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Discovery of the role of a brain regulator involved in psychiatric illnesses

It was widely accepted that families of synaptic receptors transmitted excitatory, and others inhibitory, messages to neurons. © Adobe Stock

Contrary to all expectations, GluD1 – a receptor considered to be excitatory – has been shown in the brain to play a major role in controlling neuron inhibition. Given that alterations in the GluD1 gene are encountered in a certain number of neurodevelopmental and psychiatric disorders, such as autism (ASD) and schizophrenia, this discovery opens up new therapeutic avenues to combat the imbalances between excitatory and inhibitory neurotransmissions associated with these disorders. Published in Science, this research is the result of collaborations between researchers from Inserm, CNRS and ENS at the ENS Institute of Biology (IBENS, Paris, France) with their colleagues at the MRC Laboratory of Molecular Biology in Cambridge, UK.

The complexity of the brain’s function reveals many surprises. While it was widely accepted in brain activity that families of synaptic receptors (situated at the extremity of a neuron) transmitted excitatory, and others inhibitory, messages to neurons, a study co-led by Inserm researchers Pierre Paoletti and Laetitia Mony at the ENS Institute of Biology has shed new light on this.

To understand what it is all about, we need to go back to the basics. An ‘excitatory’ synapse triggers the creation of a nerve message in the form of an electrical current if a receptor on its surface is able to bind to an excitatory neurotransmitter present in the interneuronal space, most often glutamate. This is called ‘neuronal excitation’. However, an ‘inhibitory’ synapse prevents this neuronal excitation by releasing an inhibitory neurotransmitter, often GABA. This is called ‘neuronal inhibition’. Thus, the families of glutamate receptors (iGluR) and GABA receptors (GABAAR) are considered to have opposite roles.

Toutefois, un sous-type de récepteur au glutamate appelé GluD1 intriguait les scientifiques. En effet, alors qu’il est censé avoir un rôle excitateur, celui-ci est préférentiellement retrouvé au niveau de synapses inhibitrices. Cette observation, effectuée par l’équipe de la chercheuse Inserm Cécile Charrier à l’Institut de Biologie de l’ENS en 2019, avait interpellé la communauté scientifique car le gène GluD1 est souvent associé à des troubles du neurodéveloppement comme l’autisme ou à des maladies psychiatriques de type troubles bipolaires ou schizophrénie, dans les études génétiques de population humaine. Comprendre le rôle de ce récepteur représente donc un enjeu de taille. Pour y voir plus clair, l’équipe de Pierre Paoletti a étudié ses propriétés moléculaires et sa fonction, à partir de cerveaux de souris, au niveau de l’hippocampe où il est fortement exprimé.

However, a glutamate receptor subtype called GluD1 intrigued the scientists. Although it is meant to have an excitatory role, it is preferentially found at the inhibitory synapses. This observation, made by the team of Inserm researcher Cécile Charrier at the ENS Institute of Biology in 2019, attracted the interest of the scientific community because the GluD1 gene is often associated with neurodevelopmental disorders (e.g. autism) or psychiatric conditions (e.g. bipolar disorders or schizophrenia) in human population genetic studies. Understanding the role of this receptor is therefore a major challenge. To find out more, Paoletti’s team used mouse brains to study its molecular properties and function in the hippocampus where it is strongly expressed.

 

An atypical role

Contrary to its name, the researchers already knew that the GluD1 receptor is unable to bind to glutamate. But in this study they were surprised to find that it bound GABA. Radu Aricescu’s team in Cambridge even described in the publication the fine atomic structure of the site where GluD1 interacts with GABA, using a technique called X-ray crystallography[1].

In principle, its role in the brain is therefore not excitatory of neuronal activity but inhibitory. Taking this finding into account, can we still say that this receptor belongs to the glutamate receptor family?

‘While the question remains, the analyses of phylogeny (relationships between genes and proteins) and the structural data do all show that it belongs to it. However, it is possible that certain mutations acquired during the course of evolution have profoundly modified its functional properties’, explains Paoletti.

Another source of curiosity is that this receptor does not function as a ‘conventional’ glutamate receptor or as a GABA receptor. Both cause the opening of channels in the cell membrane enabling the passage of ions responsible for the excitation or inhibition of the neuron. The GluD1 receptor however does not allow any channels to be opened. Its activity results from other internal mechanisms within the cell, which remain to be clarified.

Finally, this research suggests a major regulatory role for GluD1 in relation to the inhibitory synapses. Indeed, when activated by the presence of GABA, the inhibitory synapse is more effective. This manifests as a greater inhibitory response that lasts for a few dozen minutes.

 ‘In other words, GluD1 reinforces the inhibition signal. Perhaps by promoting the recruitment of new GABA receptors at the synapse? In any case, we are talking about a key regulator’, explains Mony.

For the scientists who contributed to this research, this discovery marks a real step forward.

These findings pave the way for a better understanding of the imbalances between excitatory and inhibitory messages in the brain in neurodevelopmental and psychiatric disorders, such as ASD and schizophrenia, or in conditions characterised by neuronal hyperexcitability, such as epilepsy. Following that, it will be important to study the potential of GluD1 as a therapeutic target for restoring better balance and reducing symptoms in these disorders’, they conclude.

 

[1] A physicochemical analysis technique based on the diffraction of X-rays  by the matter to determine its molecular composition and 3D structure.

The very first 3D map of the embryonic human head enables new insights into its development

Image 3 D glande lacrymale d’embryon humain 3D light-sheet microscope image of a lacrimal gland of a tissue-cleared 12-week-old human embryo. The different elements of the gland were coloured using virtual reality software. © Raphael Blain/Alain Chédotal, Vision Institute (Inserm/CNRS/Sorbonne Université)

Improving our knowledge of the development of the complex structures of the human head to shed new light on the congenital abnormalities that cause malformations: this is the challenge that a team of researchers from Inserm, CNRS and Sorbonne Université at the Vision Institute, Université Claude Bernard Lyon 1 and Hospices civils de Lyon is well on its way to fulfilling. Thanks to an innovative technique in which the skull structures are made transparent and 3D photos are taken of their component cells, this team has been able to establish the very first 3D atlas of the embryonic human head. These findings, to be published in Cell, have already provided deeper insights into how certain complex structures of the head are formed, such as the lacrimal and salivary glands or the arteries of the head and neck. They pave the way for new tools to study embryonic development.

