Primates’ brains are specifically tuned toward social information. This might well have organized all our neural circuits around the necessity of living with peers. As a matter of fact, social cognition is first to be impacted in many neurological and psychiatric disorders. This project aims at providing critical insight on how social beings create a shared world, by inferring social categories and cultural habits that rule their society. The ability to learn about others and to learn from others through observation is essential to primates, yet we currently don’t know how these two processes are implemented by neurons in the brain. First, we will investigate the biological mechanisms for cultural transmission of knowledge, by comparing the location and workings of brain circuits recruited when subjects acquire a novel manual task by observing a demonstrator, to brain circuits recruited when subjects learn the same manual task by trial-and-error. Second, we will investigate the location and workings of the brain circuits involved in extracting social characteristics of individuals from observation of their encounters. Finally, we will link these two issues, by investigating how brain circuits implement the fact that cultural transmission is influenced by social characteristics of the demonstrator. By combining fMRI and fMRI-guided electrophysiology, I hope to gain an understanding that encompasses whole-brain circuits, neurons, and brain-to-brain coupling, into how social categories and habits are computed in the brain, with the long-term goal of providing clinical neuroscience with new hypotheses to understand how social mechanisms are disturbed in disease.

Individuality is the sum of the behavioural characteristics that are unique to us and stable over time. In most animals, individuals display specific unique and stable behavioural characteristics, but those characteristics can be changed by social interactions. An example in our society is “peer pressure” where innate tendencies are modified by the actions of others. How does this happen at the level of the brain and its neural networks? Using the fruit fly as model organism, we propose an academic-SME research partnership to answer this important question. We have evidence that flies display individuality in behaviour when seeking an object. We also know the neural circuit responsible for this individuality, and we have shown that its developmental wiring diagram predicts the behaviour of an individual. We will test how this individuality is modified at the behavioural and neural circuit levels and what happens in the brain when different flies interact with each other. To do so, we will build new hardware and software tools and conduct innovative experiments. This basic research project is a unique endeavour that will provide important insights into the neural basis of the social influence on individuality.

Attentional and spatial deficits are common after brain damage (vascular, neurodegenerative or traumatic), and have dramatic consequences on patients’ everyday life and functional prognosis. Neurocognitive assessment and training is crucial for diagnosis, rehabilitation and prevention of these disorders. Data collection and processing in different countries, by different experts in hospitals and research centres are severely limited by the use of traditional paper-and-pencil tests. Despite their large diffusion, these tests lead to results difficult to evaluate and compare in populations of patients. A huge amount of potentially crucial information is thus lost. The introduction of Artificial Intelligence in the field of clinical diagnosis and rehabilitation is now changing the landscape. In recent years, novel techniques of technology-enhanced assessment entered the clinical practice. Their use has particularly benefitted the diagnosis and follow-up of visuo-spatial cognitive deficits, because these deficits typically manifest themselves during physical object manipulation or navigation. These techniques have the potential to collect a great amount of data, which however are not currently exploited in the best possible ways. Data from many patients with similar neurological conditions across several European countries could feed a public, anonymized database, open to researchers and clinicians. Such very large database would allow researchers to perform analyses with an unprecedented level of statistical power, depth and completeness. This approach needs diverse competences, in clinical and experimental neuropsychology, computer science, big data management and artificial intelligence. The objectives of the NeuroDataShare project are: 1. Develop an European Shared Database, using big data paradigms, openly sharing the data collected from neurocognitive assessment and trainings with a twofold scheme: (1) providing researchers with the opportunity to extract and apply data by using pattern recognition and Artificial Intelligence models; (2) providing clinicians with automatic algorithms for a rapid and easy data extraction from different patients. Design and apply the highest level of security for the data, including all the relevant features of security and anonymity, according to the most strict European laws. Create a common methodology in order to bridge the tools and procedures of the assessment and training of visuo-spatial and attentional abilities, allowing a quick digitalization of the previous and future data, feeding the database with data from neurocognitive assessment and training designing user-friendly platforms and applying co-design criteria involving clinicians, physicians, and practitioners. 2. Benefit from the potential of the data aggregation of the shared database to answer neuroscientific and clinical questions, by identifying neural and behavioural predictors of patients’ recovery and response to treatments. 3. Promote and include new methods for the tracking of the assessment and training sessions, using the new technologies, in particular applying tangible interfaces, augmented reality and gamification paradigms. 4. Apply Artificial Intelligence and machine learning methods to transfer, share and store collected data for researchers and professionals, to allow a common ground, and creating algorithms for automated interpretation of the clinical tests. 5. Increase the awareness on this theme in the scientific community, disseminating the results of the project and measuring the numerical impact of this process; 6. Create a multidisciplinary community of practices composed by neuroscientists, computer scientists, engineers, psychologists, physicians and practitioners, organizing an international conference about the digitalization of the data in the neurocognitive assessment and training; 7. Define plans to apply the set of methods developed within NeuroDataShare to other clinical fields.

