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Alzheimer’s disease: newly identified rare gene variants significantly increase the risk of developing this pathology.

Fluorescent marking of the Tau protein in a human cell hNT; the Tau protein, has a role in Alzheimer’s disease, particularly in its familial forms ©Inserm/U837

An international consortium has identified rare variants in two new genes that markedly increase the risk of developing Alzheimer’s disease (AD). The work was led by two research groups in France (headed respectively by Gaël Nicolas, Rouen and Jean-Charles Lambert, Lille) and a group in the Netherlands (headed by Henne Holstege, Amsterdam). The new results provide a better understanding of the genetics of AD and open up new research themes on more relevant in vitro and in vivo models. The consortium’s findings are also likely to catalyze the development of new strategies for treating AD. The results were published in the journal Nature Genetics in November 2022.

As the most prevalent neurodegenerative disease, AD affects about 55 million people across the world – 4% of whom are under the age of 65. It is a complex, multifactorial disease caused by interactions between many genetic and non-genetic predisposing factors. Given that AD has a large genetic component, the characterization of these factors is a major challenge for basic research and therapeutic development.

Our knowledge of the involvement of common gene variants (those present in more than 1% of the general population) in AD has improved enormously over recent last years, through the discovery of 75 chromosomal/gene regions associated with the risk of developing the disease. However, the role of rare or even very rare variants has not been extensively studied. In fact, these variants might contribute significantly to genetic predisposition to AD as a result of their direct biological effects and their great diversity.

 

Two new genes identified

It is in this context that a large international consortium has identified a number of rare mutations in two genes that markedly increase the risk of developing AD. Along with their European and American colleagues, researchers from the INSERM, the Pasteur Institute in Lille, Lille University Medical Centre, the University of the Lille, the University of Rouen Normandy, and the French National Reference Centre for Patients with Early-Onset Alzheimer’s Disease (Centre national de référence pour les malades Alzheimer jeunes (CNRMAJ)) at Rouen University Medical Centre and from the Amsterdam University Medical Center performed a high-throughput sequencing study of 16,032 AD patients and 16,522 controls. This sequencing approach provides the most precise possible picture of an individual’s genetic variants.

By specifically studying the DNA regions that code for the proteins in our body (the exons), the researchers were able to map deleterious, rare variants that might change the corresponding proteins’ biological functions. The researchers confirmed the pathological role of rare variants in the SORL1, TREM2 and ABCA7 genes and, for the first time, highlighted potentially pathological variants in two other genes (ATP8B4 and ABCA1). The potentially pathological role of variants in one other gene (ADAM10) remains to be confirmed.

Some of the rare variants in these genes are associated with a significantly greater risk of developing AD in general and early-onset forms of the disease in particular.

 

Better understanding the mechanisms of AD

The identification of the effects of these rare variants should provide a better understanding of the mechanisms that underlie AD.

In fact, two disease pathways have already been well documented in the AD brain: the accumulation of beta-amyloid peptides, and changes in and the accumulation of Tau protein. Importantly, some of the genes studied by the researchers are involved in the production or aggregation of beta-amyloid peptides – confirming the latter’s central role in the development of AD. Furthermore, the present research confirmed previous reports of the importance of microglial cells (cells that help to remove waste from the brain) in AD.

These results from the largest yet sequencing study in this field constitute a major step forward in our understanding of the genetics of AD and the underlying biological mechanisms. Furthermore, these results will open up new research themes on more relevant in vitro and in vivo models in which the newly identified genes are knocked out. By continuing this work, the consortium’s scientists’ also hope to foster the development of new strategies for treating AD.

A potential therapy to reduce the side effects of a chemotherapy

Convergent effect of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage © Dewaeles et al

Cisplatin is a chemotherapy indicated to fight tumors in many types of cancer. However, it does have major side effects – especially kidney toxicity, that can lead to acute kidney failure. In addition, patients treated with cisplatin also often report high levels of neuropathic pain. Scientists from Inserm, Université de Lille, University Hospital Lille, CNRS and Institut Pasteur de Lille within the CANTHER and Lille Neuroscience & Cognition laboratories, in collaboration with researchers from Michigan State University (USA), have identified a drug that could be a game changer for patients. Istradefylline, which is already approved for Parkinson’s disease, could not only reduce the harmful effects of cisplatin but also improve its anti-tumor properties. These findings will now need to be confirmed in a clinical trial. The study is published in The Journal of Clinical Investigation.