The head is the most complex structure in the human body. In addition to the muscles and skin that protect it, and the brain encased within the skull, it contains blood vessels, nerves, endocrine glands – which secrete hormones directly into the bloodstream – such as the pituitary glands, and exocrine glands – which secrete substances to the outside environment – such as the salivary glands, which produce saliva, or the lacrimal glands, which secrete tears.

Our current knowledge about the development of the human head and its complex structures is rudimentary and comes from studies mostly carried out in the first half of the XX century, using simple histological sections. As such, despite head malformations occurring in around one third of newborns with congenital defects, the mechanisms that control the development of the human head remain poorly understood.

A team led by Alain Chédotal, Inserm research director at the Vision Institute (Inserm/CNRS/Sorbonne Université) and professor at the MéLiS laboratory of Mechanisms in Integrated Life Sciences (Inserm/CNRS/Université Claude Bernard Lyon 1/Hospices civils de Lyon), and Yorick Gitton, CNRS staff scientist also at the Vision Institute, used an innovative microscopy method to shed new light on the development of the human head.

The team had previously used the same technology in the embryo to study the development of other human organs[1]. This technology is called ’tissue clearing’ because it makes organs transparent to light. The cleared sample is then imaged in 3D using a special microscope that scans with a fine sheet of laser light. This makes it possible to locate in situ the cells that make up the embryonic tissues.

The researchers were able to apply this technique to embryos at different stages of development, obtained from the human tissue biobank created as part of the Human Developmental Cell Atlas (HuDeCA) programme coordinated by Inserm[2]. Thanks to the images obtained, they established the first 3D map of the embryonic human head[3].

Next, the team used virtual reality to analyse the 3D images and thus ‘navigate’ within the embryos.

‘This enabled us to discover previously unknown characteristics of the development of the cranial muscles, nerves, blood vessels and exocrine glands, states Chédotal. For example, it had never been possible to study the very early stages of development of the human salivary and lacrimal glands. Our research has enabled us to begin to visualise and better understand the mechanisms behind the establishment of these anatomically extremely complex structures’, he adds.

 

œil d’embryon humain transparisé 3D light-sheet microscope image of a 12-week-old tissue-cleared human embryo eye. The 6 oculomotor muscles responsible for eye movement and the 3 motor nerves (in white, green and red) were coloured using virtual reality software. ©Raphael Blain/Alain Chédotal, Vision Institute (Inserm/CNRS/Sorbonne Université)

The scientists have also set up a web interface (hudeca.com) to access not only the images obtained in this research, but also models for 3D printing and interactive 3D reconstructions of human embryos. This platform provides valuable resources that can also contribute to the training of medical students.

In future research, the team will attempt to map the various cells of certain organs, such as the retina.

‘At this stage, it is kind of as if we have mapped the continents and countries but still have to position the cities and their inhabitants’, explains Chédotal, whose team will also collaborate with physicians to apply the technology to pathological samples.

‘The new knowledge of human embryology provided by this research, as well as the new tools developed, has major implications for understanding craniofacial malformations and neurological disorders, as well as for improving diagnostic and therapeutic strategies’, concludes the researcher.

 

[1] See our press release of 23 March 2017: https://presse.inserm.fr/en/the-human-embryo-as-you-have-never-seen-it/57363/

[2] Launched in 2019, the objective of the cross-cutting HuDeCa programme coordinated by Inserm is to build the first atlas of human embryonic and foetal cells. It also aims to structure human embryology research at French level and develop databases. In the longer term, HuDeCa is expected to serve as a basis for understanding the origin of chronic diseases or congenital malformations.

[3] With the specific exception of the brain, a structure that was not covered by this research.

Major Breakthrough in the Treatment of Parkinson’s Disease: A Neuroprosthesis Restores Fluid Walking

neuroprothèseUnlike conventional Parkinson’s treatments, this neuroprosthesis targets the spinal cord region responsible for activating the leg muscles. © CHUV

Neuroscientists from Inserm, CNRS and Université de Bordeaux in France, along with Swiss researchers and neurosurgeons (EPFL/CHUV/UNIL), have designed and tested a “neuroprosthesis” to correct the gait disorders associated with Parkinson’s disease. In a study published in Nature Medicine, the scientists describe the development process of the device they used to treat a Parkinson’s disease patient for the first time, enabling him to walk fluidly, confidently, and without falling.

Disabling gait disorders occur in around 90% of people with advanced Parkinson’s disease and are often resistant to the treatments currently available. Developing new strategies that enable patients to walk fluidly again, avoiding the risk of falls, is therefore a priority for the research teams that have been studying this disease for many years.

This is the case of Erwan Bézard, a neuroscientist at Inserm, and his team at the Institute of Neurodegenerative Diseases (CNRS/Université de Bordeaux), who are working to understand the pathogenic mechanisms behind Parkinson’s and to develop strategies to restore motricity in various diseases. For several years, he has been working with a Swiss team led by neuroscientist Prof. Grégoire Courtine and neurosurgeon Prof. Jocelyne Bloch, who specialize in the development of spinal cord neuromodulation strategies.

In 2016, the Franco-Swiss team had already published research in Nature showing the effectiveness of a brain-spine interface – known as a “neuroprosthesis” – to restore the function of a limb paralyzed following a spinal cord injury. Its promising results had encouraged the scientists to pursue their efforts, suggesting beneficial effects in Parkinson’s disease with a similar device.

