̽��ֱ�� of Cambridge - Neuron

Calcium may play a role in the development of Parkinson’s disease

sc604 — Mon, 19 Feb 2018 10:00:00 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson’s disease. Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.

̽��ֱ��findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson’s. According to the charity Parkinson’s UK, one in every 350 adults in the UK – an estimated 145,000 in all – currently has the condition, but as yet it remains incurable.

Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the sign of Parkinson’s disease.

Curiously, it hasn’t been clear until now what alpha-synuclein actually does in the cell: why it’s there and what it’s meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain and the movement of molecules in and out of nerve endings, but exactly how it behaves is unclear.

“Alpha-synuclein is a very small protein with very little structure, and it needs to interact with other proteins or structures in order to become functional, which has made it difficult to study,” said senior author Dr Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology.

Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, Kaminski Schierle and her colleagues isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

In neurons, calcium plays a role in the release of neurotransmitters. ̽��ֱ��researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.

“This is the first time we’ve seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles,” said Dr Janin Lautenschläger, the paper’s first author. “We think that alpha-synuclein is almost like a calcium sensor. In the presence of calcium, it changes its structure and how it interacts with its environment, which is likely very important for its normal function.”

“There is a fine balance of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson’s disease,” said co-first author Dr Amberley Stephens.

̽��ֱ��imbalance can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slowing of the breakdown of excess protein, by an increased level of calcium in neurons that are sensitive to Parkinson’s, or an associated lack of calcium buffering capacity in these neurons.

Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson’s disease. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson’s disease.

̽��ֱ��research was funded in part by the Wellcome Trust, the Medical Research Council, Alzheimer’s Research UK, and the Engineering and Physical Sciences Research Council.

Reference
Janin Lautenschläger, Amberley D. Stephens et al. ‘C-terminal calcium binding of Alpha-synuclein modulates synaptic vesicle interaction.’ Nature Communications (2018). DOI: 10.1038/s41467-018-03111-4

Researchers have found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson’s disease.

This is the first time we’ve seen that calcium influences the way alpha-synuclein behaves.

Janin Lautenschlӓger

Janin Lautenschläger

Tyrosine hydroxylase positive neuron stained with a synaptic marker

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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New imaging technique measures toxicity of proteins associated with Alzheimer’s and Parkinson’s diseases

sc604 — Wed, 23 Nov 2016 09:57:57 +0000

Researchers have developed a new imaging technique that makes it possible to study why proteins associated with Alzheimer’s and Parkinson’s diseases may go from harmless to toxic. ̽��ֱ��technique uses a technology called multi-dimensional super-resolution imaging that makes it possible to observe changes in the surfaces of individual protein molecules as they clump together. ̽��ֱ��tool may allow researchers to pinpoint how proteins misfold and eventually become toxic to nerve cells in the brain, which could aid in the development of treatments for these devastating diseases.

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, have studied how a phenomenon called hydrophobicity (lack of affinity for water) in the proteins amyloid-beta and alpha synuclein – which are associated with Alzheimer’s and Parkinson’s respectively – changes as they stick together. It had been hypothesised that there was a link between the hydrophobicity and toxicity of these proteins, but this is the first time it has been possible to image hydrophobicity at such high resolution. Details are reported in the journal Nature Communications.

“These proteins start out in a relatively harmless form, but when they clump together, something important changes,” said Dr Steven Lee from Cambridge’s Department of Chemistry, the study’s senior author. “But using conventional imaging techniques, it hasn’t been possible to see what’s going on at the molecular level.”

In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, naturally-occurring proteins fold into the wrong shape and clump together into filament-like structures known as amyloid fibrils and smaller, highly toxic clusters known as oligomers which are thought to damage or kill neurons, however the exact mechanism remains unknown.

For the past two decades, researchers have been attempting to develop treatments which stop the proliferation of these clusters in the brain, but before any such treatment can be developed, there first needs to be a precise understanding of how oligomers form and why.

“There’s something special about oligomers, and we want to know what it is,” said Lee. “We’ve developed new tools that will help us answer these questions.”

When using conventional microscopy techniques, physics makes it impossible to zoom in past a certain point. Essentially, there is an innate blurriness to light, so anything below a certain size will appear as a blurry blob when viewed through an optical microscope, simply because light waves spread when they are focused on such a tiny spot. Amyloid fibrils and oligomers are smaller than this limit so it’s very difficult to directly visualise what is going on.

