events that occurs in the brain, that gets a little tougher,” says Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research.

A new study from Graybiel’s lab offers insight into some of the precise impairments caused by the loss of dopamine in brain cells affected by Parkinson’s disease. The findings, which appear in the March 12 online edition of the Journal of Neuroscience, could help researchers not only better understand the disease, but also develop more targeted treatments.

The neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources — the neocortex and a tiny region known as the substantia nigra. The cortex relays sensory information as well as plans for future action, while the substantia nigra sends dopamine that helps to coordinate all of the cortical input.

“This dopamine somehow modulates the circuit interactions in such a way that we don’t move too much, we don’t move too little, we don’t move too fast or too slow, and we don’t get overly repetitive in the movements that we make. We’re just right,” Graybiel says.

Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum die, cutting off a critical dopamine source; in a process that is not entirely understood, too little dopamine translates to difficulty initiating movement. Most Parkinson’s patients receive L-dopa, which can substitute for the lost dopamine. However, the effects usually wear off after five to 10 years, and complications appear.

Protein identified that can disrupt embryonic brain development and neuron migration

Interneurons – nerve cells that function as ‘dimmers’ – play an important role in the brain. Their formation and migration to the cerebral cortex during the embryonic stage of development is crucial to normal brain functioning. Abnormal interneuron development and migration can eventually lead to a range of disorders and diseases, from epilepsy to Alzheimer’s. New research by Dr. Eve Seuntjens and Dr. Veronique van den Berghe of the Department of Development and Regeneration (Danny Huylebroeck laboratory, Faculty of Medicine) has identified two proteins, Sip1 and Unc5b, that play an important role in the development and migration of interneurons to the cerebral cortex – a breakthrough in our understanding of early brain development.

Two types of nerve cells are crucial to healthy brain functioning. Projection neurons, the more widely known of the two, make connections between different areas of the brain. Interneurons, a second type, work as dimmers that regulate the signalling processes of projection neurons. A shortage or irregular functioning of interneurons can cause short circuits in the nervous system. This can lead to seizures, a common symptom of many brain disorders. Interneuron dysfunction even appears to play a role in schizophrenia, autism and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS.

Trailblazers

Researchers have only recently understood how different kinds of neuron are formed during embryonic development. During early brain development, stem cells form projection neurons in the cerebral cortex. Interneurons are made elsewhere in the brain. These interneurons then migrate to the cortex to mix with the projection neurons. Dr. Eve Seuntjens of the Celgen laboratory led by Professor Danny Huylebroeck explains: “The journey of interneurons is very complex: their environment changes constantly during growth and there are no existing structures — such as nerve pathways — available for them to follow.”

The question is how young interneurons receive their ‘directions’ to the cerebral cortex. Several proteins play a role, says Dr. Seuntjens. “We changed the gene containing the production code for the protein Sip1 in mice so that this protein was no longer produced during brain development.  In those mice, the interneurons never made it to the cerebral cortex — they couldn’t find the way.

That has to do with the guidance signals – substances that repel or attract interneurons and thus point them in the right direction – encountered by the interneurons on their way to the cerebral cortex. Without Sip1 production, interneurons see things through an overly sharp lens, so to speak. They see too many stop signs and become blocked. That overly sharp lens is Unc5b, a protein. Unc5b is deactivated by Sip1 in healthy mice. There are several known factors that influence the migration of interneurons, but Unc5b is the first protein we’ve isolated that we now know must be switched off in order for interneuron migration to move ahead smoothly.”

The next step is to study this process in the neurons of humans. “Now that there are techniques to create stem cells from skin cells, we can mimic the development of stem cells into interneurons and study what can go wrong. From there, we can test whether certain drugs can reverse the damage. That’s all still on the horizon, but you can see that the focus of research on many brain disorders and diseases is increasingly shifting to early child development because that just might be where a cause can be found.”

Glowing Vulcan ears reveal brain’s lost neurons

These glowing shapes aren’t the ears of a rave-happy Vulcan - they’re slices from a mouse’s brain.

The slice on the right is from a mouse that lacks a gene called Arl13b - the same gene whose mutation causes Joubert syndrome in humans. This is a rare neurological condition that is linked with autism-spectrum disorders and brain structure malformations.

Without Arl13b, the nerve cells known as interneurons can’t find the right destination in the cerebral cortex during the brain’s development. Since the interneurons don’t end up in the right places, they can’t be wired up properly later on. This causes the disrupted brain development, typical of Joubert syndrome, visible in the image on the right.

The researchers hope that their findings will lead to better treatments for people who have the syndrome. 

"Ultimately, if you’re going to come up with therapeutic solutions, it’s important to understand the biology of the disease," says Eva Anton of the University of North Carolina in Chapel Hill, who worked on the research, which was published in Developmental Cell last week.

Mechanisms Underlying Childhood Neuromuscular Disease Found

A study by scientists from the Motor Neuron Center at Columbia University Medical Center (CUMC) suggests that spinal muscular atrophy (SMA), a genetic neuromuscular disease in infants and children, results primarily from motor circuit dysfunction, not motor neuron or muscle cell dysfunction, as is commonly thought. In a second study, the researchers identified the molecular pathway in SMA that leads to problems with motor function. Findings from the studies, conducted in fruit fly, zebrafish and mouse models of SMA, could lead to therapies for this debilitating and often fatal neuromuscular disease. Both studies were published today in the online edition of the journal Cell (1, 2).

“Scientists call SMA a motor neuron disease, and there is post-mortem evidence that it does cause motor neurons to die,” said Brian McCabe, PhD, assistant professor of pathology and cell biology and of neuroscience in the Motor Neuron Center, who led the first study. “However, it was not clear whether the death of motor neurons is a cause of the disease or an effect. Our findings in the fruit fly SMA model show that the disease originates in other motor circuit neurons, which then causes motor neurons to malfunction.”

In motor circuits, which coordinate muscle movement, specialized sensory neurons called proprioceptive neurons pick up and relay information to the spinal cord and brain about the body’s position in space. The central nervous system then processes and relays the signals, including via interneurons, to motor neurons, which in turn stimulate muscle movement.

“To our knowledge, this is the first clear demonstration in a model organism that defects in the function of a neuronal circuit are the cause of a neurological disease,” added Dr. McCabe.