Cisplatin is a chemotherapy used to treat several types of cancer, in particular lung, ovarian and testicular cancers. While its anti-tumor efficacy has been proven, cisplatin promotes side effects. These include intense pain (peripheral neuropathy) and kidney damage, leading to acute kidney failure in one third of cases. Currently, there is no effective solutions to limit side effects for patients exposed to cisplatin.

An international work conducted by Christelle Cauffiez, David Blum and Geoffroy Laumet[1] have now identified a molecule that reduces cisplatin-induced side effects, while preserving or even potentiating its anti-tumor properties.

 

A Parkinson’s disease drug

The scientists focused on a drug called istradefylline, which is already approved in the USA and Japan for the treatment of Parkinson’s disease. Biologically, this compound blocks the adenosine receptors receptors at the surface of cells.

Blum’s team, which is working on neurodegenerative diseases, had previously observed an increased density of these receptors in the brains of patients with dementia, a phenomenon involved in the development of these diseases. Interestingly, a comparable increase of adenosine receptors was also observed by Cauffiez’s team in the kidneys, under exposure to cisplatin.

With this in mind, the scientists decided to join forces with Laumet’s lab, a specialist of  cisplatin-induced neuropathic pain, to test the impact of istradefylline to mitigate the harmful effects of cisplatin.

 

Findings to confirm in a clinical trial

Their experiments, conducted on animal and cellular models, indeed pointed towards a beneficial role of istradefylline. In mice exposed to cisplatin, the molecule not only reduced kidney damages but also prevented neuropathic pain.

In addition, cisplatin’s ability to reduce tumor growth was increased in the animals receiving istradefylline – an effect subsequently confirmed in cell models.

Before considering the widespread application of this therapeutic approach to patients with cancer, these findings must however first be consolidated by organizing a rigorous clinical trial. The fact that istradefylline is already used in humans to treat another disease already constitutes an interesting perspective.

“In fact, we already have a lot of clinical data showing that this molecule is safe. While it is necessary to conduct a clinical study to test its efficacy in reducing the side effects of the chemotherapy, the possibility of therapeutic repositioning is a promising perspective for improving patient care in the short term,” the researchers point out.

 

[1] from the CANTHER laboratory (Inserm/Institut Pasteur de Lille/CNRS/Université de Lille/University Hospital Lille), the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille/University Hospital Lille) and the Department of Physiology of Michigan State University

Preventing dementia in seniors: meditation still under investigation

©AdobeStock

Meditation as a tool to prevent dementia and improve the mental health and well-being of elderly people is one of the avenues explored by the European Medit-Ageing research program, coordinated by Inserm. As part of this program, researchers from Inserm and Université de Caen Normandie, in collaboration with French and European teams, observed the impact of 18 months of meditation training on certain brain structures involved in regulating attention and emotions in healthy people over 65. While their findings, to be published in JAMA Neurology, show a positive impact on attentional and socio-emotional regulation capacities, they do not show any significant benefits of meditation on the volume and functioning of the brain structures studied, in comparison to control groups. However, they do call for further research to study the brain as a whole, over longer time periods, and with more participants.

In order to prevent the onset of dementia in elderly people, recent intervention strategies have been multidisciplinary and focused on lifestyle improvements. These include cognitive stimulation, physical activity, a healthy diet, and cardiovascular recommendations. However, there are no dedicated preventive interventions for psycho-affective factors such as depression, stress, and anxiety.

Mental training aimed at regulating stress and attention, such as mindful meditation, has proven to be beneficial in managing the cognitive and emotional aspects of aging, particularly to reduce stress, anxiety, and depression.

Recent research has reported that the insula and anterior cingulate cortex are brain regions particularly sensitive to meditation training. These interconnected regions are involved in self-awareness and in the processing and regulation of attention, emotions, and empathy. In young adults, meditation has already shown its capacity to structurally (e.g. in terms of volume) and functionally modify these structures, particularly in the brain of meditation experts with several thousand hours of practice under their belts.

The insula and anterior cingulate cortex are particularly sensitive to aging. It has been shown that in elderly people who are experts in meditation, gray matter volume and glucose metabolism (a physiological process essential for good brain function) were higher than in people who do not meditate.

Meditation could therefore be an interesting approach to preserve brain structures, functions, and cognitive capacities, and by extension, prevent dementia.

A team of researchers from the European Medit-Ageing research group, led by Inserm Research Director Gaël Chételat from the Physiopathology and Imaging of Neurological Disorders laboratory (Inserm/Université de Caen Normandy), in collaboration with teams from Lyon Neuroscience Research Center (Inserm/CNRS/Université Claude Bernard Lyon 1/Université Jean-Monnet-Saint-Etienne), University College London, University of Liège and University of Geneva, looked at the potential physiological, cognitive, and emotional benefit of meditation in elderly individuals.