However, new super-resolution techniques, which are 10 to 20 times better than optical microscopes, have allowed researchers to get around these limitations and view biological and chemical processes at the nanoscale.

Lee and his colleagues have taken super-resolution techniques one step further, and are now able to not only determine the location of a molecule, but also the environmental properties of single molecules simultaneously.

Using their technique, known as sPAINT (spectrally-resolved points accumulation for imaging in nanoscale topography), the researchers used a dye molecule to map the hydrophobicity of amyloid fibrils and oligomers implicated in neurodegenerative diseases. ̽��ֱ��sPAINT technique is easy to implement, only requiring the addition of a single transmission diffraction gradient onto a super-resolution microscope. According to the researchers, the ability to map hydrophobicity at the nanoscale could be used to understand other biological processes in future.

̽��ֱ��research was supported by the Medical Research Council, the Engineering and Physical Sciences Research Council, the Royal Society and the Augustus Newman Foundation.

Reference
Marie N. Bongiovanni et al. ‘Multi-dimensional super-resolution imaging enables surface hydrophobicity mapping.’ Nature Communications (2016). DOI: 10.1038/NCOMMS13544

A new super-resolution imaging technique allows researchers to track how surface changes in proteins are related to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

These proteins start out in a relatively harmless form, but when they clump together, something important changes.

Steven Lee

ZEISS Microscopy

Brain showing hallmarks of Alzheimer's disease (plaques in blue)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Neurons feel the force – physical interactions control brain development

sc604 — Mon, 19 Sep 2016 15:00:00 +0000

Scientists have found that developing nerve cells are able to ‘feel’ their environment as they grow, helping them form the correct connections within the brain and with other parts of the body. ̽��ֱ��results, reported in the journal Nature Neuroscience, could open up new avenues of research in brain development, and lead to potential treatments for spinal cord injuries and other types of neuronal damage.

As the brain develops, roughly 100 billion neurons make over 100 trillion connections to send and receive information. For decades, it has been widely accepted that neuronal growth is controlled by small signalling molecules which are ‘sniffed’ out by the growing neurons, telling them which way to go, so that they can find their precise target. ̽��ֱ��new study, by researchers from the ̽��ֱ�� of Cambridge, shows that neuronal growth is not only controlled by these chemical signals, but also by the physical properties of their environment, which guide the neurons along complex stiffness patterns in the tissue through which they grow.

“ ̽��ֱ��fact that neurons in the developing brain not only respond to chemical signals but also to the mechanical properties of their environment opens many exciting new avenues for research in brain development,” said the study’s lead author Dr Kristian Franze, from Cambridge’s Department of Physiology, Development and Neuroscience. “Considering mechanics might also lead to new breakthroughs in our understanding of neuronal regeneration. For example, following spinal cord injuries, the failure of neurons to regrow through damaged tissue with altered mechanical properties has been a persistent challenge in medicine.”

We navigate our world guided by our senses, which are based on interactions with different facets of our environment — at the seaside you smell and taste the saltiness of the air, feel the grains of sand and the coldness of the water, and hear the crashing of waves on the beach. Within our bodies, individual neurons also sense and react to their environment – they ‘taste’ and ‘smell’ small chemical molecules, and, as this study shows, ‘feel’ the stiffness and structure of their surroundings. They use these senses to guide how and where they grow.

Using a long, wire-like extension called an axon, neurons carry electrical signals throughout the brain and body. During development, axons must grow along precisely defined pathways until they eventually connect with their targets. ̽��ֱ��enormously complex networks that result control all body functions. Errors in the neuronal ‘wiring’ or catastrophic severing of the connections, as occurs during spinal cord injury, may lead to severe disabilities.

A number of chemical signals controlling axon growth have been identified. Called ‘guidance cues,’ these molecules are produced by cells in the tissue surrounding growing axons and may either attract or repel the axons, directing them along the correct paths. However, chemical guidance cues alone cannot fully explain neuronal growth patterns, suggesting that other factors contribute to guiding neurons.

One of these factors turns out to be mechanics: axons also possess a sense of ‘touch’. In order to move, growing neurons must exert forces on their environment. ̽��ֱ��environment in turn exerts forces back, and the axons can therefore ‘feel’ the mechanical properties of their surroundings, such as its stiffness. “Consider the difference between walking on squelchy mud versus hard rock – how you walk, your balance and speed, will differ on these two surfaces,” said Franze. “Similarly, axons adjust their growth behaviour depending on the mechanical properties of their environment.” However, until recently it was not known what environments axons encounter as they grow, and Franze and his colleagues decided to find out.

