̽��ֱ�� of Cambridge - Lundbeck Foundation

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.

Yes

Scientists explain emotional ‘blunting’ caused by common antidepressants

cjb250 — Mon, 23 Jan 2023 06:00:50 +0000

According to the NHS, more than 8.3 million patients in England received an antidepressant drug in 2021/22. A widely-used class of antidepressants, particularly for persistent or severe cases, is selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical that carries messages between nerve cells in the brain and has been dubbed the ‘pleasure chemical’.

One of the widely-reported side effects of SSRIs is ‘blunting’, where patients report feeling emotionally dull and no longer finding things as pleasurable as they used to. Between 40-60% of patients taking SSRIs are believed to experience this side effect.

To date, most studies of SSRIs have only examined their short term use, but, for clinical use in depression these drugs are taken chronically, over a longer period of time. A team led by researchers at the ̽��ֱ�� of Cambridge, in collaboration with the ̽��ֱ�� of Copenhagen, sought to address this by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the best-tolerated, over several weeks and assessing the impact the drug had on their performance on a suite of cognitive tests.

In total, 66 volunteers took part in the experiment, 32 of whom were given escitalopram while the other 34 were given a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and were given a series of tests to assess cognitive functions including learning, inhibition, executive function, reinforcement behaviour, and decision-making.

̽��ֱ��results of the study are published today in Neuropsychopharmacology.

̽��ֱ��team found no significant group differences when it came to ‘cold’ cognition – such as attention and memory. There were no differences in most tests of ‘hot’ cognition – cognitive functions that involve our emotions.

However, the key novel finding was that there was reduced reinforcement sensitivity on two tasks for the escitalopram group compared to those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment.

In order to assess reinforcement sensitivity, the researchers used a ‘probabilistic reversal test’. In this task, a participant would typically be shown two stimuli, A and B. If they chose A, then four out of five times, they would receive a reward; if they chose B, they would only receive a reward one time out of five. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would switch and participants would need to learn the new rule.

̽��ֱ��team found that participants taking escitalopram were less likely to use the positive and negative feedback to guide their learning of the task compared with participants on placebo. This suggests that the drug affected their sensitivity to the rewards and their ability to respond accordingly.

̽��ֱ��finding may also explain the one difference the team found in the self-reported questionnaires, that volunteers taking escitalopram had more trouble reaching orgasm when having sex, a side effect often reported by patients.

Professor Barbara Sahakian, senior author, from the Department of Psychiatry at the ̽��ֱ�� of Cambridge and a Fellow at Clare Hall, said: “Emotional blunting is a common side effect of SSRI antidepressants. In a way, this may be in part how they work – they take away some of the emotional pain that people who experience depression feel, but, unfortunately, it seems that they also take away some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provide important feedback.”

Dr Christelle Langley, joint first author also from the Department of Psychiatry, added: “Our findings provide important evidence for the role of serotonin in reinforcement learning. We are following this work up with a study examining neuroimaging data to understand how escitalopram affects the brain during reward learning.”

̽��ֱ��research was funded by the Lundbeck Foundation.

Reference
Langley, C, Armand, S, et al. Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: A double-blind, placebo-controlled semi-randomised study. Neuropsychopharmacology; 23 Jan 2023; DOI: 10.1038/s41386-022-01523-x

Scientists have worked out why common anti-depressants cause around a half of users to feel emotionally ‘blunted’. In a study published today, they show that the drugs affect reinforcement learning, an important behavioural process that allows us to learn from our environment.

Ethan Sykes

Man looking out of window

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 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.

Yes

Inflammation in the brain linked to several forms of dementia

cjb250 — Tue, 17 Mar 2020 00:14:10 +0000

Inflammation is usually the body’s response to injury and stress – such as the redness and swelling that accompanies an injury or infection. However, inflammation in the brain – known as neuroinflammation – has been recognised and linked to many disorders including depression, psychosis and multiple sclerosis. It has also recently been linked to the risk of Alzheimer’s disease.

In a study published today in the journal Brain, a team of researchers at the ̽��ֱ�� of Cambridge set out to examine whether neuroinflammation also occurs in other forms of dementia, which would imply that it is common to many neurodegenerative diseases.