In the Age-Well clinical trial involving 136 participants aged 65 or older with no known diseases, the researchers measured the impact of an 18-month meditation intervention on tissue volume and perfusion (physiological process of supplying an organ with nutrients and oxygen necessary for its metabolism) of the insula and anterior cingulate cortex. They also looked at specific cognitive and socio-affective parameters.

The participants were assigned to three groups in order to compare the potential benefit of meditation with different types of interventions. The first group followed the meditation intervention protocol (mindfulness meditation and loving kindness and compassion meditation), the second group (the “active control” group) followed a period of English-language training, and the third group (the “passive control” group) did not follow any intervention.

After 18 months of intervention, the researchers saw no significant changes in volume or perfusion of the cingulate cortex or insula in the meditation group compared to the control groups.

The fact that no anatomical differences were observed between these two groups could indicate that while meditation can modify the volume of younger and more plastic brains, 18 months of meditation training are not enough to modify the effects of aging,” analyzes Chételat. “In addition, while the results of the volume measurement are strictly negative, those of the perfusion show a trend in favor of meditation that could be interesting to explore over a longer intervention time and/or with a larger population sample,” specifies the researcher.

The research team will therefore conduct a 4-year follow-up of the participants, to investigate potential long-term effects.

In contrast, significant differences were observed in behavioral measures between the meditation group and the English-learning group, with improved regulation of attention and socio-emotional capacities in the meditation group participants. “Here the practice of meditation is showing its real benefit on the mental health of elderly people, with a significant improvement in parameters specific to well-being and fulfilment, but also to the maintenance of attentional and socio-emotional capacities, as reported by participants,” adds Antoine Lutz, responsible for the study’s meditation component.

More specific measurements and analyses will be conducted within the Age-Well trial to improve the understanding of these mechanisms. These analyses could be used to identify the measures which are most sensitive to meditation and to study the mechanisms behind its effects.

 

 

To find out more about the latest medical research on consciousness, read the special feature “Consciousness: modulating it to improve treatment” in issue 54 of Inserm, le magazine 

New Avenues to Reduce Long-Term Complications in Preterm Infants

Some GnRH neurons (green) express NOS1 (red) during their migration from the nose to the brain during fetal life. The GnRH + NOS1 double-labeled cells appear in yellow. © Vincent Prévot/Inserm

Children born prematurely have a higher risk of not just cognitive and sensory disorders, but also infertility in adulthood. In a new study, a team of researchers from Inserm, University Hospital Lille and Université de Lille at the Lille Neuroscience and Cognition laboratory has opened up interesting avenues for improving their prognosis. By conducting research into a rare disease known as congenital hypogonadotropic hypogonadism, the scientists have discovered the key role of an enzyme and the therapeutic potential of the neurotransmitter that it synthesizes – nitric oxide – in reducing the risk of long-term complications in the event of prematurity. Their findings are described in Science Translational Medicine.

Congenital hypogonadotropic hypogonadism is a rare disease characterized by delayed puberty or the complete absence of puberty in adolescence, leading to infertility. Some forms of the disease are caused by a lack of production of GnRH, a hormone produced in the brain that remotely controls the development and functioning of male and female gonads through various intermediaries.

The team of Vincent Prévot, Inserm Research Director, specializes in the dialogues between the brain and the rest of the body.

Here the scientists looked at nitric oxide, a neurotransmitter that regulates the activity of GnRH neurons, and more specifically NOS1, the enzyme that synthesizes it.

“Nitric oxide suppresses the electrical activity of the GnRH neurons and modulates the release of this hormone, so NOS1 dysfunction was not ruled out as being the cause of congenital hypogonadotropic hypogonadism,” explains Prévot, the principal coordinator of the study.

To go further, his team collaborated with a laboratory in Lausanne (Switzerland) which has a cohort of 341 patients with this disease. Using DNA samples, they looked for the presence of rare mutations on the gene encoding the NOS1 enzyme and found five different mutations that could explain the disease. Some of the individuals concerned had, in addition to fertility problems, sensory and cognitive disorders (intellectual disability or loss of hearing or smell).

An application in the context of preterm birth?

The next stage of the study consisted of developing a NOS1-deficient mouse model[1] in order to better understand the role of this enzyme. The researchers encountered puberty problems, as well as sensory and neurological alterations, as observed in humans with congenital hypogonadotropic hypogonadism. They also saw an exacerbation of minipuberty in these animals. Minipuberty occurs in all mammals just after birth (between one and three months of age in humans) and triggers an initial brain activation of the axis controlling reproduction prior to the “real” puberty in adolescence.