They developed a new technique, based on atomic force microscopy, to measure the stiffness of developing Xenopus frog brains at high resolution – revealing what axons might feel as they grow through the brain. ̽��ֱ��study found complex patterns of stiffness in the developing brain that seemed to predict axon growth directions. ̽��ֱ��researchers showed that axons avoided stiffer areas of the brain and grew towards softer regions. Changing the normal brain stiffness caused the axons to get lost and fail to find their targets.

In collaboration with Professor Christine Holt’s research group, the team then explored how exactly the axons were feeling their environments. They found that neurons contain ion channels called Piezo1, which sit in the cell membrane: the barrier between cell and environment. These channels open only when a large enough force is applied, similar to shutter valves in air mattresses. Opening of these channels generates small pores in the membrane of the neurons, which allows calcium ions to enter the cells. Calcium then triggers a number of reactions that change how neurons grow.

When neuronal membranes were stiffened using a substance extracted from a spider venom, which made it harder to open the channels, neurons became ‘numb’ to environmental stiffness. This caused the axons to grow abnormally without reaching their target. Removing Piezo1 from the cells, similarly abolishing the axons’ capacity to feel differences in stiffness, had the same effect.

“We already understand quite a bit about the detection and integration of chemical signals” said Franze. “Adding mechanical signals to this picture will lead to a better understanding of the growth and development of the nervous system. These insights will help us answer critical questions in developmental biology as well as in biomedicine and regenerative biology.”

Reference:
David E Koser et al. ‘Mechanosensing is critical for axon growth in the developing brain.’ Nature Neuroscience (2016). DOI: 10.1038/nn.4394

Researchers have identified a new mechanism controlling brain development: that neurons not only ‘smell’ chemicals in their environment, but also ‘feel’ their way through the developing brain.

Considering mechanics might lead to new breakthroughs in our understanding of neuronal regeneration.

Kristian Franze

Eva Pillai

Brain of a frog embryo. ̽��ֱ��coloured structures are cell nuclei (containing DNA), the white structure in the center corresponds to the optic tract, which contains the neuronal axons studied.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Researchers identify when Parkinson’s proteins become toxic to brain cells

sc604 — Mon, 14 Mar 2016 19:00:00 +0000

Researchers have used a non-invasive method of observing how the process leading to Parkinson’s disease takes place at the nanoscale, and identified the point in the process at which proteins in the brain become toxic, eventually leading to the death of brain cells.

̽��ֱ��results suggest that the same protein can either cause, or protect against, the toxic effects that lead to the death of brain cells, depending on the specific structural form it takes, and that toxic effects take hold when there is an imbalance of the level of protein in its natural form in a cell. ̽��ֱ��work could help unravel how and why people develop Parkinson’s, and aid in the search for potential treatments. ̽��ֱ��study is published in the journal Proceedings of the National Academy of Sciences.

Using super-resolution microscopy, researchers from the ̽��ֱ�� of Cambridge were able to observe the behaviour of different types of alpha-synuclein, a protein closely associated with Parkinson's disease, in order to find how it affects neurons, and at what point it becomes toxic.

Parkinson’s disease is the second-most common neurodegenerative disease worldwide (after Alzheimer’s disease). Close to 130,000 people in the UK, and more than seven million worldwide, have the disease. Symptoms include muscle tremors, stiffness and difficulty walking. Dementia is common in later stages of the disease.

“What hasn’t been clear is whether once alpha-synuclein fibrils have formed they are still toxic to the cell,” said Dr Dorothea Pinotsi of Cambridge’s Department of Chemical Engineering and Biotechnology, the paper’s first author.

Pinotsi and her colleagues from Cambridge’s Department of Chemical Engineering & Biotechnology and Department of Chemistry, and led by Dr Gabriele Kaminski Schierle, have used optical ‘super-resolution’ techniques to look into live neurons without damaging the tissue. “Now we can look at how proteins associated with neurodegenerative conditions grow over time, and how these proteins come together and are passed on to neighbouring cells,” said Pinotsi.

̽��ֱ��researchers used different forms of alpha-synuclein and observed their behaviour in neurons from rats. They were then able to correlate what they saw with the amount of toxicity that was present.