Stroke is a leading cause of death, killing approximately 30.000 French people each year. Stroke occurs when blood flow to an area of the brain is cut off, causing death of oxygen- and nutriment-deprived brain cells downstream of obstructed blood vessels. Stroke also causes inflammatory cell accumulation and cerebral edema, which is accumulation of excessive fluid collecting in brain tissue. Because edema compresses brain tissue and aggravates neurological damage, it is a major risk factor for morbidity and mortality in stroke patients. In addition, inflammatory cell accumulation causes secondary brain damage and neurotoxicity. Better treatment options against cerebral edema and inflammation require insight into mechanisms promoting drainage of cerebrospinal (CSF) and interstitial fluid (ISF). The drainage of cerebral fluids is performed by a circuitry including the cerebral glymphatic system and a meningeal lymphatic vasculature that connects with deep cervical lymph nodes. Lymphatic vasculature ensures both the clearance of toxic molecules produced by brain cell activity and the immune surveillance of brain tissues, allowing immune cell recirculation. Abnormal brain lymphangiogenesis is likely to affect homeostasis of cerebral fluids and brain immunity, with health-impairing consequences on the response to injuries and neurological diseases in humans. VegfC is the major regulator of lymphangiogenesis; it signals via its high-affinity receptor, Vegfr3 that is expressed on the surface of lymphatic endothelial cells (LECs) and stimulates LEC migration, proliferation and survival. We have shown that, in addition to lymphangiogenesis, VegfC/Vegfr3 signaling is a potent and direct regulator of brain neurogenesis. VegfC is expressed in the adult brain, where it stimulates neurogenesis by activating neural stem cells (NSCs) both in mice and humans. The VegfC/Vegfr3 system is thus uniquely endowed with the dual ability to promote growth of lymphatic vessels and activate NSCs. We hypothesize that VegfC/Vegfr3 signaling regulates meningeal lymphangiogenesis and that promoting this signaling will allow to alleviate edema and immune cell accumulation in the brain, and simultaneously activate NSC, thereby enhancing brain repair. In line with this hypothesis, preliminary results obtained by the consortium demonstrated that, in the mouse, the adult meningeal lymphatic vasculature is plastic and VegfC-dependent, allowing us to completely delete or expand the lymphatic vessel coverage of the skull though AAV-mediated expression of VegfC trap or VegfC, respectively. We have also established innovative tools and techniques to carry out live-imaging of meningeal vessels by multiphoton confocal microscopy, to perform 3D-imaging of the head volume including meningeal vessels, and to induce the controlled expression of VegfC in vivo. The ultimate goal of this proposal is therefore to take advantage of our conceptual and technological advances on VegfC and meningeal lymphatic biology to develop novel strategies to improve brain repair which would simultaneously promote cerebral fluid drainage, immune cell recirculation and NSC activation. To this aim, we propose to characterize the role of meningeal lymphatic vasculature in stroke (WP2), the role of inflammation in mice with reduced/enhanced meningeal lymphatic vessels during stroke (WP3), and the potential of VegfC/Vegf3 signaling in NSCs to improve brain repair after stroke (WP4). Hence, the major conceptual innovation of the present project is to integrate the lymphangiogenic and neurogenic functions of VegfC for improving brain tissue drainage and repair after an ischemic injury. Gain of knowledge in the function of recently discovered meningeal lymphatics could moreoever lead to the identification of innovative therapeutic targets to prevent or treat neurodegenerative diseases associated with defects in ISF drainage such as Alzheimer’s disease or other proteinopathies.

Individual animals differ in traits and preferences. These differences shape their interactions, their prospects for survival, their susceptibility to diseases but also their response to drugs or treatments modulating neural circuits. While there are some evidences that neurogenesis or neuromodulation play a role in the process of individuation, both circuit and molecular-level understandings of this phenomenon are lacking. Determining the neuronal substrate of our individuality and how it is shaped during adulthood is a major frontier in neurosciences and the focus of this proposal. It aims at deciphering neural circuits involved in individuation and to question whether long-range connectivity in the adult brain is stable or subject to structural modifications depending on individual performance. To disentangle the social, environmental or stochastic causes of the individuation process, we use two complementary behavioural assays. These aims discriminate mice based on individual behaviour and to study the mechanisms responsible for these differences at a circuit and molecular levels. The first of these assays will take advantage of our recently developed system “Souris-City” (SC), a large environment where animals live together and perform self-initiated cognitive tests in isolation. This system tracks social and cognitive activities over very long periods of time at the resolution of individual mice, enabling the assessment of individual traits and strategies. On the other hand, we will use nest building behaviour as a complementary scalable assay. Mice build nests naturally in a laboratory setting and the time they invest on this task varies from mouse to mouse. Because of the quantitative outcome, ease of implementation and non-obligatory nature of the task, nesting is an ideal model to study how brain circuits integrate many cues to freely engage in a complex task, but also how neuronal plasticity can introduce individual variations in the engagement in this behaviour. Overall three complementary goals will be addressed. - We will characterize neural networks associated with these two specific behaviours and seek to identify the substrates differentiating the brains of two individuals at the level of the long-range connectivity in the key circuits controlling these behaviours. - We will explore the idea that adult plasticity can be a source of behavioural variability leading to individuation. We will combine next-generation whole brain imaging methods with RNA-sequencing of the neurons involved in variable behaviours. This will shed a light on whether variations in the transcriptome of these neurons point to molecular changes affecting their excitability, synaptic transmission or structural connectivity. - Finally, in the “Souris-City” we will build a predictive model of nicotine addiction based on the interface of precise, automated behaviour recordings, whole brain activity mapping and axonal tracing of key circuits involved in nicotine response. This will determine which individual differences in neural structures could underlie different susceptibilities to nicotine. Our work program spans technological development, automated behavioural analyses, electrophysiology, projection mapping and activity-dependent transcriptome analysis in mouse. Each member of this consortium brings unique complementary areas of technical expertise as well as converging theoretical interests to generate data that support a Systems Biology approach to understanding the mechanisms of individuation. This approach challenges the classical view that brain circuits are rigids after the closing of the developmental embryonic and post-natal critical windows, and puts forward alternative ways mouse models for neuropsychiatric disorders are phenotyped and facilitate screening for novel treatment strategies.