 

Avoiding Falls and Freezing

In this new study, the team developed a similar neuroprosthesis to compensate for falls and the phenomenon of freezing – when the feet remain glued to the ground during walking – that is sometimes associated with Parkinson’s disease.

Unlike conventional treatments for Parkinson’s, which target the brain regions directly affected by the loss of dopamine-producing neurons, this neuroprosthesis targets the spinal cord region responsible for activating the leg muscles during walking, which is not believed to be directly affected by the disease. However, the spinal cord is under the voluntary control of the motor cortex, whose activity is modified by the loss of dopaminergic neurons.

Drawing on their complementary expertise, the French and Swiss teams were able to develop and test the neuroprosthesis in a non-human primate model reproducing the locomotor deficits caused by Parkinson’s disease. The system not only reduced the locomotor deficits, but also restored walking capacity in this model by reducing freezing.

“The idea of developing a neuroprosthesis that electrically stimulates the spinal cord to harmonize gait and correct the locomotor disorders of Parkinson’s patients is the result of several years of research on the treatment of paralysis caused by spinal cord lesions”, explains Erwan Bézard, Inserm research director at the Institute of Neurodegenerative Diseases (Université de Bordeaux/CNRS).

“Previous attempts to stimulate the spinal cord have failed because they provide blanket stimulation of the locomotor centers without taking physiology into account. In our case, the stimulation overlays the natural functioning of the spinal cord neurons to target, with spatiotemporal coordination, the different muscle groups responsible for walking,” add Courtine and Bloch, co-directors of NeuroRestore, the research center based in French-speaking Switzerland.

These promising results paved the way for clinical development, to test the device in a patient.

 

Improvement Thanks to the Neuroprosthesis

A first patient, aged 62, who has been living with the disease for three decades, underwent surgery two years ago at Vaud University Hospital (CHUV) in Lausanne. During a precision neurosurgical procedure, Marc, originally from Bordeaux, was fitted with this new neuroprosthesis, consisting of a field of electrodes placed against the region of his spinal cord that controls gait, and an electrical-impulse generator implanted under the skin of his abdomen.

Thanks to the targeted programming of spinal-cord stimulations that adapt to his movements in real time, Marc has quickly seen his gait problems improve. After a few weeks of rehabilitation with the device, his walking has almost returned to normal.

This neuroprosthesis therefore opens up new prospects for treating the gait disorders suffered by many people with Parkinson’s disease. However, at this stage, this therapeutic concept has only demonstrated its efficacy in one person, with an implant that still has to be optimized for large-scale deployment.

The scientists are therefore working to develop a commercial version of the device[1] that incorporates all the essential features for optimal daily use. Clinical trials on more patients are also due to start early next year[2].

“Our ambition is to enable widespread access to this innovative technology in order to significantly improve the quality of life of patients with Parkinson’s disease, throughout the world”, conclude the researchers.

 

[1] In partnership with ONWARD Medical, a company based in Switzerland that will develop these implants.

[2] Thanks to a one-million-dollar donation from the Michael J. Fox Foundation for Parkinson’s research, NeuroRestore will embark on clinical trials on six new patients early next year. These trials aim not only to validate the technology developed in collaboration with ONWARD, but also to identify the patient profiles most likely to benefit from this innovative therapy. Founded by actor Michael J. Fox (Back to the Future), who himself has Parkinson’s disease, this foundation is the leading private donor in the field of Parkinson’s disease research.

Asleep but Open to the World: We Can Still Respond to External Stimuli

Sleep is generally defined as a period during which the body and mind are at rest, as if disconnected from the world. © Nicolas Decat

When we sleep we are not completely cut off from our environment: we are still able to hear and understand words. These observations, resulting from the close collaboration between researchers from Inserm, CNRS, Sorbonne Université and AP-HP at the Brain Institute and the Department of Sleep Disorders at Pitié-Salpêtrière Hospital in Paris, call into question the very definition of sleep and the clinical criteria that distinguish between its different stages. They are detailed in a new study published in Nature Neuroscience.

Sleep is generally defined as a period during which the body and mind are resting, as if disconnected from the world. However, a new study led by Delphine Oudiette, Inserm researcher, Isabelle Arnulf (Sorbonne Université, AP-HP) and Lionel Naccache (Sorbonne Université, AP-HP) at the Brain Institute, shows that the boundary between wakefulness and sleep is much more porous than it would appear.

The scientists have shown that sleepers with no particular disorders are able to capture verbal information transmitted by a human voice and respond to it by contracting facial muscles. What is more, this astonishing ability manifests itself intermittently during almost all stages of sleep — as if windows to the outside world were temporarily opened.

These new data on sleep behavior suggest that it may eventually be possible to develop standardized protocols for communication with sleepers in order to better understand how mental activity changes during sleep.

On the horizon: a new access route to the cognitive processes that underpin normal and pathological sleep.

 

A Thousand and One Variations in Consciousness

Even if it seems familiar to us because we do it every night, sleep is a very complex phenomenon. Our research has taught us that wakefulness and sleep are not stable states: both resemble a kaleidoscope of conscious moments… and moments that do not appear to be so,” explains Prof. Lionel Naccache, neurologist at Pitié-Salpêtrière Hospital AP-HP and neuroscience researcher.

It is essential to improve our understanding of the brain mechanisms that underlie these intermediate states between wakefulness and sleep.

When out of sync, they can be associated with disorders such as sleepwalking, sleep paralysis, hallucinations, the feeling of not sleeping at night or, on the contrary, sleeping with the eyes open“, explains Prof. Isabelle Arnulf, head of the Sleep Disorders Department at Pitié-Salpêtrière Hospital AP-HP.

However, in order to distinguish between wakefulness and the different stages of sleep, we have so far used simple and inaccurate physiological indicators, such as specific brain waves made visible through electroencephalography. Such indicators do not capture in detail what is going on inside the heads of sleepers, especially as they are sometimes in contradiction with what the sleepers tell us themselves.