They found that when they added alpha-synuclein fibrils to the neurons, they interacted with alpha-synuclein protein that was already in the cell, and no toxic effects were present.

“It was believed that amyloid fibrils that attack the healthy protein in the cell would be toxic to the cell,” said Pinotsi. “But when we added a different, soluble form of alpha-synuclein, it didn’t interact with the protein that was already present in the neuron and interestingly this was where we saw toxic effects and cells began to die. So somehow, when the soluble protein was added, it created this toxic effect. ̽��ֱ��damage appears to be done before visible fibrils are even formed.”

̽��ֱ��researchers then observed that by adding the soluble form of alpha-synuclein together with amyloid fibrils, the toxic effect of the former could be overcome. It appeared that the amyloid fibrils acted like magnets for the soluble protein and mopped up the soluble protein pool, shielding against the associated toxic effects.

“These findings change the way we look at the disease, because the damage to the neuron can happen when there is simply extra soluble protein present in the cell – it’s the excess amount of this protein that appears to cause the toxic effects that lead to the death of brain cells,” said Pinotsi. Extra soluble protein can be caused by genetic factors or ageing, although there is some evidence that it could also be caused by trauma to the head.

̽��ֱ��research shows how important it is to fully understand the processes at work behind neurodegenerative diseases, so that the right step in the process can be targeted.

“With these optical super-resolution techniques, we can really see details we couldn’t see before, so we may be able to counteract this toxic effect at an early stage,” said Pinotsi.

̽��ֱ��research was funded by the Medical Research Council, the Engineering and Physical Sciences Research Council, and the Wellcome Trust.

Reference:
Dorothea Pinotsi et. al. ‘Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons.’ Proceedings of the National Academy of Sciences (2016). DOI: 10.1073/pnas.1516546113

Observation of the point at which proteins associated with Parkinson’s disease become toxic to brain cells could help identify how and why people develop the disease, and aid in the search for potential treatments.

̽��ֱ��damage appears to be done before visible fibrils are even formed.

Dorothea Pinotsi

Zoomed-in super-resolution (dSTORM) images of the fibrils inside the neuron formed of exogenous ‘’seed’’ fibrils (green) elongated by endogenous α-synuclein (red).

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

̽��ֱ��amazing axon adventure

sc604 — Fri, 05 Feb 2016 09:45:21 +0000

To read these words, light is first refracted by the cornea, through the pupil in the iris and onto the lens, which focuses images onto the retina. ̽��ֱ��images are received by light-sensitive cells in the retina, which transmit impulses to the brain. These impulses are carried by a set of neurons called the retinal ganglion cells. Once the impulses reach the brain, the brain then has to piece together the information it receives into an understandable image. All of this happens in a fraction of a second.

Information travels from the retina to the brain via axons – the long, threadlike parts of neurons – sent out by the retinal ganglion cells. During embryonic development, axons are sent out to find their specific targets in the brain, so that images can be processed.

For an axon in a growing embryo, the journey from retina to brain is not a straightforward one. It’s a very long way for a tiny axon, through a constantly changing series of environments that it has never encountered before. So how do axons know where to go, and what can it tell us about how the brain is made and maintained?

Two ̽��ֱ�� of Cambridge researchers, Professor Christine Holt of the Department of Physiology, Development and Neuroscience, and Dr Stephen Eglen of the Department of Applied Mathematics and Theoretical Physics, are taking two different, but complementary, approaches to these questions.

With funding from the European Research Council and the Wellcome Trust, Holt’s research group is aiming to better understand the molecular and cellular mechanisms that guide and maintain axon growth, which in turn will aid better understanding of how nerve connections are first established.

“It’s an impressive navigational feat,” says Holt. “ ̽��ֱ��pathway between the retina and the brain may look homogeneous, but in reality it’s like a patchwork quilt of different molecular domains.”

On the pathway through this patchwork quilt, there is a set of distinct beacons, breaking the axon’s journey down into separate steps. Every time the growing axon reaches a new beacon, it has to make a decision about which way to go. At the tip of the axon is a growth cone, which ‘sniffs out’ certain chemical signals emitted from the beacons, helping it to steer in the right direction.

̽��ֱ��growth cones are receptive to certain signals and blind to others, so depending on what the axon encounters when it reaches a particular beacon, it will behave in a certain way. Holt’s research group uses a variety of techniques to determine what the signals are at the steering points where axons alter their direction of growth or their behaviour, such as the optic chiasm where certain axons cross to the opposite side of the brain, or at the point where they first leave the eye.

