Activity in dendrites is critical in memory formation

Why do we remember some things and not others? In a unique imaging study, two Northwestern University researchers have discovered how neurons in the brain might allow some experiences to be remembered while others are forgotten. It turns out, if you want to remember something about your environment, you better involve your dendrites.

Using a high-resolution, one-of-a-kind microscope, Daniel A. Dombeck and Mark E. J. Sheffield peered into the brain of a living animal and saw exactly what was happening in individual neurons called place cells as the animal navigated a virtual reality maze.

The scientists found that, contrary to current thought, the activity of a neuron’s cell body and its dendrites can be different. They observed that when cell bodies were activated but the dendrites were not activated during an animal’s experience, a lasting memory of that experience was not formed by the neurons. This suggests that the cell body seems to represent ongoing experience, while dendrites, the treelike branches of a neuron, help to store that experience as a memory.

"There are a lot of theories on memory but very little data as to how individual neurons actually store information in a behaving animal," said Dombeck, assistant professor of neurobiology in the Weinberg College of Arts and Sciences and the study’s senior author. "Now we have uncovered signals in dendrites that we think are very important for learning and memory. Our findings could explain why some experiences are remembered and others are forgotten."

In the brain’s hippocampus, there are hundreds of thousands of place cells — neurons essential to the brain’s GPS system. Dombeck and Sheffield are the first to image the activity of individual dendrites in place cells.

Their findings contribute to our understanding of how the brain represents the world around it and also point to dendrites as a new potential target for therapeutics to combat memory deficits and debilitating diseases, such as Alzheimer’s disease (AD). Disruption to the brain’s GPS system is one of the first symptoms of AD, with many patients unable to find their way home. Understanding how place cells and their dendrites store these types of memories could help us find new ways to treat the disease.

The Northwestern study will be published Oct. 26 by the journal Nature.

Neuroscientist John O’Keefe discovered place cells in 1971 (and received this year’s Nobel Prize in physiology and medicine), but it is only in the last few years that scientists, such as Dombeck and Sheffield, have been able to image these neurons that represent a map of where we are in our environment.

In their study, Dombeck and Sheffield found dendrite signals that could explain how an animal can experience something without storing the experience as a memory.

They saw that dendrites are not always activated when the cell body is activated in a neuron. Signals produced in the dendrites (used to store information) and signals within the neuron cell body (used to compute and transmit information) can be either highly synchronized or desynchronized depending on how well the neurons remember different features of the maze.

Scientists have long believed that the neuronal tasks of computing and storing information are connected — when neurons compute information, they are also storing it, and vice versa. The Northwestern study provides evidence against this classic view of neuronal function.

"We experience events all the time, which must be represented in the brain by the activity of neurons, but not all these events can be recalled later," said Mark E. J. Sheffield, a postdoctoral fellow in Dombeck’s lab and first author of the study.

"A daily commute to work, for example, requires the activity of millions of neurons, but you would be hard pressed to remember what was happening halfway through your commute last Tuesday," Sheffield said. "How is it then that the neurons could be activated during the commute without storing that information in the brain? Now we may have an explanation for how this occurs."

Dombeck and Sheffield built their own laser scanning microscope that can image neurons on multiple planes. They then studied individual animals navigating (on a trackball) a virtual reality maze constructed using the video game Quake II.

Each lit-up structure seen in the images they took indicate a neuron firing action potentials. The activity of these neurons represents an animal’s experience of where it is in the environment, the researchers said. Whether the neurons store this experience or not appears to depend on the activity of the neurons’ dendrites.

(Image credit)

(Image caption: A neuron in which the axon originates at a dendrite. Signals arriving at this dendrites become more efficiently forwarded than signals input elsewhere. Credit: Alexei V. Egorov, 2014)

Communication without detours

Certain nerve cells take a shortcut for the transmission of information: signals are not conducted via the cell`s center, but around it like on a bypass road. The previously unknown nerve cell shape is now presented in the journal “Neuron" by a research team from Heidelberg, Mannheim and Bonn.

Nerve cells communicate by using electrical signals. Via widely ramified cell structures—the  dendrites—, they receive signals from other neurons and then transmit them over a thin cell extension—the axon—to other nerve cells. Axon and dendrites are usually interconnected by the neuron’s cell body. A team of scientists at the Bernstein Center Heidelberg-Mannheim, Heidelberg University, and the University of Bonn has now discovered neurons in which the axon arises directly from one of the dendrites. Similar to taking a bypass road, the signal transmission is thus facilitated within the cell.