We need more refined physiological measurements that are aligned with the sleeper’s feelings and ability to respond to the outside world; this is to better define their level of vigilance“, adds Delphine Oudiette, Inserm researcher in cognitive neuroscience.

 

A Game Between Unconsciousness and Lucidity

The research team[1] therefore explored this avenue and recruited 22 people without sleep disorders and 27 narcoleptic patients — i.e. victims of irrepressible sleep episodes.

People with narcolepsy have the particularity of having many lucid dreams, namely in which they are aware of being asleep and can sometimes shape the scenario. In addition, they easily and quickly reach REM sleep (the stage where the lucid dream emerges) during the day, making them good candidates for studying consciousness during sleep under experimental conditions.

One of our previous studies had shown that two-way communication, between the scientist and the dreamer and vice versa, is possible during lucid REM sleep, explains Oudiette. For our latest study, we wanted to know if these findings could be extrapolated to other sleep stages and to individuals who do not have lucid dreams. “

The study participants were asked to take a nap. The researchers had them do a “lexical decision” test in which a human voice uttered a series of words, both real and made up. The participants had to respond by smiling or frowning, in order to place the words in one of the two categories. Throughout the experiment, the participants were monitored using polysomnography—a comprehensive examination to record their brain and heart activity, eye movements, and muscle tone. Finally, upon waking, they had to report whether or not they had a lucid dream during their nap, and whether they remembered interacting with someone.

Most of the participants, whether narcoleptic or not, managed to respond correctly to the verbal stimuli while sleeping. These events were admittedly more frequent during episodes of lucid dreams, characterized by a high level of consciousness; however, we observed them occasionally in both groups, during all sleep phases”, specifies Arnulf.

By combining these physiological and behavioral data with the subjective reports of the participants, the researchers also show that it is possible to predict the opening of these windows of connection with the environment, i.e. the times when the sleepers were able to respond to stimuli. These were heralded by an acceleration of brain activity, and by physiological indicators usually associated with rich cognitive activity.

In people who had a lucid dream during their nap, the ability to dialog with the investigator and talk about this experience on waking was also characterized by a specific electrophysiological signature, adds Naccache. Our data suggest that lucid dreamers have privileged access to their inner world, and that this increased awareness also extends to the outside world.

Further research will be needed to determine whether the increase in these windows is correlated with sleep quality, and whether they could be used to improve certain sleep disorders or promote learning.

More advanced neuroimaging techniques, such as magnetoencephalography and intracranial recording of brain activity, will help us to better understand the brain mechanisms that orchestrate sleep behaviors“, concludes Oudiette.

Finally, these new data could help to revise the definition of sleep, a state that is ultimately very active, perhaps more conscious than we thought, and open to the world and others.

This study was funded by the French National Research Agency and the French Society for Sleep Research and Medicine (SFRMS).

[1] Including PhD students Başak Türker, Esteban Munoz Musat and Emma Chabani, whose participation was essential to the conduct of this study. 

Infection of Certain Neurons With SARS-CoV-2 Could Cause Persistent Symptoms

SRAS-CoV2

Illustration of SARS-CoV-2 infection (immunoreactivity for the S-protein in white) in the olfactory neurons expressing the olfactory marker protein (OMP, in red) in the human nasal epithelium. © Vincent Prévot/Inserm

The brain impacts of infection with SARS-CoV-2, responsible for COVID-19, are increasingly well documented in the scientific literature. Researchers from Inserm, Lille University Hospital and Université de Lille, at the Lille Neuroscience & Cognition unit, in collaboration with their colleagues at Imperial College London, focused more specifically on the impacts of this infection on a population of neurons known for regulating sexual reproduction via the hypothalamus (the neurons that express the GnRH hormone). Their findings suggest that SARS-CoV-2 infection can lead to the death of these neurons and cause certain symptoms that persist over time. The findings of this study have been published in eBioMedicine.

Numerous scientific studies have documented the brain impacts of SARS-CoV-2 infection. One such effect is that a significant proportion of men have low testosterone levels that persist over time. Persistence beyond a period of four weeks is referred to as “long COVID”.

For many years, a research team from Inserm, Lille University Hospital and Université de Lille has been studying the role of certain neurons that express gonadotropin-releasing hormone (GnRH). From the hypothalamus, these neurons control all the processes associated with reproductive function: puberty, acquisition of secondary sexual characteristics, and fertility in adulthood.

These are the same scientists who had, for example, previously revealed that GnRH neuron dysfunction in an animal model of Down syndrome could affect the cognitive function impairment associated with this condition.

In this latest study, the scientists wanted to test the hypothesis that SARS-CoV-2 infection may have harmful consequences on this population of neurons that regulate reproduction.

 

The Virus Penetrates GnRH Neurons and Alters Their Functions

Following hormone measurements (testosterone and luteinizing hormone) performed three months and then one year after infection in a small group of 47 men[1], the scientists observed that contact with the virus could alter the functions of GnRH neurons, leading to a fall in testosterone levels in certain patients some time after the infectious episode.

The scientists then wanted to verify whether the infection of the GnRH neurons and the subsequently observed hormone abnormalities could be associated with cognitive deficits. To do this, they listed the cognitive symptoms reported by the cohort patients, who underwent extensive testing three months and then one year after the infection.

The outcome was that the proportion of patients reporting memory or attention disorders, regardless of frequency or severity, and also concentration difficulties, tended to be slightly higher in the patients with abnormal hormone measurements, characterized by a decrease in testosterone levels.

“Although these were measurements made on a small sample of only male patients, these findings are very interesting and warrant further exploration in other larger-scale studies,” explains Waljit Dhillo, professor at Imperial College London and co-last author of this study.

To supplement their analyses, the researchers went on to study the cortexes of patients who died as a result of COVID-19. They identified the presence of the virus in the hypothalamus and the death of part of the GnRH neuron population.