While Holt uses experiments to understand the development of the visual system, Eglen uses mathematical models as a complementary technique to try to answer the same questions.

“You’ve got much more freedom in a theoretical model than you do in an experiment,” he says. “A common experimental approach is to remove something genetically and see what happens. I think of that a little like taking the battery out of your car. Doing that will tell you that the battery is necessary for the car to function, but it doesn’t really tell you why.”

Theoretical models allow researchers to approach the questions around neural development from a different angle. To capture the essence of the neural system, they try to represent the building blocks of development and see what kind of behaviour would result.

But no model yet can fully capture the complexities of how the visual system develops, which Eglen views not only as a challenge for him as a mathematician, but also as a challenge back to the experimental community.

“It had been thought that if we built a model and took out all of the guidance molecules, there would be no topographic order whatsoever,” says Eglen. “But instead we found that there is still residual order in how the neurons are wired up, so there must be extra molecules or mechanisms that we don’t know about. What we’re trying to do is to take biology and put it into computers so that we can really test it.”

“In the past 15–20 years, there’s been a revolution in terms of being able to identify the specific molecules that act as guidance receptors or signals, but there’s still so much we don’t yet know, which is why we’re using both theoretical and experimental techniques to answer these questions,” says Holt. “And in addition to this question of wiring, we’re also looking at the problem of mapping – how do the terminal ends of the axons find their ultimate destination in the brain?”

Holt’s group has found that the same guidance molecule can have different roles depending on what aspect of growth is going on – but the question then becomes how do you wire the brain with so few molecules?

Adding to the complexity was another puzzling discovery – that the growth cones of axons can make proteins. Previous knowledge held that new proteins could be synthesised only within the main cellular part of each neuron, the cell body (where the nucleus is located), and then transported into axons. However, Holt’s group found that the growth cones of axons are also capable of synthesising proteins ‘on demand’ when they encounter new guidance beacons, suggesting that messenger RNA (mRNA) molecules play a role in helping axons to navigate to their correct destinations. mRNAs are the molecules from which new proteins are synthesised, and further experiments found that axons contain hundreds or even thousands of different types of this nuclear material.

In addition to their role in axon growth when the brain is wiring itself up during development, certain types of mRNA are also important in maintaining the connections in the adult brain, by keeping mitochondria – the energy-producing ‘batteries’ of cells – healthy, which, in turn, keeps axons healthy.

“It is a whole new view to the idea of degeneration in later life – a lot of different components have to work together to get local protein synthesis to work, so if just one of those components fails, degeneration can occur,” says Holt. “We’ve also found that many of the types of mRNA that are being translated in axons are the same ones that you see in diseases like Huntingdon’s and Parkinson’s, so basic knowledge of this sort is essential for the development of clinical therapies in nerve repair and for understanding these and other neurodegenerative disorders.”

How does the brain make connections, and how does it maintain them? Cambridge neuroscientists and mathematicians are using a variety of techniques to understand how the brain ‘wires up’, and what it might be able to tell us about degeneration in later life.

It’s an impressive navigational feat. ̽��ֱ��pathway between the retina and the brain may look homogeneous, but in reality it’s like a patchwork quilt.

Christine Holt

K-M. Leung

A growing axon tip exhibits polarised mRNA translation (red)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Modelling how the brain makes complex decisions

sc604 — Thu, 04 Feb 2016 10:17:10 +0000

Researchers have constructed the first comprehensive model of how neurons in the brain behave when faced with a complex decision-making process, and how they adapt and learn from mistakes.

̽��ֱ��mathematical model, developed by researchers from the ̽��ֱ�� of Cambridge, is the first biologically realistic account of the process, and is able to predict not only behaviour, but also neural activity. ̽��ֱ��results, reported in ̽��ֱ��Journal of Neuroscience, could aid in the understanding of conditions from obsessive compulsive disorder and addiction to Parkinson’s disease.

̽��ֱ��model was compared to experimental data for a wide-ranging set of tasks, from simple binary choices to multistep sequential decision making. It accurately captures behavioural choice probabilities and predicts choice reversal in an experiment, a hallmark of complex decision making.

Our decisions may provide immediate gratification, but they can also have far-reaching consequences, which in turn depend on several other actions we have already made or will make in the future. ̽��ֱ��trouble that most of us have is how to take the potential long-term effects of a particular decision into account, so that we make the best choice.

