Scientists shed light on brain computations

University of Queensland (UQ) scientists have made a fundamental breakthrough into how the brain decodes the visual world.

Using advanced electrical recording techniques, researchers at UQ’s Queensland Brain Institute (QBI) have discovered how output cells of the eye’ balls retina compute the direction of a moving object.

QBI’s Dr Ben Sivyer and Associate Professor Stephen Williams have found that dendrites – the branching process of a neuron that conducts impulses toward the cell – play a critical role in decoding images.

“In the past decade our research shows that dendrites provide neurons with powerful processing capabilities,” Associate Professor Williams said.

“However the function of dendritic processing in the real-time operation of neuronal networks has remained elusive.”

To gain further insight, the group measured electrical activity from multiple sites in retinal ganglion cells when visual stimuli moved through space.

“The retina, a thin neuronal network at the posterior part of the eyeball, is ideal for investigating the role of active dendritic integration in neuronal circuit function,” he said.

“This is because this network can be maintained intact in a dish and retains its responsiveness to natural stimuli.”

He said while it had long been known that the retinal network extracted and signalled specific aspects of visual stimuli, the new work has discovered how such responses are computed.

“We found that retinal ganglion cells compute the direction of light stimuli through exquisitely controlled local integration compartments in the dendritic tree, a finding which highlights the key function that dendrites play in brain computations,” said Associate Professor Williams.

QBI Director Professor Perry Bartlett said this new insight was vital to brain research.

“Discovering how nerve cells process information is fundamental to understanding how we learn, and to developing new strategies to enhance learning in education and in disease processes in the brain,” he said.

Queensland Minister for Science and Innovation Ian Walker congratulated Dr Sivyer and Associate Professor Williams on their internationally significant findings.

“This is another example of Queensland leading the world in health and medical research,” he said.

“Dendrite research also has flow-on implications for brain-function studies in a range of areas.

“While all of these areas are important, I will be particularly interested to see its application to dementia research, which has been a major focus for recent Queensland Government support.”

The paper, Direction selectivity is computed by active dendritic integration in retinal ganglion cells, is published in the prestigious journal Nature Neuroscience.

Human Cortical Neurons with interconnecting dendrites, 4,200X by David Scharf.

Cortical Neurons make up the brain’s cortex which in part makes up the cerebral cortex, responsible for memory, attention, perceptual awareness, thought, language, and consciousness.

(Image Credit: BNPS/RPS/David Scharf)

Previously Unstudied Gene Is Essential for Normal Nerve Development

Our ability to detect heat, touch, tickling and other sensations depends on our sensory nerves. Now, for the first time, researchers at Albert Einstein College of Medicine of Yeshiva University have identified a gene that orchestrates the crucially important branching of nerve fibers that occurs during development. The findings were published online today in the journal Cell.

The research focuses on dendrites, the string-like extensions of sensory nerves that penetrate tissues of the skin, eyes and other sensory organs. “The formation of dendritic branches—‘arbors’ as we call them—is vital for allowing sensory nerves to collect information and sample the environment appropriately,” said Hannes Buelow, Ph.D., senior author of the Cell paper and associate professor of genetics at Einstein. “These arbors vary greatly in shape and complexity, reflecting the different types of sensory input they receive. The loss of dendritic complexity has been linked to a range of neurological problems including Alzheimer’s disease, schizophrenia and autism spectrum disorders.” Dr. Buelow is also associate professor in the Dominick P. Purpura Department of Neuroscience.

The Human Genome Project, completed in 2003, revealed that humans possess some 20,500 genes and determined the DNA sequence of each. But for many of those genes, their function in the body has remained unknown. The newly identified gene falls into this “previously unknown function” category. In fact, the gene belongs to an entire class of genes that had no known function in any organism.

One way to learn what genes do is to study a model organism like the roundworm, which possesses a similar number of genes as people but only 956 cells, of which 302 are nerve cells (neurons). By knocking out or mutating roundworm genes and observing the effects, researchers can obtain insight into how genes influence the animal’s structure or physiology.

The Einstein scientists were looking for genes that organize the structure of the developing nervous system. They focused on a pair of roundworm sensory neurons, known as PVD neurons, which together produce the largest web of dendrites of any neurons in the roundworm—a sensory web that covers almost the entire skin surface of the worm and detects pain and extreme temperatures.

Suspecting that a gene acts in the skin to “instruct” nearby dendrites to branch, the researchers set out to identify the one responsible. To find it, they induced random mutations in the worms, singled out those worms displaying defects in PVD dendrite branching, and then identified the gene mutations that caused the defective branching.

This lengthy procedure, known as a genetic screen, was carried out by Yehuda Salzberg, Ph.D., the study’s lead author and a postdoctoral fellow in Dr. Buelow’s lab. The screen revealed that four mutations in the same gene caused defective branching of PVD dendrites. The researchers showed that this gene’s expression in the skin produces an extracellular protein that triggers normal branching of PVD dendrites during development. The dendritic branches of PVD neurons had previously been described as resembling menorahs, so the Einstein scientists named this gene mnr-1 and dubbed its protein menorin, or MNR-1.

