An international group of researchers has discovered seven new regions in the human genome associated with an increased risk of developing age-related macular degeneration (AMD), one of the main causes of blindness. Thierry Léveillard, INSERM’s director of research at the Institut de la Vision (INSERM / UPMC / CNRS), is coordinator of the European AMD Gene Consortium group, an international network of researchers representing 18 research groups. The results were placed online on 03 March 2013 in the journal Nature Genetics.

© Inserm

AMD affects the macula, the region of the retina responsible for central vision. It is thanks to the macula that a human being can perform certain tasks requiring good visual acuity, such as reading, driving and recognising facial features. As AMD progresses, the performance of such tasks becomes harder and is eventually impossible. Although certain forms of AMD are treatable if the condition is detected sufficiently early, there is no cure.

Scientists have shown that age, diet and smoking affect the risk of a person developing AMD. Genetics also plays an important role. AMD is often hereditary and is most common in certain population groups.

In 2005, researchers showed that certain variations of the coding gene for factor H of the complement – a component of the innate immune system – are associated with a serious risk of developing AMD.

In this new study, the AMD Gene Consortium collected data from 18 research groups in order to increase the power of previous analyses. An analysis by the consortium consisted of data taken from more than 17,000 AMD sufferers, and these were compared with data from more than 60,000 individuals not suffering from AMD. The current analysis identified seven new genetic regions associated with the condition. As in the case of the 12 regions previously discovered, these seven regions are dispersed throughout the genome, indicating genes and functions that affect AMD.

“The challenge represented by the genetic complexity of AMD could be overcome by an association between all the centres working on this condition that causes blindness throughout the world; this is a demonstration of how union is strength”

Since 2005, a total of 19 regions have been identified as being associated with AMD. They involve a variety of biological functions, including regulation of the innate immune system, maintaining cell structure, the growth and permeability of blood vessels, the metabolising of lipids and atherosclerosis.

As with other common conditions such as type II diabetes, the risk of an individual developing AMD is probably determined by not one but several genes. A more complete analysis of the DNA of areas surrounding the 19 regions identified by the AMD Gene Consortium could indicate several rare genetic variations that might have a decisive effect on the risk of AMD. The discovery of such genes could considerably improve scientists’ understanding of the pathogenesis of AMD and contribute significantly to the search for more effective treatments.

According to José-Alain Sahel, Director of the Institut de la Vision (INSERM / UPMC / CNRS): “

Without the methodical and coordinated clinical identification work performed at all the centres, the identification of such markers would be random. These clinical relationships will soon be very important in the application of predictive and personalised medicine.” 

The iCub humanoid robot on which the team directed by Peter Ford Dominey, CNRS Director of Research at Inserm Unit 846 known as the “Institut pour les cellules souches et cerveau de Lyon” [Lyon Institute for Stem Cell and Brain Research] (Inserm, CNRS, Université Claude Bernard Lyon 1) has been working for many years will now be able to understand what is being said to it and even anticipate the end of a sentence. This technological prowess was made possible by the development of a “simplified artificial brain” that reproduces certain types of so-called “recurrent” connections observed in the human brain. The artificial brain system enables the robot to learn, and subsequently understand, new sentences containing a new grammatical structure. It can link two sentences together and even predict how a sentence will end before it is uttered. This research has been published in the Plos One journal. 

© P Latron/inserm

INSERM and CNRS researchers and the Université Lyon 1 have succeeded in developing an “artificial neuronal network” constructed on the basis of a fundamental principle of the workings of the human brain, namely its ability to learn a new language. The model was developed after years of research in the INSERM 846 Unit of the Institut de recherche sur les cellules souches et cerveau, through studying the structure of the human brain and understanding the mechanisms used for learning.

One of the most remarkable aspects of language-processing is the speed at which it is performed. For example, the human brain processes the first words of a sentence in real time and anticipates what follows, thus improving the speed with which humans process information. Still in real time, the brain continually revises its predictions through interaction between new information and a previously created context. The region inside the brain linking the frontal cortex and the striatum plays a crucial role in this process.

Based on this research, Peter Ford Dominey and his team have developed an “artificial brain” that uses a “neuronal construction” similar to that used by the human brain.

Thanks to so-called recurrent construction (with connections that create locally recurring loops) this artificial brain system can understand new sentences having a new grammatical structure. It is capable of linking two sentences and can even predict the end of a sentence before it is provided.

To put this advance into a real-life situation, the INSERM researchers incorporated this new brain into the iCub humanoid robot.

In a video demonstration, a researcher asks the iCub robot to point to a guitar (shown in the form of blue object) then asking it to move a violin to the left (shown by a red object). Before performing the task, the robot repeats the sentence and explains that it has fully understood what it has been asked to do.

For researchers, the contribution that this makes to research into certain diseases is of major importance. This system can be used to understand better the way in which the brain processes language. “We know that when an unexpected word occurs in a sentence, the brain reacts in a particular way. These reactions could hitherto be recorded by sensors placed on the scalp”, explains Peter Ford Dominey. The model developed by Dr Xavier Hinaut and Dr Peter Ford Dominey makes it possible to identify the source of these responses in the brain. If this model, based on the organisation of the cerebral cortex, is accurate, it could contribute to possible linguistic malfunctions in Parkinson’s disease.