There are two main types of decisions: habit-based and goal-based. An example of a habit-based decision would be a daily commute, which is generally the same every day. Just as certain websites are cached on a computer so that they load faster the next time they are visited, habits are formed by ‘caching’ certain behaviours so that they become virtually automatic.

An example of a goal-based decision would be a traffic accident or road closure on that same commute, forcing the adoption of a different route.

“A goal-based decision is much more complicated from a neurobiological point of view, because there are so many more variables – it involves exploring a branching set of possible future situations,” said the paper’s first author Dr Johannes Friedrich of Columbia ̽��ֱ��, who conducted the work while a postdoctoral researcher in Cambridge’s Department of Engineering. “If you think about a detour on your daily commute, you need to make a separate decision each time you reach an intersection.”

Habit-based decisions have been thoroughly studied by neuroscientists and are fairly well-understood in terms of how they work at a neural level. ̽��ֱ��mechanisms behind goal-based decisions however, remain elusive.

Now, Friedrich and Dr Máté Lengyel, also from Cambridge’s Department of Engineering, have built a biologically realistic solution to this computational problem. ̽��ֱ��researchers have shown mathematically how a network of neurons, when connected appropriately, can identify the best decision in a given situation and its future cumulative reward.

“Constructing these sorts of models is difficult because the model has to plan for all possible decisions at any given point in the process, and computations have to be performed in a biologically plausible manner,” said Friedrich. “But it’s an important part of figuring out how the brain works, since the ability to make decisions is such a core competence for both humans and animals.”

̽��ֱ��researchers also found that for making a goal-based decision, the synapses which connect the neurons together need to ‘embed’ the knowledge of how situations follow on from each other, depending on the actions that are chosen, and how they result in immediate reward.

Crucially, they were also able to show in the same model how synapses can adapt and re-shape themselves depending on what did or didn’t work previously, in the same way that it has been observed in human and animal subjects.

“By combining planning and learning into one coherent model, we’ve made what is probably the most comprehensive model of complex decision-making to date,” said Friedrich. “What I also find exciting is that figuring out how the brain may be doing it has already suggested us new algorithms that could be used in computers to solve similar tasks,” added Lengyel.

̽��ֱ��model could be used to aid in the understanding of a range of conditions. For instance, there is evidence for selective impairment in goal-directed behavioural control in patients with obsessive compulsive disorder, which forces them to rely instead on habits. Deep understanding of the underlying neural processes is important as impaired decision making has also been linked to suicide attempts, addiction and Parkinson's disease.

Reference:
Johannes Friedrich and Máté Lengyel. ‘Goal-Directed Decision Making with Spiking Neurons.’ ̽��ֱ��Journal of Neuroscience (2016). DOI: 10.1523/JNEUROSCI.2854-15.2016

Researchers have built the first biologically realistic mathematical model of how the brain plans and learns when faced with a complex decision-making process.

By combining planning and learning into one coherent model, we’ve made what is probably the most comprehensive model of complex decision-making to date

Johannes Friedrich

Seung Lab

EyeWire Candy Neurons

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Attribution-Noncommercial-ShareAlike

Graphene shown to safely interact with neurons in the brain

sc604 — Fri, 29 Jan 2016 10:09:03 +0000

Researchers have successfully demonstrated how it is possible to interface graphene – a two-dimensional form of carbon – with neurons, or nerve cells, while maintaining the integrity of these vital cells. ̽��ֱ��work may be used to build graphene-based electrodes that can safely be implanted in the brain, offering promise for the restoration of sensory functions for amputee or paralysed patients, or for individuals with motor disorders such as epilepsy or Parkinson’s disease.

̽��ֱ��research, published in the journal ACS Nano, was an interdisciplinary collaboration coordinated by the ̽��ֱ�� of Trieste in Italy and the Cambridge Graphene Centre.

Previously, other groups had shown that it is possible to use treated graphene to interact with neurons. However the signal to noise ratio from this interface was very low. By developing methods of working with untreated graphene, the researchers retained the material’s electrical conductivity, making it a significantly better electrode.

“For the first time we interfaced graphene to neurons directly,” said Professor Laura Ballerini of the ̽��ֱ�� of Trieste in Italy. “We then tested the ability of neurons to generate electrical signals known to represent brain activities, and found that the neurons retained their neuronal signalling properties unaltered. This is the first functional study of neuronal synaptic activity using uncoated graphene based materials.”