“These findings may be worrying on several levels in terms of the role of these neurons in reproduction and their involvement in certain cognitive functions. They point to the necessity to optimize and generalize the medical follow-up of people with persistent symptoms following COVID-19 infection,” concludes Vincent Prévot, Inserm research director and co-last author of this study.

The study also encourages further research into the neurological impacts of long COVID.

 

[1]These data were collected as part of a larger study evaluating adrenal and thyroid function following Sars-CoV-2 infection: https://pubmed.ncbi.nlm.nih.gov/34008009/

Restoring Vision Through a New Brain-Machine Interface: Sonogenetic Therapy

 thérapie sonogénétique

Sonogenetic therapy consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. © Alexandre Dizeux/Physics for Medicine Paris

Restore vision using a combination of ultrasound and genetics? This is the goal of an international team led by Inserm research directors Mickael Tanter and Serge Picaud from Paris’ Physics for Medicine unit (ESPCI Paris/PSL Université/Inserm/CNRS) and Vision Institute (Sorbonne Université/Inserm/CNRS), respectively, in partnership with the Institute of Molecular and Clinical Ophthalmology in Basel. In a new study, they provide proof of concept of this so-called “sonogenetic” therapy in animals. This consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. The results show that when used on rodent neurons sonogenetics can induce a behavioral response associated with light perception. This discovery makes it possible to envisage, in the longer term, an application in blind people with optic nerve atrophy. The study has been published in Nature Nanotechnology.

Sonogenetic therapy consists of genetically modifying certain neurons in order to activate them remotely by ultrasound. This technology had previously been tested in culture and the first in vivo tests did not enable the researchers to become aware of its therapeutic potential linked to its very high spatiotemporal resolution. The genetic modification in question consists of introducing the genetic code of a mechanosensitive ion channel into the cells. The neurons that express this channel can then be remotely activated by low-intensity ultrasound applied to the surface of the brain without the need for contact (see diagram below).

Ultrasound waves can access tissue deep down, such as in the visual cortex – even from the surface of the dura mater[1] that surrounds the brain – and target very specific areas. It is these waves that form the basis for high-resolution brain imaging or ultrasound technologies. In this case, they enable highly selective activation, because only those neurons carrying the mechanosensitive channel and targeted by the ultrasound beam are stimulated.

In a recent study, a team of researchers led by Inserm research directors Mickael Tanter and Serge Picaud tested the efficacy of this sonogenetic therapy in animals. The aim of this research is to provide a solution to restore vision to patients having lost the connection between their eyes and brain due to conditions such as glaucoma, diabetic retinopathy, or hereditary or dietary optic neuropathies.

Their findings show that sonogenetic stimulation of the visual cortex induces a behavioral response associated with light perception. The animal learns an associative behavior in which it seeks to drink as soon as it perceives light. Ultrasound stimulation of its visual cortex induces the same reflex, but only if the neurons in the cortex express the mechanosensitive channel. The animal’s behavior suggests that sonogenetic stimulation of its cortex induced the light perception at the origin of the behavioral reflex.

The study showed that therapy works on different types of neurons, whether in the retina or visual cortex of the rodents, thereby demonstrating the universal nature of this approach.

By converting the images of our environment into the form of a coded ultrasound wave to directly stimulate the visual cortex – at rates of several tens of images per second – sonogenetic therapy appears to offer genuine hope for restoring vision to patients who have lost optic nerve function.

More generally, this sonogenetic stimulation approach offers innovative technology for interrogating brain function. Unlike current neuron stimulators or prostheses, its “non-contact” and selective cell type functioning represents a major innovation in relation to electrode devices.

“This sonogenetic therapy to ultimately restore the vision of blind people illustrates the power of a multidisciplinary project and a beautiful human adventure between a retinal biologist like Serge Picaud, and myself, a wave physicist for medicine,” declares Tanter, Inserm research director at the Physics for Medicine unit in Paris (ESPCI Paris/PSL Université/Inserm/CNRS).

“The development of a clinical trial of sonogenetic therapy still has many steps to go through to validate its efficacy and safety. If the results are confirmed, this therapy could succeed in restoring patients’ vision in a stable and safe manner,” concludes Picaud, Inserm research director and director of the Vision Institute (Sorbonne Université/Inserm/CNRS).

[1] Outermost layer of the meninges that protect the brain

Towards a Better Understanding of the Role of Male Hormones in Women with Multiple Sclerosis

sclérose en plaque

The image shows the brain region where demyelination is typically induced. The red cells correspond to all of the microglial cells with inflammatory properties when demyelination has just occurred. If the spontaneous regeneration process of myelin is effective, their inflammatory nature then diminishes in favor of an anti-inflammatory and pro-regenerative nature. The green cells are a subpopulation of these microglial cells that become anti-inflammatory.© Zahaf et al.

Multiple sclerosis (MS), an autoimmune disease for which there is no cure as yet, affects three women for every one man. Faced with this observation, scientists are studying the role of the sex hormones in order to better understand the differences between men and women in relation to the disease and its progression. A team led by Inserm researcher Elisabeth Traiffort in Unit U1195 “Diseases and hormones of the nervous system” (Inserm/Université Paris-Saclay) has recently shown that although male hormones – androgens – are present at very low levels in women, their presence is necessary to regenerate the myelin sheath which is destroyed in MS. These findings have been published in Nature Communications.

Multiple sclerosis (MS) is an autoimmune disease. In its most common form, relapsing-remitting MS[1], which accounts for 85% of cases, it manifests as inflammatory flares during which the patient’s immune cells attack and destroy the myelin in the central nervous system (see box). This phenomenon causes lesions that lead to motor, sensory, and visual disorders.

These symptoms are reversible at the beginning of the disease, thanks to the spontaneous repair of the destroyed myelin. However, over time, symptoms gradually become irreversible, reflecting the failure of the repair process, marking entry to the progressive phase of the disease. While current treatments reduce the frequency and severity of the inflammatory flares, thereby improving patient quality of life, they remain ineffective against the progression of the disease.