Here the researchers observed that the peak of the sex hormone associated with this minipuberty was twice as high in NOS1-deficient mice.

“This caught our attention because premature infants also tend to present a more intense minipuberty than usual. And the greater the prematurity, the greater the risk of neurosensory and mental complications in adulthood,” reiterates Konstantina Chachlaki, Inserm researcher and first author of the study.

Based on these observations, the researchers tested the administration of nitric oxide in NOS1-deficient mice just after their birth, during the minipuberty period. What they saw was the reversal of all the symptoms they had developed: the puberty problems and sensory and neurological disorders disappeared, and this was over the long term, for the remainder of their lives.

An ongoing clinical trial

These promising findings could help to improve the care of preterm infants. Nitric oxide is also given to some children born prematurely, to facilitate the opening of the bronchi in the event of breathing difficulties.

“In light of this consistency of observations and practices, we decided to set up a clinical trial to test the effect of nitric oxide in preterm infants by studying reproductive and neurosensory parameters,” explain Prévot and Chachlaki, who are coordinating a European project dedicated to…“Administering nitric oxide at birth could reduce the risk of reproductive, sensory and intellectual complications in children born prematurely. This is what we are going to try to verify in the wake of these astonishing discoveries in mice,” they continue.

The miniNO trial was launched at University Hospital Lille in partnership with a hospital in Athens (Greece). The objective is to verify whether children receiving this treatment go on to experience normal minipuberty and puberty, and whether they develop fewer sensory and neurological complications compared to premature infants who were not administered nitric oxide at birth.

 

[1] In which the gene encoding the NOS1 enzyme was disactivated.

A Therapy Found to Improve Cognitive Function in Patients with Down Syndrome

Here, the pump, which is similar in aspect to a band aid, is being placed on a patient’s arm. This medical device allows for a pulsatile delivery of GnRH, under the skin. © 2022 CHUV Eric Deroze

 

An Inserm team at the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille, Lille University Hospital) has joined forces with its counterparts at Lausanne University Hospital (CHUV) to test the efficacy of GnRH injection therapy in order to improve the cognitive functions of a small group of patients with Down syndrome. First the scientists revealed a dysfunction of the GnRH neurons in an animal model of Down syndrome and its impacts on the cognitive function impairment associated with the condition. Then a pilot study testing GnRH pulsatile injection therapy was conducted in seven patients. The results were promising : the therapy led to improved cognitive function and brain connectivity. This study has been published in Science.

Down syndrome, also known as trisomy 21, affects around one in 800 births and results in a variety of clinical manifestations, including decline in cognitive capacity. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer’s disease. Gradual loss of the ability to smell, typical of neurodegenerative diseases, is also commonly encountered from the prepubertal period, with potential sexual maturation deficits occurring in men.

GnRH-secreting neuron dysfunction identified in Down syndrome

Recent discoveries have suggested that the neurons expressing gonadotropin-releasing hormone (GnRH) – which is known for regulating reproduction via the hypothalamus – could also act on other brain regions with a potential role in other functions, such as cognition.

With this idea in mind, the Lille Neuroscience & Cognition laboratory team led by Inserm Research Director Vincent Prévot studied the mechanism which regulates GnRH in mouse models of Down syndrome.

The laboratory demonstrated that five strands of microRNA regulating the production of this hormone – which are found on chromosome 21 – are dysfunctional. This supernumerary chromosome then leads to abnormalities in the neurons that secrete GnRH. These findings were confirmed at both genetic and cellular levels. The Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies seen in the mice were closely linked to dysfunctional GnRH secretion.

Restoring GnRH production to restore cognitive function

The Inserm scientists were then able to demonstrate that restoring physiological GnRH system function restores cognitive and olfactory functions in trisomic mice.

These findings in mice were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine of the University of Lausanne and head of the Endocrinology, Diabetology, and Metabolism Department at CHUV. Her research focuses on congenital GnRH deficiency, a rare disease which manifests by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy in order to reproduce the natural pulsatile rhythm of this hormone’s secretion, in order to induce puberty.

The researchers therefore decided to test the efficacy of pulsatile GnRH therapy on cognitive and olfactory deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team was able to demonstrate the restoration of olfactory and cognitive functions in mice.

Pulsatile GnRH therapy improves cognitive function and neural connectivity in a small patient group

The next stage for the scientists and doctors involved a pilot clinical trial in patients to evaluate the effects of this treatment. Seven men with Down syndrome, between 20 and 50 years of age, received one subcutaneous dose of GnRH every two hours for 6 months via a pump placed on the arm. Cognition and olfactory tests as well as MRI exams were performed before and after the treatment.