This research has another important implication, that of contributing to the ability of robots to learn a language one day. “At present, engineers are simply unable to program all of the knowledge required in a robot. We now know that the way in which robots acquire their knowledge of the world could be partially achieved through a learning process – in the same way as children”, explains Peter Ford Dominey.

©P Latron/Inserm

The movement of molecules in the neuron extensions known as axons is a process that is vital for the survival of cells and the smooth operation of the nervous system. It is performed by vesicles that travel fast thanks to the energy-hungry molecular engines. At the “Signalling, neurobiology and cancer” Laboratory (Institut Curie/CNRS/Inserm) at the Institut Curie, the team headed by Frédéric Saudou[1], INSERM Director of Research, has shown that the vesicles have their own energy production system needed for travelling and do not depend on the mitochondria that are the main source of cell energy. This mechanism works by means of glycolysis, the first stage in the conversion of glucose and for the huntingtin protein, the protein that mutates in Huntington’s Disease, a neurodegenerative condition. The results were published on 31 January 2013 in the Cell journal.

Unlike carcinomas in which the cell proliferates, neurodegenerative conditions such as Alzheimer’s Disease, Parkinson’s Disease and Huntington’s Disease are due to the accelerated death of neurones. At the “Signalling, neurobiology and cancer” Laboratory (Institut Curie/CNRS/Inserm), part of the Institut Curie, the research team headed by Frédéric Saudou is studying the function of the huntingtin protein which mutates in Huntington’s Disease. “When it is altered, by a process that is still not fully understood, huntingtin causes the accelerated death of neurons in the striatum, the region of the brain in which Huntington’s disease first manifests” explains Frederic Saudou.

His team has shown the essential role played by huntingtin in the swift travel of vesicles through the neuron extensions or axons. axones. Huntingtin stimulates the progress of these vesicles by interacting with molecular engines, enabling them to travel to specific regions of the brain such as the striatum, the brain structure that is attacked in victims of Huntington’s Disease.

ATP, the engine essential for transporting the vesicles

So where does the cell energy come from that is vital for ensuring the transport of the vesicles in the axons over long distances, that may in some cases be as long as one metre? The adenosine triphosphate (ATP) molecule is an energy source shared by all animal and plant species. In humans, it is mostly produced by specialist organelles in the cells, known as the mitochondria. “In this project we have shown that a process other than the mitochondria is involved in the supply of energy to the molecular engines[1] responsible for movement along the axons” explains Frédéric Saudou. In fact, the inhibition of the mitochondrial function has no effect on this swift movement. On the other hand, the genetic inactivation of an enzyme that is essential for glycolysis, the first stage in the conversion of glucose into energy significantly reduces movement.

A mechanism that is dependent on the huntingtin protein

“The enzymes responsible for glycolysis are situated directly on the vesicle and produce the energy needed for the movement of the axons. We then tried to discover the mechanism responsible for fixing it on the vesicle membrane. Our researches have established that attachment to the vesicle is performed by the huntingtin protein. We do not yet know, however, whether this function is disrupted in Huntington’s disease” stresses Frédéric Saudou. Researchers do not exclude the existence, however, of other mechanisms that link the glycolysis enzymes to the vesicle membrane.

OpenViBE2 (2009-2013) is a collaborative research project, supported by finance from the ANR, that is based on the potential of the technologies known as “brain-computer interfaces”(ico) in the field of video games.This is a project that has brought together the scientific expertise needed through a multi-disciplinary consortium consisting of nine partners – the university laboratories who pioneered the field (INRIA, INSERM, cea, GIPSA-Lab), well-known video-game manufacturers (ubisoft, blacksheep studio, kylotonn games) and specialists in usage and transfer (lutin, clarte).After three years of work and achieving numerous scientific advances associated with the development of innovative industry prototypes, OpenViBE2 has made it possible to have greater control over the future of such technologies on the French market as well as internationally.

© Inserm / Hirsch, Philippe

• Acting on thought thanks to brain-computer interfaces 

Researchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and is published in the Diabetes review: it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.

In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration (see the picture below). We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the aging process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.

The “Alzheimer & Tauopathies” team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 “Nuclear receptors, cardiovascular diseases and diabetes”, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.

“At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein”

This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.

“Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder” underlines the researcher. “Our work is now focussing on identifying the factors responsible for this aggravation” he adds.

The degeneration of neurons in Alzheimer’s disease

© Wikipedia – Zwarck  / licence Creative Commons  CC-BY-SA-2.5

In the case of healthy neurons (top), the Tau protein is normal.
In the case of diseased neurons (bottom), abnormal tangles of Tau proteins (phosphorylated) form, causing degeneration.

This research was supported by LabEx DISTALZ (development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease) within the framework of future investments.