 

What is Myelin?

An axon is the single extension through which a neuron communicates with its target cell. Myelin is a biological membrane that wraps around axons to form a sheath. The myelin sheath serves to isolate and protect the nerve fibers. It also acts as an accelerator to the propagation speed of the nerve messages that transport information along the axon. Demyelination is the destruction of the myelin sheath following a nervous system attack.

 

Current research aims to gain a better understanding of the mechanisms of the disease and develop new therapeutic avenues that would prevent patients from entering the progressive phase, particularly by promoting the regeneration of myelin. Inserm researcher Elisabeth Traiffort and her team at the “Diseases and hormones of the nervous system” unit (Inserm/Université Paris-Saclay) are working for example to better understand the differences between women and men in MS, in order to determine whether it could be beneficial or even necessary to adapt therapeutic management to the patient’s sex. Remember that the disease is predominantly female, since three out of every four patients are women.

Investigating the Role of Androgens in Women

While the hormonal environments of men and women are very different, they cannot be restricted to high androgen levels in men and fluctuating levels of estrogen and progesterone in women. We know that men also produce estrogens, particularly in the brain where an enzyme is found that converts androgens into estrogens, while women produce small amounts of androgens. It was on this last aspect that Inserm researcher Traiffort and her colleagues focused their latest study.

Research has already shown that androgens protect neurons in the central nervous system of men with relapsing-remitting forms of MS and induce the regeneration of myelin sheaths destroyed in males, in animal models of the disease. But what is the role of the small amounts of androgens that are also found in the central nervous system of women? Can these androgens present at much lower levels than in men also impact the progression of the disease in female patients?

The scientists worked with animal models of the disease and also on tissues from patients supplied by organ donation banks. They first showed that in regions where myelin is destroyed, the AR receptor that enables androgens to transmit their signal is strongly expressed in the nervous tissue of women with MS, as it is in the female mouse models of the disease. This observation would suggest the existence of an essential role of androgens in the demyelinated tissue of the affected women.

In accordance with this hypothesis, the scientists have shown that despite only being present in small quantities in female mice, androgens still have a beneficial effect on the optimal regeneration of the destroyed myelin. Indeed, when the signals transmitted by the androgens are completely absent, this regeneration is greatly reduced.

Finally, other findings in animals and in human tissues suggest that these same androgens also have major anti-inflammatory effects on demyelinated nerve tissue in females unlike what is observed in males. The beneficial effects of androgens in women with MS could therefore also be linked to a decrease in the level of local inflammation, in areas where myelin is destroyed. This finding is interesting if we consider the current hypothesis that disease progression could be closely associated with the inflammatory cells residing in nervous tissue.

“While the low levels of androgens detected in women could point to a minor role for these hormones in the disease, we show that this is not the case. Our data suggest the use of appropriate doses of androgens in women with MS and the need to consider the patient’s sex when treating this and in all likelihood other conditions involving the destruction of myelin in the central nervous system,” concludes Traiffort.

 

This research was carried out with the support of the ARSEP Foundation.

[1] There are two active forms of the disease. The most common is the relapsing-remitting form, which accounts for 85% of MS cases at diagnosis. It is characterized by flares, in which symptoms appear within a few hours or days, often associated with the extreme and unusual fatigue suggestive of the diagnosis. Then the symptoms disappear completely or partially within a few weeks. The “primary” progressive form accounts for only 15% of cases. It is characterized by the slow and continuous worsening of the neurological symptoms, with no flares or remission.

Pre- and Postnatal Chlordecone Exposure Could Affect the Cognitive Development and Behavior of Children

Chlordécone

Chlordecone is an organochlorine insecticide that was used in the French West Indies from 1973 to 1993 to control the banana root borer. © Adobe Stock

Despite the fact that chlordecone has not been used as an insecticide in the French West Indies for 30 years now, its persistence in the environment continues to contaminate the populations. While its neurotoxic properties are well established, its impact on neurodevelopment remains to be clarified. An international research team involving Inserm researchers at the Research Institute for Environmental and Occupational Health (Inserm/Université de Rennes/EHESP School of Public Health) studied the impact of pre- and postnatal chlordecone exposure on the cognitive and behavioral abilities at 7 years of age of 576 children from the TIMOUN mother-child cohort in Guadeloupe[1]. Their research shows that this exposure is associated with poorer scores on tests evaluating cognitive abilities and behavioral disorders, with the impact differing according to the child’s sex. These results, published in Environmental Health, call for consideration to be given to the potential impact of these effects at population level, in order to optimize prevention policies.

Chlordecone is an organochlorine insecticide that was used in the French West Indies from 1973 to 1993 to control the banana root borer. Its persistence in the environment is responsible for contaminating the population through the consumption of contaminated foodstuffs. Chlordecone is now considered to be neurotoxic, toxic to reproduction and development, carcinogenic, and an endocrine disruptor. Experimental studies in animals have also shown that exposure of females to chlordecone during gestation leads to neurobehavioral and learning disorders in the offspring, the nature and intensity of which varies according to sex.

The neurotoxicity of chlordecone can be explained by its ability to interact with numerous neurotransmitters[2] and by its hormonal properties, particularly its action on estrogens. Yet estrogens play a crucial role, which differs according to chromosomal sex, in the development of the brain.

In the face of these observations, and in order to better estimate the potential impact of pre- and postnatal exposure to chlordecone on child neurodevelopment, Inserm researchers from the Research Institute for Environmental and Occupational Health (Inserm/Université de Rennes/EHESP School of Public Health), as part of an international research team, examined the intellectual abilities and behaviors of 576 children from the TIMOUN mother-child cohort in Guadeloupe.

In order to assess the children’s levels of pre- and postnatal exposure to chlordecone, the concentration of the pesticide was measured in umbilical cord blood at birth and in the blood of the children at 7 years of age. Their intellectual abilities were assessed according to 4 criteria: verbal comprehension, information processing speed, working memory[3], and perceptive reasoning[4].