“Input signals at this dendrite do not need not be propagated across the cell body,” explains Christian Thome of the Bernstein Center Heidelberg-Mannheim and Heidelberg University, one of the two first authors of the study. For their analyses, the scientists specifically colored the places of origin of axons of so-called pyramidal cells in the hippocampus. This brain region is involved in memory processes. The surprising result: “We found that in more than half of the cells, the axon does not emerge from the cell body, but arises from a lower dendrite,” Thome says.

The researchers then studied the effect of signals received at this special dendrite. For this purpose, they injected a certain form of the neural transmitter substance glutamate into the brain tissue of mice that can be activated by light pulses. A high-resolution microscope allowed the neuroscientists to direct the light beam directly to a specific dendrite. By the subsequent activation of the messenger substance, they simulated an exciting input signal.

“Our measurements indicate that dendrites that are directly connected to the axon, actively propagate even small input stimuli and activate the neuron,” says second first author Tony Kelly, a member of the Sonderforschungsbereich (SFB) 1089 at the University of Bonn. A computer simulation of the scientists predicts that this effect is particularly pronounced when the information flow from other dendrites to the axon is suppressed by inhibitory input signals at the cell body.

“That way, information transmitted by this special dendrite influences the behavior of the nerve cell more than input from any other dendrite,” Kelly says. In a future step, the researchers attempt to figure out which biological function is actually strengthened through the specific dendrite—and what therefore might be the reason for the unusual shape of these neurons.

Sleep After Learning Strengthens Connections Between Brain Cells and Enhances Memory

In study published today in Science, researchers at NYU Langone Medical Center show for the first time that sleep after learning encourages the growth of dendritic spines, the tiny protrusions from brain cells that connect to other brain cells and facilitate the passage of information across synapses, the junctions at which brain cells meet. Moreover, the activity of brain cells during deep sleep, or slow-wave sleep, after learning is critical for such growth.

The findings, in mice, provide important physical evidence in support of the hypothesis that sleep helps consolidate and strengthen new memories, and show for the first time how learning and sleep cause physical changes in the motor cortex, a brain region responsible for voluntary movements. 

“We’ve known for a long time that sleep plays an important role in learning and memory. If you don’t sleep well you won’t learn well,” says senior investigator Wen-Biao Gan, PhD, professor of neuroscience and physiology and a member of the Skirball Institute of Biomolecular Medicine at NYU Langone Medical Center. “But what’s the underlying physical mechanism responsible for this phenomenon? Here we’ve shown how sleep helps neurons form very specific connections on dendritic branches that may facilitate long-term memory. We also show how different types of learning form synapses on different branches of the same neurons, suggesting that learning causes very specific structural changes in the brain.”

On the cellular level, sleep is anything but restful: Brain cells that spark as we digest new information during waking hours replay during deep sleep, also known as slow-wave sleep, when brain waves slow down and rapid-eye movement, as well as dreaming, stops. Scientists have long believed that this nocturnal replay helps us form and recall new memories, yet the structural changes underpinning this process have remained poorly understood.

To shed light on this process, Dr. Gan and colleagues employed mice genetically engineered to express a fluorescent protein in neurons. Using a special laser-scanning microscope that illuminates the glowing fluorescent proteins in the motor cortex, the scientists were then able to track and image the growth of dendritic spines along individual branches of dendrites before and after mice learned to  balance on a spin rod. Over time mice learned how to balance on the rod as it gradually spun faster. “It’s like learning to ride a bike,” says Dr. Gan. “Once you learn it, you never forget.”

After documenting that mice, in fact, sprout new spines along dendritic branches, within six hours after training on the spinning rod, the researchers set out to understand how sleep would impact this physical growth. They trained two sets of mice: one trained on the spinning rod for an hour and then slept for 7 hours; the second trained for the same period of time on the rod but stayed awake for 7 hours. The scientists found that the sleep-deprived mice experienced significantly less dendritic spine growth than the well-rested mice. Furthermore, they found that the type of task learned determined which dendritic branches spines would grow.

Running forward on the spinning rod, for instance, produced spine growth on different dendritic branches than running backward on the rod, suggesting that learning specific tasks causes specific structural changes in the brain.

“Now we know that when we learn something new, a neuron will grow new connections on a specific branch,” says Dr. Gan. “Imagine a tree that grows leaves (spines) on one branch but not another branch. When we learn something new, it’s like we’re sprouting leaves on a specific branch.”