The mnr-1 gene’s newly identified function in orchestrating dendrite branching is presumably not limited to roundworms. Versions of this gene are present in multicellular animals from the simplest to the most complex, including humans. Genes conserved in this way, through millions of years of evolution, tend to be genes that are absolutely necessary for maintaining life.

Further study revealed that menorin synthesized in the skin was necessary but not sufficient to prompt PVD dendrite branching. The menorin protein appears to form a complex with SAX-7/L1CAM, a well-known cell-adhesion protein found in the skin and elsewhere in the roundworm. The researchers found evidence that dendrite branching ensues when this two-protein complex is sensed by DMA-1, a receptor molecule found on growing sensory dendrites.

"A fair amount was already known about factors within sensory neurons that regulate dendrite branching," said Dr. Buelow. "But until now, we knew next to nothing about external cues that pattern the sensory dendrites crucial to the functioning of any of our five senses. Hopefully, our success in finding two skin-derived cues that orchestrate dendrite branching will help in identifying cues involved in other sensory organs and possibly in the brain. Finding such cues could conceivably lead to therapies for replacing dendrite arbors depleted by injury or disease."

How Neurons Get Wired

Two different versions of the same signaling protein tell a nerve cell which end is which, UA researchers have discovered. The findings could help improve therapies for spinal injuries and neurodegenerative diseases.

University of Arizona scientists have discovered an unknown mechanism that establishes polarity in developing nerve cells. Understanding how nerve cells make connections is an important step in developing cures for nerve damage resulting from spinal cord injuries or neurodegenerative diseases such as Alzheimer’s.

In a study published on Aug. 12 in the journal Proceedings of the National Academy of Sciences, UA doctoral student Sara Parker and her adviser, assistant professor of cellular and molecular medicine Sourav Ghosh, report that the decision which will be the “plus” and the “minus” end in a newborn nerve cell is made by a long and a short version of the same signaling molecule.

Nerve cells – or neurons – differ from many other cells by their highly asymmetric shape: Vaguely resembling a tree, a neuron has one long, trunk-like extension ending in a tuft of root-like bristles. This is called the axon. From the opposite end of the cell body sprout branch-like structures known as dendrites. By connecting the “branches” of their dendrites to the “root tips” of other neurons’ axons, nerve cells form networks, which can be as simple as the few connections involved in the knee-jerk reflex or as complex as those in the human brain.

Parker and her team found that embryonic nerve cells manufacture a well-known signaling enzyme called Atypical Protein Kinase C (aPKC) in two varieties: a full-length one and a truncated one. Both varieties compete to bind the same molecular partner, a protein called Par3. If the short form of aPKC pairs up with Par3, it tells the cell to grow a dendrite, and if the long one pairs up with Par3, it will make an axon instead.

When the researchers blocked the production of the short form, the nerve cell grew multiple axons and no dendrites. When they created an artificial abundance of the short form, dendrites formed at the expense of axons. UA undergraduate student Sophie Hapak performed many of the experiments revealing how the two isoforms compete for Par3.

"We show that wiring a neuronal circuit is much more complex than previously thought," said Ghosh. "The process has a built-in robustness that explicitly defines which part of the cell is ‘positive’ and which is ‘negative.’"

"In order to have a functioning neuronal circuit, you have to have receiving and sending ends," Parker said. "Initially, when a neuron is formed, it lacks the polarity it needs once it develops into a part of a circuit. The mechanism we discovered establishes that polarity."

"How the various brain regions are wired is the basis of emotion, memory and all cognitive functions," said Ghosh, who is a member of the UA’s BIO5 Institute. "Establishing neuronal polarity in single neurons is absolutely essential for neuronal circuits to form."

"If we understand this mechanism, we could think about methods to spur new axons after the original ones were severed in a traumatic spinal cord injury, for example," Ghosh said.

The findings defy conventional wisdom, which maintains that a developing neuron will make dendrites by default unless instructed by the long form of aPKC to make an axon instead. By cultivating and studying neurons just after they formed, Parker and her group found that both forms of aPKC, long and short, are initially distributed equally throughout the cell. These forms subsequently segregate into different parts of the cell as the neuron matures and establishes polarity.

Because the cells were isolated from rat brains and kept in culture, the researchers could demonstrate that no external clues from other cells are needed to instruct a developing neuron. Whether the establishment of polarity is a random process or whether other signals yet to be identified play a role in regulating the abundance of the two aPKC varieties is not known.

What do memories look like?

Oscar Wilde called memory “the diary that we all carry about with us.” Now a team of scientists has developed a way to see where and how that diary is written.

Led by Don Arnold and Richard Roberts of USC, the team engineered microscopic probes that light up synapses in a living neuron in real time by attaching fluorescent markers onto synaptic proteins — all without affecting the neuron’s ability to function.

The fluorescent markers allow scientists to see live excitatory and inhibitory synapses for the first time and, importantly, how they change as new memories are formed.