From the clinical viewpoint, cognitive performance increased in 6 of the 7 patients with better three-dimensional representation, better understanding of instructions, improved reasoning, attention, and episodic memory.

However, the treatment had no impact on the ability to smell. This improvement in cognitive functions was associated with changes in functional connectivity as observed by brain imaging conducted by the CHUV Department of Clinical Neurosciences.

One of the most significant examples concerns the change in the representation of 3D objects shown by the drawing above. On the left, a cube drawn before the start of treatment. On the right, a bed drawn 6 months later by one of the participants.

These data suggest that the treatment acts on the brain by strengthening the communication between certain regions of the cortex.

“Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions,” explains Prévot. “In Down syndrome, pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects,” adds Pitteloud.

These promising findings now justify the launch of a larger study – with the inclusion of women – to confirm the efficacy of this treatment in people with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer’s disease.

Questioning the Universal Application of Neurocognitive Tests

Crowd

Human interactions are enabled by a set of neurocognitive mechanisms defined by the concept of “social cognition”. © Ryoji Iwata /Unsplash

Human interactions are enabled by a set of neurocognitive mechanisms defined by the concept of “social cognition”. In order to identify social cognition disorders, specialists use internationally validated evaluation tests. However, these are most often developed in western, industrialized countries, which could question the relevance of applying them to all humanity. A research team from Inserm, University Hospital Lille, and Université de Lille within the Lille Neuroscience & Cognition laboratory looked at the impact of cultural differences on the performances on two of the neurocognitive tests most used worldwide, comparing the results of around 600 healthy participants across 12 countries. Their study, to be published in Neuropsychology, highlights notable differences in performance from one country to another and calls for more consideration to be given to the social sciences when developing such tests.

The concept of “social cognition” designates the various cognitive processes (perception, memorization, reasoning, emotion…) involved in social interactions. Disorders of social cognition are encountered in many diseases, such as schizophrenia and Parkinson’s, and in neurodevelopmental disorders, such as autism. They are responsible for highly incapacitating interpersonal difficulties that strongly impact the lives of patients and those around them. Consequently, the detection, quality of evaluation, and treatment of such disorders represent a major challenge for mental health specialists.

To evaluate social cognition capacities and diagnose a potential disorder, there are tests used internationally that measure “cognitive functions” – namely the capacities that enable us to interact effectively with others.

However, these reference cognitive tests are most often developed in western, industrialized, and democratic countries and their “norms” for the most part based on profiles of well-educated, rich, white people. Insofar as such individuals constitute only 12 % of humanity, their overrepresentation in the development of neuropsychological tests calls into question the relevance of their application to other populations.

A team of scientists led by Inserm researcher Maxime Bertoux within the Lille Neuroscience & Cognition laboratory (Inserm/University Hospital Lille/Université de Lille) sought to determine whether cultural differences have a notable impact on the results of the most commonly used social cognition tests. This involved conducting a vast international study on 587 healthy participants, from 18 to 89 years of age, across 12 countries (Germany, England, Argentina, Brazil, Canada, Chili, China, Colombia, Spain, France, Italy, and Russia). Neuropsychologists subjected the participants to two types of test evaluating the capacities considered essential in social cognition.

The first, devised in the UK, evaluated the capacity to decode social rules and infer others’ mental state by asking the participants to identify, in various short scenes, whether one of the characters was committing a social faux pas (for example, mistaking a customer for a waiter in a restaurant). The second test, devised in the US, evaluated the capacity to recognize the expression of emotions by asking the participants to identify various facial expressions on photographs.

The results of the study show that a large proportion of the divergences in performance on these two tests (around one quarter for the faux pas test and over 20 % for the emotions recognition test) is attributable to the differences in nationality of the participants.

The best performances in the faux pas test were obtained by the English participants, without the literal translation from English to the other participants’ native languages having an impact on the results.

For example, 100 % of the English participants considered it a faux pas to mistake a customer for a waiter in a restaurant versus only 65 % of the Canadian participants. Furthermore, while 100 % of the English participants considered it normal to give up their seat on a bus for an elderly person, 21 % of the Chinese participants considered it a faux pas.

In the results of the emotional facial expression recognition test, the comparison between the countries reveals that some emotions were not identified in the same way by all participants. While positive expressions such as joy were interpreted unambiguously from one country to another, the interpretation of negative emotions was much more variable. For example, fear was confused with surprise by the majority of the Canadian and Brazilian participants, whereas the English and Argentinians had virtually no difficulty differentiating them.