The mothers also completed a questionnaire to measure the presence of behavioral difficulties in their child which can be categorized as either “internalizing” – in the form of emotional symptoms and interpersonal problems with peers, or “externalizing” – in the form of social behavior problems (anger, defiance, etc.), hyperactivity, and/or inattention.

Prenatal exposure to chlordecone was found to be associated, for each doubling of the level of exposure, with a 3% increase in the score estimating “internalizing” behavioral difficulties at 7 years of age, with a stronger association among girls (+7%) than among boys (0%).

Postnatal chlordecone exposure was found to be associated with poorer scores estimating general intellectual abilities (0.64 IQ point decrease for each doubling of the level of exposure). This manifests, particularly in boys, as a decrease in perceptive reasoning, working memory and verbal comprehension. In addition, postnatal exposure was associated with a greater number of “externalizing” behavioral difficulties in both boys and girls.

These findings indicate that exposure to chlordecone during periods of in utero development or during childhood is associated with a reduction in intellectual abilities and an increase in behavioral difficulties, with effects sometimes differing in nature and intensity according to sex.

“This is consistent with the estrogenic properties of this pesticide and its effects that vary according to sex and period of brain development,” explains Luc Multigner, Inserm research director who participated in this research.

According to the research team, it is therefore justified to pursue public policies aimed at reducing exposure to chlordecone, particularly among the most vulnerable populations, such as children and pregnant women. The team also calls for monitoring of the prevalence and management of children presenting with psychomotor retardation, sensory, neuromotor or intellectual disorders and/or interpersonal difficulties.

Although the neurological and neurobehavioral effects observed in this study are relatively moderate and subtle at the individual level, they may, given the widespread exposure of the French West Indian population to chlordecone, have a non-negligible impact at the population level,” concludes Multigner.

 

[1] The TIMOUN mother-child cohort was designed to evaluate the health impact of chlordecone exposures on pregnancy and childhood development. Led by the Research Institute for Environmental and Occupational Health (Inserm/Université de Rennes/EHESP School of Public Health) and the Gynecology-Obstetrics Department of University Hospital Guadeloupe, this cohort consists of 1,068 women included during their pregnancy between 2004 and 2007. Following their birth, the children were monitored at 3, 7 and 18 months of age and then at 7 years of age.

[2] Neurotransmitters are chemical substances that ensure the transmission of information between nerve cells.

[3] Working memory is a form of short-term memory that uses the information obtained in the present moment in the performance of a specific task.

[4] Perceptive reasoning measures the cognitive ability to integrate and manipulate visual and spatial information in order to solve complex visual problems.

Predicting the Onset of Anxiety Disorders in Adolescence Thanks to Artificial Intelligence

Anxiété

Anxiety disorders are the most common psychiatric conditions in adolescence, with nearly one in three individuals affected. © Adobe Stock

Anxiety disorders are the most common psychiatric conditions in adolescence, with nearly one in three individuals affected. Some of these disorders – such as panic disorder or generalized anxiety disorder[1] – tend to emerge slightly later in life or consolidate in early adulthood. Therefore, identifying those who are at high risk of developing clinical anxiety (which meets specific diagnostic criteria) is crucial. For the first time, a team led by Inserm researchers Jean-Luc Martinot and Éric Artiges at the Developmental Trajectories and Psychiatry laboratory (Inserm/ENS Paris-Saclay) and the Borelli Center[2] (CNRS/Université Paris-Saclay) looked for factors that would predict the onset of anxiety disorders in adolescence. They monitored the mental health of a group of adolescents aged 14 to 23. Thanks to artificial intelligence, they have identified the warning signs most predictive in adolescence of the onset of anxiety disorders in these young adults. The results of this study have been published in Molecular Psychiatry.

A person is considered to suffer from an anxiety disorder when they experience intense and long-lasting anxiety that has no relation to an actual danger or threat, and which disrupts their usual functioning and daily activities. These disorders, which are encountered very frequently in the general population (with around 21% of adults thought to be affected at least once in their lifetime), often begin in childhood or adolescence. Therefore, being able to better identify them in these age groups would avoid worsening of the symptoms over the course of life.

While previous studies have highlighted the predictive power of artificial intelligence in psychiatric diseases such as depression and addictions[3], none had looked for predictors of anxiety disorders.

Researchers at the Developmental Trajectories and Psychiatry laboratory (Inserm unit 1299) at the Borelli Center (CNRS unit 9010) sought to detect warning signs in adolescence of the onset of anxiety disorders in adulthood.

In order to do this, the scientists monitored a group of over 2,000 European adolescents who were 14 years of age at the time of their inclusion in the Imagen cohort[4]. The volunteers all completed online questionnaires on their psychological health when they were 14, 18 and 23 years of age. Monitoring the volunteers over time made it possible to measure changes in the anxiety diagnosis.

An in-depth statistical learning study based on an artificial intelligence algorithm then determined whether some of the responses given in adolescence (at age 14) had an incidence on the individual diagnosis of anxiety disorders in adulthood (at age 18-23).

The researchers identified three major predictors or warning signs which, when present in adolescence, significantly increase the statistical risk of anxiety disorders in adulthood. These are neuroticism, hopelessness, and emotional symptoms.

 

Neuroticism designates the persistent tendency to feel negative emotions (fear, sadness, awkwardness, anger, guilt, disgust), as well as poor impulse control and poor ability to manage stress.

Despair is associated with low scores on the questionnaires evaluating optimism and self-confidence.

Emotional symptoms cover responses to the questionnaires indicating symptoms such as “headache/stomachache”; “a lot of worries, often worried”; “often unhappy, down or tearful”; “nervous in new situations, easily loses confidence”; “is easily afraid”.

 

Part of the study was also given over to observing the brains of the volunteers using magnetic resonance imaging (MRI). As brain development involves a change in the volume of different brain regions in adolescence, the researchers wanted to identify in these images a possible change in gray matter volume that could be predictive of future anxiety disorders.