̽��ֱ��team recruited 31 patients with three different types of frontotemporal dementia (FTD). FTD is a family of different conditions resulting from the build-up of several abnormal ‘junk’ proteins in the brain.

Patients underwent brain scans to detect inflammation and the junk proteins. Two Positron Emission Tomography (PET) scans each used an injection with a chemical ‘dye’, which lights up special molecules that reveal either the brain’s inflammatory cells or the junk proteins.

In the first scan, the dye lit up the cells causing neuroinflammation. These indicate ongoing damage to the brain cells and their connections. In the second scan, the dye binds to the different types of ‘junk’ proteins found in FTD.

̽��ֱ��researchers showed that across the brain, and in all three types of FTD, the more inflammation in each part of the brain, the more harmful build-up of the junk proteins there is. To prove the dyes were picking up the inflammation and harmful proteins, they went on to analyse under the microscope 12 brains donated after death to the Cambridge Brain Bank.

“We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other,” said Dr Thomas Cope from the Department of Clinical Neurosciences at Cambridge.

Dr Richard Bevan Jones added, “There may be a vicious circle where cell damage triggers inflammation, which in turn leads to further cell damage.”

̽��ֱ��team stress that further research is needed to translate this knowledge of inflammation in dementia into testable treatments. But, this new study shows that neuroinflammation is a significant factor in more types of dementia than was previously thought.

“It is an important discovery that all three types of frontotemporal dementia have inflammation, linked to the build-up of harmful abnormal proteins in different parts of the brain. ̽��ֱ��illnesses are in other ways very different from each other, but we have found a role for inflammation in all of them,” says Professor James Rowe from the Cambridge Centre for Frontotemporal Dementia and a Fellow of Darwin College .

“This, together with the fact that it is known to play a role in Alzheimer’s, suggests that inflammation is part of many other neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease. This offers hope that immune-based treatments might help slow or prevent these conditions.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, Association of British Neurologists, Patrick Berthoud Charitable Trust, and the Lundbeck Foundation.

Reference
Bevan-Jones, WR & Cope, TE et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain; 17 Mar 2020; DOI: 10.1093/brain/awaa033

Inflammation in the brain may be more widely implicated in dementias than was previously thought, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��researchers say it offers hope for potential new treatments for several types of dementia.

We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other

Thomas Cope

Yes

Cambridge scientist shares world’s largest neuroscience prize for research on the brain’s reward system

cjb250 — Mon, 06 Mar 2017 14:00:33 +0000

̽��ֱ��capacity to link reward to events and actions is the foundation of human and animal survival, and problems with the processing of reward lie at the heart of many neurological and psychiatric disorders.

̽��ֱ��Brain Prize, awarded by the Lundbeck Foundation in Denmark, is worth €1 million. Awarded annually, it recognises one or more scientists who have distinguished themselves by an outstanding contribution to neuroscience.

̽��ֱ��research of this year’s winners has far-reaching implications for understanding human behaviour, including decision-making, gambling, drug addiction, compulsive behaviour and schizophrenia.

Reward is essential to survival because humans and other animals need to learn to direct their decisions and their actions towards outcomes that will satisfy their needs, and away from danger. This means that they have to learn which events in the environment predict future rewards and punishments. For instance, if you feel hungry and see a building with a sign ‘restaurant’, you are likely to enter because the sign predicts that your hunger will be reduced if you go inside.

̽��ֱ��sense of reward is surprisingly complicated. It is influenced and determined by many things, such as taste and smell, as well as by fundamental motivations such as hunger or thirst. In turn, it influences choices, decisions and even attention. Many regions of the brain process information associated with reward, but one central linchpin for the regulation of learning and performance is a neurotransmitter (chemical messenger) in the brain called dopamine.

Thirty years ago, German-born Wolfram Schultz, professor of neuroscience now at the ̽��ֱ�� of Cambridge, was studying learning in monkeys at the ̽��ֱ�� of Fribourg in Switzerland. He developed methods for recording activity from neurons (nerve cells) that use dopamine to transmit information to other neurons. He found that before learning, these dopamine neurons respond whenever a reward - fruit juice - is given to the monkey, but if the monkey is shown various visual patterns and has to respond to one of them in order to secure the reward, the pattern of response changes as the animal learns. ̽��ֱ��dopamine neurons now respond when the correct visual pattern appears, and the response to the reward itself disappears. If no reward is given, the activity of dopamine neurons actually decreases at the expected time after the visual signal; but if the reward is delivered at an unexpected time, the neurons respond to it.