This study shows that individual and cultural factors have a strong impact on social cognition measures, declares Bertoux. Beyond the effect of age, gender, and education, there is an influence of local concepts, norms and habits on the categorization of emotions, inferring others’ intentions and understanding their behavior. As such, the use of tests devised by rich, white US or UK scientists, would favor the performance of the participants from the same country, culture, and social level.

Of course, this does not mean that the inhabitants of one country are superior or inferior to those of another, adds the researcher. Our study shows that a test devised in a specific context favors those who are familiar with that context. For example, identifying a faux pas requires detecting that an implicit social rule has been broken – but social rules fluctuate from one country to another.” 

These findings therefore question the international applicability of a neuropsychological test devised and validated in one country, particularly when it comes to evaluating and diagnosing cognitive disorders. 

For its future studies, the research team would like to enrich its data by including more participants and countries – particularly regions of the world not represented in this research, such as Africa and the Middle East –, but also by exploring the neurocognitive and cultural variations within vast countries such as China and Canada. “The neurosciences need to interact more with the social sciences in exploring and considering cultural diversity in order to build a more rigorous, relevant, and inclusive neuropsychology,” concludes Bertoux.

Inserm and CNRS to Lead Large-Scale Program on Psychiatry Research

dépression

Psychiatric illnesses constitute a major public health problem. © Danie Franco/Unsplash

On July 18, 2022, France’s minister for Higher Education and Research Sylvie Retailleau announced an unprecedented psychiatry research effort in the form of 80 million euros allocated over five years to the precision-psychiatry project-program PROPSY, led by Inserm and CNRS as part of the Priority Research and Resources Programs (PEPRs). With this ambitious research program centered around four of the most incapacitating psychiatric disorders, the two institutes aim to develop precision psychiatry in order to revolutionize both their diagnosis and patient care.

Led jointly by Inserm and CNRS, the project will involve partners whose competences are both renowned and complementary, such as Fondation FondaMental, CEA, Sorbonne Université, Université de Bordeaux, Université de Lille, Université de Paris, and Université Paris Est Créteil.

Psychiatric illnesses constitute a major public health problem, affecting 20 % of French people on a daily basis – and very often their loved ones. Developing early in life, these illnesses often strike young adults and are sadly linked to a 10-to-20-year reduction in life expectancy. In response to the diagnoses – that are sometimes long in coming – the therapeutic options are often thin on the ground, with those that are available having incapacitating side effects. Not to mention the considerable socioeconomic impact, with recent estimations putting the direct and indirect costs at 160 billion euros in 2019 – representing over 5 % of GDP.

Faced with these two observations, it would appear imperative to improve the coordination of France’s psychiatry research forces and increase the research-care continuum. These are the proposals of PROPSY, a project led by Inserm and CNRS which has recently been selected to receive 80-million-euro funding over five years.

Centered around four of the most incapacitating disorders, bipolar disorder, major depressive disorders, schizophrenia, and autism spectrum disorders, this exploratory PEPR will broaden the field of precision medicine in psychiatry.

This will make it possible to provide each patient with the best care. In order to achieve this ambition, the multiple challenges will be to:

  • Better understand the causes and mechanisms behind mental illnesses
  • Discover prognostic markers for these disorders and identify homogenous patient subgroups
  • Develop targeted therapeutic strategies that include eHealth, immunomodulators, brain stimulation, and biotherapies
  • Reduce stigma and false representations
  • Support the development of a French biomedical sector in mental health, including pharma, MedTech and digital, through public-private partnerships
  • Create a new generation of scientists and medical staff in psychiatry by renewing the approach to these illnesses and thanks to training initiatives

Selected as part of the call for Priority Research and Resources Programs, PROPSY will include the funding of projects already identified – such as the French Minds longitudinal cohort of 3 000 adult patients who will undergo exhaustive clinical, behavioral, and environmental evaluation with the help of digital tools, biological markers, and brain imaging – as well as open calls for proposals.

We are proud that the government has selected our research program,” confide Gilles Bloch, Inserm CEO and Marion Leboyer, 2021 Inserm Grand Prize recipient, Executive Director of the FondaMental foundation and project scientific lead. “With the negative impact of the health crisis on mental health (an over 30 % increase in cases of depression), this extremely important decision represents hope for millions of patients, their families, as well as researchers and medical staff. “

 

With the benefit of better support for patients, the PROPSY PEPR will enable research and patient care to join forces to meet the public health challenges related to psychiatric disorders,” adds Antoine Petit, Chairman and CEO of CNRS.