Our understanding of the brain has increased to such a degree that by interfacing directly between the brain and the outside world we can now harness and control some of its functions. For instance, by measuring the brain's electrical impulses, sensory functions can be recovered. This can be used to control robotic arms for amputee patients or any number of basic processes for paralysed patients – from speech to movement of objects in the world around them. Alternatively, by interfering with these electrical impulses, motor disorders (such as epilepsy or Parkinson’s) can start to be controlled.

Scientists have made this possible by developing electrodes that can be placed deep within the brain. These electrodes connect directly to neurons and transmit their electrical signals away from the body, allowing their meaning to be decoded.

However, the interface between neurons and electrodes has often been problematic: not only do the electrodes need to be highly sensitive to electrical impulses, but they need to be stable in the body without altering the tissue they measure.

Too often the modern electrodes used for this interface (based on tungsten or silicon) suffer from partial or complete loss of signal over time. This is often caused by the formation of scar tissue from the electrode insertion, which prevents the electrode from moving with the natural movements of the brain due to its rigid nature.

Graphene has been shown to be a promising material to solve these problems, because of its excellent conductivity, flexibility, biocompatibility and stability within the body.

Based on experiments conducted in rat brain cell cultures, the researchers found that untreated graphene electrodes interfaced well with neurons. By studying the neurons with electron microscopy and immunofluorescence the researchers found that they remained healthy, transmitting normal electric impulses and, importantly, none of the adverse reactions which lead to the damaging scar tissue were seen.

According to the researchers, this is the first step towards using pristine graphene-based materials as an electrode for a neuro-interface. In future, the researchers will investigate how different forms of graphene, from multiple layers to monolayers, are able to affect neurons, and whether tuning the material properties of graphene might alter the synapses and neuronal excitability in new and unique ways. “Hopefully this will pave the way for better deep brain implants to both harness and control the brain, with higher sensitivity and fewer unwanted side effects,” said Ballerini.

“We are currently involved in frontline research in graphene technology towards biomedical applications,” said Professor Maurizio Prato from the ̽��ֱ�� of Trieste. “In this scenario, the development and translation in neurology of graphene-based high-performance biodevices requires the exploration of the interactions between graphene nano- and micro-sheets with the sophisticated signalling machinery of nerve cells. Our work is only a first step in that direction.”

“These initial results show how we are just at the tip of the iceberg when it comes to the potential of graphene and related materials in bio-applications and medicine,” said Professor Andrea Ferrari, Director of the Cambridge Graphene Centre. “ ̽��ֱ��expertise developed at the Cambridge Graphene Centre allows us to produce large quantities of pristine material in solution, and this study proves the compatibility of our process with neuro-interfaces.”

̽��ֱ��research was funded by the Graphene Flagship, a European initiative which promotes a collaborative approach to research with an aim of helping to translate graphene out of the academic laboratory, through local industry and into society.

Reference:
Fabbro A., et. al. ‘Graphene-Based Interfaces do not Alter Target Nerve Cells.’ ACS Nano (2016). DOI: 10.1021/acsnano.5b05647

Researchers have shown that graphene can be used to make electrodes that can be implanted in the brain, which could potentially be used to restore sensory functions for amputee or paralysed patients, or for individuals with motor disorders such as Parkinson’s disease.

We are just at the tip of the iceberg when it comes to the potential of graphene and related materials in bio-applications and medicine.

Andrea Ferrari

Modified by Susanna Bosi from image licensed from ktdesign/shutterstock.com

Graphene Neuron Interface

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Neural circuit in the cricket brain detects the rhythm of the right mating call

sc604 — Fri, 11 Sep 2015 18:00:00 +0000

Scientists have identified an ingeniously elegant brain circuit consisting of just five nerve cells that allows female crickets to automatically identify the chirps of males from the same species through the rhythmic pulses hidden within the mating call.

̽��ֱ��circuit uses a time delay mechanism to match the gaps between pulses in a species-specific chirp – gaps of just few milliseconds. ̽��ֱ��circuit delays a pulse by the exact between-pulse gap, so that, if it coincides with the next pulse coming in, the same species signal is confirmed.

It’s one of the first times a brain circuit consisting of individual neurons that identifies an acoustic rhythm has been characterised. ̽��ֱ��results are reported today (11 September) in the journal Science Advances.