The synapses appear as bright spots along dendrites (the branches of a neuron that transmit electrochemical signals). As the brain processes new information, those bright spots change, visually indicating how synaptic structures in the brain have been altered by the new data.

“When you make a memory or learn something, there’s a physical change in the brain. It turns out that the thing that gets changed is the distribution of synaptic connections,” said Arnold, associate professor of molecular and computational biology at the USC Dornsife College of Letters, Arts and Sciences, and co-corresponding author of an article about the research that appears in Neuron on June 19.

The probes behave like antibodies, but they bind more tightly and are optimized to work inside the cell — something that ordinary antibodies can’t do. To make these probes, the team used a technique known as “mRNA display,” which was developed by Roberts and Nobel laureate Jack Szostak.

“Using mRNA display, we can search through more than a trillion different potential proteins simultaneously to find the one protein that binds the target the best,” said Roberts, co-corresponding author of the article and professor of chemistry and chemical engineering with joint appointments at USC Dornsife and the USC Viterbi School of Engineering.

Arnold and Roberts’ probes (called “FingRs”) are attached to green fluorescent protein (GFP), a protein isolated from jellyfish that fluoresces bright green when exposed to blue light. Because FingRs are proteins, the genes encoding them can be put into brain cells in living animals, causing the cells themselves to manufacture the probes.

The design of FingRs also includes a regulation system that cuts off the amount of FingR-GFP that is generated after 100 percent of the target protein is labeled, effectively eliminating background fluorescence — generating a sharper, clearer picture.

These probes can be put in the brains of living mice and then imaged through cranial windows using two-photon microscopy.

The new research could offer crucial insight for scientists responding to President Barack Obama’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which was announced in April.

Modeled after the Human Genome Project, the objective of the $100 million initiative is to fast-track research that maps out exactly how the brain works and “better understand how we think, learn and remember,” according to the BRAIN Initiative website.

After 100 Years, Understanding the Electrical Role of Dendritic Spines

It’s the least understood organ in the human body: the brain, a massive network of electrically excitable neurons, all communicating with one another via receptors on their tree-like dendrites. Somehow these cells work together to enable great feats of human learning and memory. But how?

Researchers know dendritic spines play a vital role. These tiny membranous structures protrude from dendrites’ branches; spread across the entire dendritic tree, the spines on one neuron collect signals from an average of 1,000 others. But more than a century after they were discovered, their function still remains only partially understood.

A Northwestern University researcher, working in collaboration with scientists at the Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus, has recently added an important piece of the puzzle of how neurons “talk” to one another. The researchers have demonstrated that spines serve as electrical compartments in the neuron, isolating and amplifying electrical signals received at the synapses, the sites at which neurons connect to one another.

The key to this discovery is the result of innovative experiments at the Janelia Farm Research Campus and computer simulations performed at Northwestern University that can measure electrical responses on spines throughout the dendrites.

A paper about the findings, “Synaptic Amplification by Dendritic Spines Enhances Input Cooperatively,” was published November 22 in the journal Nature.

“This research conclusively shows that dendritic spines respond to and process synaptic inputs not just chemically, but also electrically,” said William Kath, professor of engineering sciences and applied mathematics at Northwestern’s McCormick School of Engineering, professor of neurobiology at the Weinberg College of Arts and Sciences, and one of the paper’s authors.

One neuron has huge impact on brain behaviour

Researchers from Queensland and the USA have made a unique discovery about how the brain computes sensory information.

The study by scientists at the Queensland Brain Institute (QBI) at The University of Queensland (UQ) and the Howard Hughes Medical Institute in the USA was conducted to better understand how circuits of nerve cells underlie behaviour.

Using advanced optical imaging in animal models, the research team was able to pinpoint a single neuron in the neocortex that signaled sensory behavior. This led to the discovery that active processes in its thin dendritic appendages are responsible for implementing the integration of sensory and motor signals.

“We have long known that active dendrites provide neurons with powerful processing capabilities,” says QBI’s Associate Professor Stephen Williams, who collaborated on the study. “However, little has been known about the role of neuronal dendrites in behaviourally related circuit computations. “We were pleasantly surprised to discover that the dendrites of nerve cells operate during behaviour to implement the integration of sensory and motor signals,” he said.

Such multi-modal integration enables the brain to perform at lightning speed, allowing animals to react to their environment in relation to existing knowledge. The paper, titled ‘Nonlinear dendritic integration of sensory and motor input during an active sensing task’ was published in the prestigious journal, Nature.

Branching out: A mathematical law of dendritic connectivity

Neuroscientists have derived a surprisingly simple and general equation that directly relates dendrite length with the number of branch points, dendrite spanning volume, and number of synapses. More specifically, they’ve shown that optimal dendritic wiring successfully predicts a 2/3 power law between these three factors. (A power law is a mathematical relationship between two quantities – found throughout the natural world – in which one quantity varies as a power of the other, often identifying simple rules underlying complex structures.) Their theory is both consistent with data gleaned from many types of neurons from a wide range of species yet specific to dendritic trees, leading them to conclude that their findings suggest that there are distinct design principles for dendritic arbors compared with vascular, bronchial, and botanical trees.