Researchers described how the cerebellum modulates our ability to socialize

This image of the cerebellum of a mouse expressing a fluorescent protein in Purkinje cells expressing dopamine D2 receptors © Emmanuel Valjent, Institut de Génomique Fonctionnelle (Montpellier)

The cerebellum is essential for sensorimotor control but also contributes to higher cognitive functions including social behaviors. In a recent study, an international research consortium including scientists from Inserm – University of Montpellier (France), the Institut de Neurociències Universitat Autònoma de Barcelona (INc-UAB) (Spain), and the University of Lausanne (Switzerland) uncovered how dopamine in the cerebellum modulates social behaviors via its action on D2 receptors (D2R). By using different mouse models and genetic tools, the researchers’ work shows that changes in D2R levels in a specific cerebellar cell type, the Purkinje cells, alter sociability and preference for social novelty without affecting motor functions. These new findings pave the way to determine whether socially related psychiatric disorders, such as autism spectrum disorders (ASD), bipolar mood disorder, or schizophrenia, are also associated with altered dopamine receptors expression in specific cerebellar cell types.

Dopamine (DA) neurons are a major component of the brain reward system. By encoding motivational value and salience, they tighly regulate motivation, emotional states and social interactions. Although the regulation of these processes has been largely ascribed to neural circuits embedded in limbic regions, recent evidence indicate that the cerebellum, a region primarily involved in motor control, may also contribute to higher cognitive functions including social behaviors. However, whether cerebellar dopamine signaling could participate to the modulation of these functions remained unexplored. Researchers from Inserm – Montpellier University (France), the Institut de Neurociències UAB (Spain), and the University of Lausanne (Switzerland) uncovered a new role for dopamine as modulator of social behaviors in the mouse cerebellum.

By combining cell type-specific transcriptomics, immunofluorescence analyses and 3D imaging, researchers first demonstrated the presence of dopamine D2 receptors (D2R) in Purkinje cells (PCs), the output neurons of the cerebellar cortex. Using patch-clamp recordings, they were able show D2R modulated synaptic excitation onto PCs. “This first set of results was already determinant for us, as they unveiled that D2R were present in the cerebellum and that, despite their low expression level, they were functional”, highlights Dr Emmanuel Valjent, research director at Inserm (France), and coordinator of the study.

The researchers then went on to study their functions. By using genetic approaches to invalidate or overexpress D2R selectively in PCs, they analyzed the impact of these alterations on motor and non-motor cerebellar functions. “We have uncovered an unexpected causal link between PCs D2R expression levels right in the center of the cerebellum, the Crus I/II lobules, and the modulation of social behaviors. Reducing the expression of this specific dopamine receptor impaired the sociability of mice as well as their preference for social novelty, while  their coordination and motor functions remained unaffected” explains Dr. Laura Cutando, Marie-Curie researcher at the Mitochondrial Neuropathology research group at INc-UAB, and first author of the article.

This study constitutes a first step towards a better understanding of the role of dopamine in the cerebellum and the mechanisms underlying psychiatric disorders such as schizophrenia, ADHD and anxiety disorders, which have all in common aberrant DA signaing and altered social behaviors.

Do Some Cognitive Biases Contaminate Even Our Simplest Mental Mechanisms?

Enfants apprenant à écrire à l'école

©woodleywonderworks via Flickr

 

When we implement complex cognitive processes, for example when making decisions, we are subject to cognitive bias. But what about simpler processes, such as those involved in the most basic learning? In a new study analyzing data from all previous research in the field, researchers from Inserm and ENS-PSL show that not only are positivity and confirmation biases present even in the simplest human and animal cognitive processes, but also that incorporating them into learning algorithms would enhance their performance. This research, published in Trends in Cognitive Sciences, suggests that these biases could initially have been a very old evolutionary advantage.

Cognitive biases, such as positivity and confirmation biases, are known to influence our beliefs and decisions. Until recently, it was assumed that they were specific to so-called “high-level” cognitive processes, namely those that come into play when we reason about complex and uncertain proposals.  For example, it is well known that people overestimate the likelihood of desirable events (France winning the World Cup) and underestimate that of undesirable events (a marriage ending in divorce). 

In a study published in Trends in Cognitive Sciences, Stefano Palminteri, Inserm researcher at the ENS-PSL/Inserm Laboratory for Cognitive and Computational Neuroscience and Maël Lebreton, researcher at the Paris School of Economics, challenge this conception of the involvement of positivity and confirmation biases.