Physical inactivity is a major public health problem that has both social and neurobiological causes. According to the results of an Ipsos survey published on Monday 31 December, the French have put “taking up a sport” at the top of their list of good resolutions for 2013. However, Francis Chaouloff, research director at Inserm’s NeuroCentre Magendie (Inserm Joint Research Unit 862, Université Bordeaux Ségalen), Sarah Dubreucq, a PhD student and François Georges, a CNRS research leader at the Interdisciplinary Institute for Neuroscience (CNRS/Université Bordeaux Ségalen) have just discovered the key role played by a protein, the CB1 cannabinoid receptor, during physical exercise. In their mouse studies, the researchers demonstrated that the location of this receptor in a part of the brain associated with motivation and reward systems controls the time for which an individual will carry out voluntary physical exercise. These results were published in the journal Biological Psychiatry. 

©fotolia

The collective appraisal conducted by Inserm in 2008 highlighted the many preventive health benefits of regular physical activity. Such activity is limited, however, by our lifestyle in today’s industrial society. While varying degrees of physical inactivity may be partly explained by social causes, they are also rooted in biology.

“The inability to experience pleasure during physical activity, which is often quoted as one explanation why people partially or completely drop out of physical exercise programmes, is a clear sign that the biology of the nervous system is involved”, explains Francis Chaouloff.

But how exactly? The neurobiological mechanisms underlying physical inactivity had yet to be identified.

Francis Chaouloff (Giovanni Marsicano’s team at the NeuroCentre Magendie; Inserm joint research unit, Université Bordeaux Ségalen) and his team have now begun to decipher these mechanisms. Their work clearly identifies the endogenous cannabinoid (or endocannabinoid) system as playing a decisive role, in particular one of its brain receptors. This is by no means the first time that data has pointed to interactions between the endocannabinoid system, which is the target of delta9-tetrahydrocannabinol (the active ingredient of cannabis), and physical exercise. It was discovered ten years ago that physical exercise activated the endocannabinoid system in trained sportsmen, but its exact role remained a mystery for many years. Three years ago, the same research team in Bordeaux observed that when given the opportunity to use a running wheel, mutant mice lacking the CB1 cannabinoid receptor, which is the principal receptor of the endocannabinoid system in the brain, ran for a shorter time and over shorter distances than healthy mice. The research published in Biological Psychiatry this month seeks to understand how, where and why the lack of CB1 receptor reduces voluntary exercise performance (by 20 to 30%) in mice allowed access to a running wheel three hours per day.

The researchers used various lines of mutant mice for the CB1 receptor, together with pharmacological tools. They began by demonstrating that the CB1 receptor controlling running performance is located at the GABAergic nerve endings. They went on to show that the receptor is located in the ventral tegmental area of the brain (see diagram below), which is an area involved in motivational processes relating to reward, whether the reward is natural (food, sex) or associated with the consumption of psychoactive substances.

Longitudinal section of the mouse brain (top) and diagram of interactions between the endocannabinoid, GABAergic and dopaminergic systems during voluntary physical exercise (bottom)

©Inserm/F. Chaouloff

Left: stimulating the CB1 receptors excites the dopaminergic neurons in the ventral tegmental area involved in motivation.
Right: the absence of CB1 receptors lowers performance by 20 to 30% owing to reduced motivation.

VTA: Ventral tegmental area/NAcc: nucleus accumbens/PFC: prefrontal cortex/DA: dopamine 

Based on the results of this study and earlier work, the Bordeaux team suggests the following neurobiological explanation: at the beginning and for the duration of physical exercise, the CB1 receptor is constantly simulated by the endocannabinoids, lipid molecules that naturally activate this receptor in response to pleasant stimuli (rewards) and unpleasant stimuli (stress). Endocannabinoid stimulation of the CB1 receptor during physical exercise inhibits the release of GABA, an inhibitory neurotransmitter that controls the activity of the dopamine neurons associated with the motivation and reward processes. This stimulation of the CB1 receptor “inhibits inhibition”, in other words, it activates the dopaminergic neurons in the ventral tegmental area. The CB1 receptor must therefore be stimulated before the exercise can go on for longer and the body must receive the necessary motivation.

Conversely, without these CB1 receptors, the “GABAergic brake” continues to act on the dopaminergic neurons in the ventral tegmental area, leading to the reduced performance levels observed above.

It is already known that CB1 receptors play a regulatory role in the motivation to consume rewards, whether natural or not. What is original about this research is that it shows that physical exercise can be added to the array of natural rewards regulated by the endocannabinoid system. “If confirmed, this motivational hypothesis would imply that the role played by the CB1 receptor has more to do with ‘staying power’ in the exercise than with actual physical performance levels” explain the researchers.

This work reveals that the endocannabinoid system plays a major role in physical exercise performance through its impact on motivational processes. It thus opens up new avenues of research into the mediators of pleasure – and even addiction – associated with regular physical exercise. “After endorphins, we now need to consider endocannabinoids as another potential mediator of the positive effects that physical exercise has on our mood,” the researchers conclude.