Finally, the scientists showed that brain cells in the motor cortex that activate when mice learn a task reactivate during slow-wave deep sleep. Disrupting this process, they found, prevents dendritic spine growth. Their findings offer an  important insight into the functional role of neuronal replay—the process by which the sleeping brain rehearses tasks learned during the day—observed in the motor cortex.

“Our data suggest that neuronal reactivation during sleep is quite important for growing specific connections within the motor cortex,” Dr. Gan adds.

(Image: Shutterstock)

The control of dendritic branching by mitochondria

A fundamental difference between neurons in real brains and those in artificial neural networks is the way the neurons in each are connected. In artificial nets, the synapses between neurons often have adjustable strengths, but the structure and scale of the input dendritic field generally counts for little. For real neurons, where a “connection” between cells is not just a synapse but rather a whole net unto itself, structure and scale are everything. The architect of this dendritic structure is neither a DNA code nor a spontaneous developmental physics that condenses order from a protein-lipid chaos. This structure is in fact the byproduct of competitive, yet cooperative mitochondria that administer that code to themselves and to their host to control its interaction with other similarly controlled hosts.

Reseachers from Osaku University have found that if mitochondria are depleted from developing dendrites in pyramidal cells, there is increased branching in the proximal region of the dendrites. In their paper last week in the Journal of Neuroscience, they also show that these dendrites grow longer. Since mitochondria distribute not just energy but also metabolites, proteins, and mRNAs throughout the cell, these results may be somewhat surprising. However depending on what manipulations have been done to alter the mitochondria, many things might be expected to happen to dendrites and the cell in general.

Read more

Existence of new neuron repair pathway discovered

Most of your neurons can’t be replaced.

Other parts of your body – such as skin and bone – can be replaced by the body growing new cells, but when you injure your neurons, you can’t just grow new ones; instead, the existing cells have to repair themselves.

In the case of axon injury, the neuron is able to repair or sometimes even fully regenerate its axon. But neurons have two sides – the axon (which sends signals to other cells) and the dendrite (which receives signals from other cells).

Melissa Rolls, an associate professor of biochemistry and molecular biology at Penn State and director of the Huck Institutes’ Center for Cellular Dynamics, has done extensive comparisons of axons and dendrites – culminating recently in a paper published in Cell Reports.

“We know that the axon side can repair itself,” says Rolls, “and we know a bunch of the molecular players. But we really didn’t know whether neurons have the same capacity to regenerate their dendrites, and so that’s what we set out to find in this study.”

“Our lab uses a Drosophila model system, where the dendrites are very accessible to manipulation,” she says, “so we decided that we would start by removing all the dendrites from the neurons to see if they could regenerate. We didn’t start with anything subtle, like taking off just a few dendrites. We said ‘Let’s just push the system to its maximum and see if this is even possible.’ And we were surprised because we found that not only is it possible, it’s actually much faster than axon regeneration: at least in the cells that we’re using, axon regeneration takes a day or two to initiate, while dendrite regeneration typically initiates within four to six hours and it works really well. All the cells where we removed the dendrites grew new dendrites – none of them died; so it’s clear that these cells have a way to both detect dendrite injury and initiate regrowth of the injured part.”

Read more

Scientists identify clue to regrowing nerve cells

Researchers at Washington University School of Medicine in St. Louis have identified a chain reaction that triggers the regrowth of some damaged nerve cell branches, a discovery that one day may help improve treatments for nerve injuries that can cause loss of sensation or paralysis.

The scientists also showed that nerve cells in the brain and spinal cord are missing a link in this chain reaction. The link, a protein called HDAC5, may help explain why these cells are unlikely to regrow lost branches on their own. The new research suggests that activating HDAC5 in the central nervous system may turn on regeneration of nerve cell branches in this region, where injuries often cause lasting paralysis.

“We knew several genes that contribute to the regrowth of these nerve cell branches, which are called axons, but until now we didn’t know what activated the expression of these genes and, hence, the repair process,” said senior author Valeria Cavalli, PhD, assistant professor of neurobiology. “This puts us a step closer to one day being able to develop treatments that enhance axon regrowth.”

The research appears Nov. 7 in the journal Cell.

Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages.

In the peripheral nervous system — the network of nerve cells outside the brain and spinal column — cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons.

Working with peripheral nervous system cells grown in the laboratory, Yongcheol Cho, PhD, a postdoctoral research associate in Cavalli’s laboratory, severed the cells’ axons. He and his colleagues learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms.

In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.

When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus.

When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.

“This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches,” Cavalli said. “We’re working on that now.”