The researchers drew on the various existing data in the scientific literature on “reinforcement learning”. This is a basic cognitive process of learning through rewards and punishments that humans share with many animals. This literature review reveals that very simple reinforcement learning tests can reveal behavioral signatures of positivity and confirmation biases in people who are subjected to them. These biases appear to be much more common than previously thought and are even present in the simplest cognitive processes such as learning to make good decisions through trial and error (reward and punishment).

What is more, these biases do not seem to be exclusive to humans: the behavioral signatures also appear in similar tests conducted in animals. This suggests that these biases may have emerged during evolution in a common ancestor, long before the appearance of Homo sapiens, raising the question of why evolution has selected and maintained what may at first glance be perceived as processes that can generate seemingly irrational behavior.

Palminteri and Lebreton believe that they have identified part of the answer to this question through the findings of studies based on computerized simulations. These studies compared the performance of reinforcement learning algorithms – with some algorithms incorporating positivity and confirmation biases and others not. These simulations show that the presence of a confirmation bias in the algorithm actually enables it to learn more effectively in a wide range of situations. These biases could therefore actually promote survival, which would explain why they have not been corrected during the course of evolution.

The article opens up new avenues of research that would allow us to deepen our understanding of the cognitive biases and processes related to reinforcement learning. In particular, the researchers suggest exploring the role of these biases in the development and maintenance of pathological states, such as addiction and depression. These findings also suggest that including these biases in artificial intelligence algorithms could paradoxically improve their performance.

Il existerait un lien entre la taille du réseau social et la structure du cerveau

Mère macaque toilettant son jeune singe.

A macaque grooming her offspring. An image that illustrates how macaques form relationships. © Noah Snyder-Mackler

The more social relationships we have, the more certain structures in our brain are developed. This has been the hypothesis of various neuroscience research projects for several years. With previous findings having highlighted the role of our social environment as one of the key factors behind the expansion of the cerebral cortex, researchers from Inserm and Université Lyon Claude Bernard Lyon 1, in collaboration with the University of Pennsylvania, went one step further in elucidating this link. They were more specifically interested in a species of macaques whose brain architecture is comparable to that of humans. By observing these non-human primates in their natural state and by analyzing images of their brains, they discovered that the number of companions they have is predictive of the size of certain brain regions associated with social cognition and empathy. The findings of this study have been published in Science Advances.

The links between social network and brain size have already been the subject of neuroscientific studies. For example, scientists have already looked at variations in the size of the human brain amygdala in relation to the number of Facebook friends that a person has1.

In order to build on this research and attempt to find out more about the organization and functions of the neural networks in humans, research teams have worked with an animal species whose brain characteristics are similar to those of humans: the Rhesus macaque.

In a new study, researchers from Inserm and Université Claude Bernard Lyon 1 at the Stem Cell and Brain Research Institute, in collaboration with the University of Pennsylvania, studied a group of these non-human primates in their natural state for several months before taking images of their brains. The fact that the animals were free ranging enabled the scientists to understand the social group in its full complexity. They were therefore able to measure the intensity2 of the interactions with other individuals and identify an animal’s position within the group social hierarchy.

For example, some of the observations focused on grooming partners, which represent direct, important relationships for macaques.

Alongside these behavioral observations, the scientists analyzed brain scans of individuals from the group, which consisted of 103 rhesus macaques, including 68 adults and 21 young macaques under 6 years of age.

In the adults, they found that the greater the number of social partners, the greater the size of some regions of the brain’s temporal lobe – the ventral dysgranular insula and the mid-superior temporal sulcus3 – regions considered essential for understanding emotions and the perception of how others behave.

In order to better understand how this phenomenon occurs, the scientists also collected brain scans from 21 newborn macaques. The research showed that they are not born with these differences in brain structure size but that they are established during their development.

According to the researchers’ observations, there is therefore no correlation between social network size and brain volume at birth. These findings suggest that exposure to the social environment over the course of life contributes to the maturation of brain networks.

“Which is interesting because if we had seen the same correlation in young macaques, this could have meant that having a very popular mother (with many interactions with the group) could have predisposed the newborn to also become popular. But in fact our data suggest that the differences we see in adults are strongly determined by our social environments, perhaps more than by our innate predisposition,” explains Jérôme Sallet, Inserm Research Director.

Following this study, the researchers now wish to look at anatomical changes at cell level, in order to reveal the mechanisms behind the increased size of the brain regions that were identified using brain imaging.

 

1 Kanai R., Bahrami B., Roylance R. and Rees G. 2012. Online social network size is reflected in human brain structure, Proc. R. Soc. B.

2 The researchers measured the number of interactions between the animals, their duration and whether these interactions were cooperative or aggressive.

3 The mid-superior temporal sulcus is involved in social cognition and perception.

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