̽��ֱ�� of Cambridge - Christine Holt

Journeys of discovery: Christine Holt on how our brains wire-up

Anonymous — Wed, 18 Oct 2023 08:22:01 +0000

Christine Holt knew she’d solved one of the key puzzles of how brains wire-up, but convincing others was no easy matter.

Cambridge scientist Professor Christine Holt wins world’s top neuroscience award

jg533 — Thu, 23 Mar 2023 15:15:51 +0000

̽��ֱ��Lundbeck Foundation has announced today the recipients of ̽��ֱ��Brain Prize 2023, the world’s largest award for outstanding contributions to neuroscience.

Professor Christine Holt shares the award with two other neuroscientists, Professor Erin Schuman at the Max Planck Institute for Brain Research, and Professor Michael Greenberg at Harvard Medical School.

A profound aspect of our nervous system is that during development and adulthood our brains are subject to extensive change, known as neural plasticity. Collectively, the scientists have made significant advances in unveiling the cellular and molecular mechanisms that enable the brain to develop, and to restructure itself in response to external stimuli as it adapts, learns, and even recovers from injury.

“Receiving the Brain Prize is an honour beyond my wildest dreams, and I’m absolutely delighted. It’s an incredible recognition of the work that we have been doing over the last forty years,” said Christine Holt, Professor of Developmental Neuroscience in the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge.

̽��ֱ��Brain Prize, which is considered the world’s most significant prize for brain research, includes approximately €1.3 million to be shared by the three recipients. ̽��ֱ��prize is awarded annually by the Danish Lundbeck Foundation to researchers who have made highly original and influential discoveries in brain research.

“Our work has revealed the surprisingly fast and precise mechanism by which brains ‘wire-up’ during development, and actively maintain their wiring throughout life,” said Holt.

She added: “This provides key insights into the causes of neurodevelopmental and neurodegenerative diseases. Fundamental knowledge of this sort is essential for developing clinical therapies in nerve repair.”

̽��ֱ��brain is an extraordinarily complex organ made up of billions of individual cells - called neurons - that are wired together in very precise ways. This organisation underlies our ability to sense and interact with the outside world.

If the brain wiring connections fail to form, or form incorrectly, then serious neurological deficits may result - such as blindness. Similarly, if the connections fail to be maintained, as occurs in many neurodegenerative diseases - such as dementia - then important neurological function may be lost.

Holt’s work on the developing brain revealed that each neuron sends out a long ‘wire’ - called an axon - that navigates a remarkable journey to its own specific target in the brain. When an axon first grows out from a neuron it is tipped with a specialised growth cone, which finds its way using guidance cues - much like reading signposts along a road.

Holt found that an important aspect of this navigation system is the autonomy of growth cones in reading and responding to guidance cues. ̽��ֱ��growth cone contains all the machinery necessary to make the new proteins the axons need to steer along the right pathway. She also found that proteins are continuously made in our axons every day – an important process enabling the developing and adult brain to be shaped by experience.

Other laboratories around the world are now looking at how mutations in these proteins affect the growth and survival of axons. ̽��ֱ��hope is that new therapies can be developed for treating neurodevelopmental and neurodegenerative diseases.

“It is such a great honour to share the prize with Erin Schuman and Mike Greenberg. Their beautiful work has been an inspiration to me over the years. It’s been an exciting journey of discovery that may eventually lead to advances in therapies for neurodegenerative disease and neural repair. Thank you most sincerely to the Lundbeck Foundation,’’ said Holt.

‘‘In order to establish appropriate neural connections during development or to adapt to new challenges in adulthood through learning and memory, brain circuits must be remodeled, and the new patterns of connectivity maintained; processes that require the synthesis of new proteins for those connections,” said Professor Richard Morris, Chair of ̽��ֱ��Brain Prize Selection Committee.

He added: “ ̽��ֱ��Brain Prize winners of 2023, Michael Greenberg, Christine Holt, and Erin Schuman have revealed the fundamental principles of how this enigmatic feature of brain function is mediated at the molecular level. Together, they have made ground-breaking discoveries by showing how the synthesis of new proteins is triggered in different neuronal compartments, thereby guiding brain development and plasticity in ways that impact our behavior for a lifetime.’’

̽��ֱ��Brain Prize is the world’s largest neuroscience research prize, awarded each year by the Lundbeck Foundation. ̽��ֱ��Brain Prize recognises highly original and influential advances in any area of brain research, from basic neuroscience to applied clinical research. Recipients of ̽��ֱ��Brain Prize may be of any nationality and work in any country in the world. Since it was first awarded in 2011 ̽��ֱ��Brain Prize has been awarded to 44 scientists from 9 different countries.

Brain Prize recipients are presented with their award by His Royal Highness, ̽��ֱ��Crown Prince of Denmark, at a ceremony in the Danish capital, Copenhagen.

̽��ֱ��Brain Prize 2023 is awarded for critical insights into the molecular mechanisms of brain development and plasticity.

Receiving the Brain Prize is an honour beyond my wildest dreams...It’s an incredible recognition of the work that we have been doing over the last forty years.

Christine Holt

Professor Christine Holt

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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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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̽��ֱ��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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