While the imaging did not improve the prediction of anxiety disorders in their entirety compared to just the data from the questionnaires, it could enable a more precise determination of the type of anxiety disorder that an individual is likely to develop.

“Our study reveals for the first time that individualized prediction of the onset of future anxiety disorders in adolescence is possible. These identified predictors or warning signs could make it possible to detect people at risk earlier on and offer them an appropriate and personalized intervention, while limiting the progression of these diseases and their impacts on daily life,” explains Jean-Luc Martinot, Inserm research director and child psychiatrist, co-author of the study.

troubles anxieux

 

[1] There are several types of anxiety disorder: generalized anxiety, panic disorder, specific phobias, agoraphobia, social anxiety disorder, and separation anxiety disorder.

[2] Applied mathematics research center

[3] Whelan R., Watts R., Orr C. et al. Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature 512, 185-189 (2014).

[4] Imagen is a European cohort study that enrolled 2,223 adolescents at age 14 between 2008 and 2011. It is composed of young people from the general population and not patients.

ASD: Towards a Better Understanding of the Molecular Mechanisms of Autism

autisme

Images showing the human brain anatomy in two axial slices obtained by MRI (left), then the corresponding molecular images showing a larger number of mGluR5 receptors in the brain of an adult subject with ASD (right) compared to a control subject (middle). © Laurent Galineau

 

While great progress has been made in recent years in the understanding of autism spectrum disorder (ASD), its underlying molecular mechanisms remain fairly poorly documented. Several hypotheses have been put forward regarding the possible dysfunction of certain neurotransmitters in the brain, but rigorous scientific studies are still lacking in order to validate them. In a new publication, researchers from Inserm and Université de Tours at the Imaging & Brain unit have shown that specific receptors of glutamate, one of the most important neurotransmitters in the nervous system, are expressed in large quantities in the brains of adults with ASD. However, this overexpression of the receptors does not occur at earlier stages of development. The study, sponsored by Tours university hospital and published in Molecular Psychiatry, paves the way for a better understanding of ASD to help refine therapeutic research.

Autism spectrum disorder (ASD) is caused by neurodevelopmental particularities and affects around 700 000 people in France. This term brings together a large variety of clinical realities and as such a large variety of specific individual needs. The development of treatments that specifically target severe autism-related disorders has long been hampered by a piecemeal understanding of the underlying molecular and genetic mechanisms.

At present, those affected may therefore use treatments for potential comorbidities such as sleep disorders or epilepsy, but there is no therapeutic solution to improve behavioral disorders or the associated alterations in social interactions.

One avenue put forward to explain the development of ASD is dysfunction of glutamate – the main excitatory neurotransmitter of the central nervous system. Studies have recently suggested that glutamate receptors called mGluR5 (see inset) are expressed in increased quantities in certain brain regions in people with ASD.

mGluR5 and glutamate

mGluR5 is a receptor that is abundantly expressed in the central nervous system and particularly in the cerebral cortex, hippocampus, lateral septum, dorsal striatum, and nucleus accumbens, which are all brain regions involved in cognition, motor control and emotivity.

mGluR5 belongs to a subgroup of eight receptors that are activated by glutamate, the main excitatory neurotransmitter of the central nervous system.

Pharmacological intervention on these receptors, particularly mGluR5 blockade, is already being evaluated for various disorders such as anxiety, depression, schizophrenia, Parkinson’s disease, and addictions.

Compensatory mechanism

In order to further understand the molecular mechanisms of ASD, Frédérique Bonnet-Brilhault’s team at the Imaging & Brain unit (unit 1253 Inserm/Université de Tours) sought to better characterize glutamate dysfunction in the brains of adults with ASD.

They started by quantifying the glutamate levels in the cingulate cortex of 12 adults with ASD and 14 adults without ASD (referred to as “control” participants), using several methodological approaches. Next, they looked at the expression of the mGluR5 receptors in the participants’ brains.

The scientists observed that the glutamate levels varied widely in the adults with ASD. However, they found that the quantity of mGluR5 receptors expressed was particularly high in the brains of all these individuals, compared to the controls.

Then, to better understand how the quantity of mGluR5 varies at different stages of development, the team also quantified these receptors in the brains of young rats, grouped into animal models of ASD and “control” animals.

Their analyses show that the quantities of mGluR5 in the “ASD rats” and the “control rats” did not differ during childhood. However, in adolescence, larger quantities of these receptors were present in certain brain regions of the “ASD rats”.

The fact that mGluR5 receptors are expressed in large quantities in the adult human participants with ASD, but not at the earliest stages of development in the animal models, suggests that the overexpression of these receptors is not a cause of this disorder, but rather a consequence that emerges progressively throughout life.

“Our findings suggest that the changes in the quantity of mGluR5 receptors expressed during development could be a compensatory mechanism for the early dysfunction in the brain communication systems, rather than a primary element that causes the development of ASD,” explains Bonnet-Brilhault.

At a time when research in adults with ASD is a real priority, this work points to the need to understand the development trajectory of each individual with ASD to distinguish the causes of the adaptation mechanisms.

An overview of ASD

“Typical” autism, described by the child psychiatrist Leo Kanner in 1943, is now part of much broader group, known as Autism Spectrum Disorder (ASD), a term that takes better account of the diversity of the situations. ASD is characterized by:

  • alterations in social interactions
  • communication problems (language and non-verbal communication)
  • behavioral disorders: a restricted and repetitive repertoire of interests and activities (stereotypies: tendency to repeat the same movements, words, or behaviors)
  • unusual sensory reactions

ASD can also be associated with other conditions, such as anxiety disorders, sleep problems, motor function deficits, or epilepsy.

Within this wide range of clinical diversity, it is important to identify the “strengths” or “talents” that may result from this atypical brain development. The development of therapies must therefore target what corresponds to the individuals’ complaints while preserving their specific characteristics.

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