Using tiny electrodes, scientists from Cambridge ̽��ֱ��’s Department of Zoology explored the brain of female crickets for individual auditory neurons responding to digitally-manipulated cricket chirps (even a relatively simple organism such as a cricket still has a brain containing up to a million neurons).

Once located, the nerve cells were stained with fluorescent dye. By monitoring how each neuron responded to the sound pulses of the cricket chirps, scientists were able to work out the sequence the neurons fired in, enabling them to unpick the time delay logic of the circuit.

Sound processing starts in hearing organs, but the temporal, rhythmic features of sound signals – vital to all acoustic communication from birdsong to spoken language – are processed in the central auditory system of the brain.

Scientists say that the simple, time-coded neural network discovered in the brain of crickets may be an example of fundamental neural circuitry that identifies sound rhythms and patterns, and could be the basis for “complex and elaborate neuronal systems” in vertebrates.

“Compared to our complex language, crickets only have a few songs which they have to recognise and process, so, by looking at their much simpler brain, we aim to understand how neurons process sound signals,” said senior author Dr Berthold Hedwig.

Like in Morse code, contained within each cricket chirp are several pulses, interspersed by gaps of a few milliseconds. It’s the varying length of the gaps between pulses that is each species’ unique rhythm.

It is this ‘Morse code’ that gets read by the five-neuron circuit in the female brain.

Crickets’ ears are located on their front legs. On hearing a sound like a chirp, nerve cells respond and carry the information to the thoracic segment, and on to the brain.

Once there, the auditory circuit splits and sends the information into two branches:

One branch (consisting of two neurons) acts as a delay line, holding up the processing of the signal by the same amount of time as the interval between pulses – a mechanism specific to a cricket species’ chirp. ̽��ֱ��other branch sends the signal straight through to a ‘coincidence detector’ neuron.

When a second pulse comes in, it too is split, and part of the signal goes straight through to the coincidence detector. If the second pulse and the delayed signal from the first pulse ‘coincide’ within the detector neuron, then the circuit has a match for the pulse time-code within the chirp of their species, and a final output neuron fires up, when the female listens to the correct sound pattern.

“Once the circuit has a second pulse, it can define the rhythm. ̽��ֱ��first pulse is initial excitation; the second pulse is then superimposed with the delayed part of the first. ̽��ֱ��output neuron only produces a strong response if the pulses collide at the coincidence detector, meaning the timing is locked in, and the mating call is a species match,” said Hedwig.

“With hindsight, I would say it’s impossible to make the circuitry any simpler – it’s the minimum number of elements that are required to do the processing. That’s the beauty of nature, it comes up with the most simple and elegant ways of dealing with and processing information,” he said.

To find the most effective sound pattern, the scientists digitally manipulated the natural pulse patterns and played the various patterns to female crickets mounted atop a trackball inside an acoustic chamber containing precisely located speakers.

If a particular rhythm of pulses triggered the female to set off in the direction of that speaker, the trackball recorded reaction times and direction.

Once they had honed the pulse patterns, the team played them to female crickets in modified mini-chambers with opened-up heads and brains exposed for the experiments.

Microelectrodes allowed them to record the key auditory neurons (“it takes a couple of hours to find the right neuron in a cricket brain”), tag and dye them, and piece together the neural circuitry that reads rhythmic pulses occurring at intervals of few milliseconds in male cricket chirps.

Added Hedwig: “Through this series of experiments we have identified a delay mechanism within a neuronal circuit for auditory processing – something that was first hypothesised over 25 years ago. This time delay circuitry could be quite fundamental as an example for other types of neuronal processing in other, perhaps much larger, brains as well.”

̽��ֱ��research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

Reference:
Stefan Schöneich, Konstantinos Kostarakos, Berthold Hedwig. An auditory feature detection circuit for sound pattern recognition. Science Advances (2015). DOI: 10.1126/sciadv.1500325

Delay mechanism within elegant brain circuit consisting of just five neurons means female crickets can automatically detect chirps of males from same species. Scientists say this example of simple neural circuitry could be “fundamental” for other types of information processing in much larger brains.

That’s the beauty of nature, it comes up with the most simple and elegant ways of dealing with and processing information

Berthold Hedwig

Cricket walking and responding to sound

Berthold Hedwig and Stefan Schöneich

Left: cricket on a trackball during experiment. Right: Auditory neuron in cricket brain.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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