“This is the biological process that makes us want to buy a bigger car or house, or be promoted at work,” said Schultz. Every time we get the reward, our dopamine neurons affect our behaviour. “They are like little devils in our brain that drive us towards more rewards.”

Dopamine neurons play a ‘devilish’ role in drug addiction. “Addictive drugs generate, hijack and amplify the reward signal and induce exaggerated and uncontrolled effects of dopamine on the brain,” Schultz explained.

British computational neuroscientist, Peter Dayan, director of the Gatsby Computational Neuroscience Unit, ̽��ֱ�� College London, is recognised internationally as a leader in the rapidly developing field of computational neuroscience. When working at the Salk Institute in California, Dayan realised that the pattern of activity of dopamine neurons described by Schultz corresponds to a signal known - from the earliest days of artificial intelligence - as a ‘reward prediction error’.

This signal is the difference between the reward that is actually delivered and the reward that is predicted to be delivered. Prediction errors sculpt our expectations and experience of the world.

“For example, imagine that you choose between restaurants based on predicting how good they are. Then, if the one you chose is better than expected, the positive prediction error allows you to update your prediction. Next time you are faced with a restaurant choice, you are more likely to pick the one that was better,” said Dayan.

This link between dopamine and prediction error was one of the spurs for an explosion of work using theoretical ideas and computational models to link artificial intelligence, economics, mathematics, engineering and statistics to swathes of results in psychology and neuroscience.

Professor Ray Dolan was born in the Irish Republic and is the director of the new Max Planck Centre for Computational Psychiatry and Ageing at ̽��ֱ�� College London, and the Wellcome Centre for Neuroimaging. Dolan has been a leader in the development and use of methods for imaging the human brain, in order to understand the mechanisms of emotion, learning and decision-making.

Through his pioneering application of mathematical models to brain imaging and behaviour, together with his discoveries on the action of dopamine and other neurotransmitters, he has shown how humans learn about reward and punishment and also how we learn about the preferences of other people.

Dayan and Dolan have worked collaboratively over the past decade to probe how reward learning impacts on complex human questions, including motivational drive, variation in happiness, and a propensity towards gambling.

“One puzzling clinical problem is why some patients treated with drugs that boost dopamine function, for example in Parkinson’s disease, fall prey to pathological gambling. Our work has shown that this effect is, at least in part, due to dopamine amplifying an innate tendency to repeat activities that are rewarding,” said Dolan.

Schultz gratefully acknowledged the contributions of his many colleagues and collaborators, as well as the institutions and funding agencies that have supported his work, especially the ̽��ֱ�� of Cambridge and the Wellcome Trust.

“ ̽��ֱ��Brain Prize is a fantastic reward for our research group. I can hear our dopamine neurons jumping up and down!” Schultz said.

Professor Sir Colin Blakemore, chairman of the Brain Prize selection committee said, “ ̽��ֱ��judges concluded that the discoveries made by Wolfram Schultz, Peter Dayan and Ray Dolan were crucial for understanding how the brain detects reward and uses this information to guide behaviour. This work is a wonderful example of the creative power of interdisciplinary research, bringing together computational explanations of the role of activity in the monkey brain with advanced brain imaging in human beings to illuminate the way in which we use reward to regulate our choices and actions. ̽��ֱ��implications of these discoveries are extremely wide-ranging, in fields as diverse as economics, social science, drug addiction and psychiatry.”

̽��ֱ��winners will share the prize of €1 million, which will be presented to them at a ceremony on 4 May in Copenhagen by His Royal Highness Crown Prince Frederik of Denmark.

Adapted from a press release by the Lundbeck Foundation.

A Cambridge neuroscientist has today won the world’s most valuable prize for brain research, shared with two London neuroscientists. This year, ̽��ֱ��Brain Prize for 2017 is awarded to Cambridge’s Wolfram Schultz, together with Peter Dayan and Ray Dolan from ̽��ֱ�� College London for their analysis of how the brain recognises and processes reward.

̽��ֱ��Brain Prize is a fantastic reward for our research group. I can hear our dopamine neurons jumping up and down!

Wolfram Schultz

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

Yes