Visual confidence refers to our ability to estimate the correctness of our visual perceptual decisions. As compared to other forms of metacognition, meta-perception has attracted a burst of studies recently, no doubt because perception already benefits from strong theoretical frameworks. We have recently refined these existing frameworks by proposing to clearly distinguish sensory evidence from some “confidence evidence” that drives the confidence decision. The problem now is to characterize the properties and consequences of this confidence evidence, and this is the aim of the present proposal. As the number of studies grows, it becomes clear that visual confidence is not simply a noisy estimate of the perceptual decision, but instead depends on a large number of factors. We have identified four axes that we believe will contribute to shape confidence evidence: (1) individual variability, (2) task accessibility, (3) global confidence, and (4) perceptual learning. The purpose of the first axis is to understand which cues are used for confidence, and for this purpose, we will study confidence variability across individuals. Some of the idiosyncratic variability in confidence judgment efficiency might come from a variable temptation to exaggerate the impact of stimulus noise on the estimation of one own performance. In the second axis, we will try to understand what in a task determines the accessibility to visual confidence. In particular, we will test the hypothesis that more high-level tasks, such as face identification, lead to better confidence efficiency that low-level tasks, such as detecting whether two line segments are aligned. The aim of the third axis is to understand how individuals construct a sense of confidence for a task as a whole, not for a single isolated judgment. We will start by carefully studying how confidence builds up within a set of stimuli and compare how such a global confidence compares with a single decision confidence. Finally, in the fourth axis, we will study how perceptual learning benefits from visual confidence. In particular, we will test the extent to which confidence evidence can be seen as an internal error signal that can act as a proxy for an external feedback. We believe that a better understanding of these four fundamental aspects of confidence evidence will help us derive an accurate and useful model of visual confidence, and ultimately of metacognition.

Neurons have a very complex and dynamic morphology, which is believed to hold the key to understanding the ability of the mammalian brain to process and store huge amounts of information. While the branching patterns of dendrites are largely stable over the lifetime of an animal, neuronal synapses are highly plastic and constantly subject to activity-dependent remodelling, which may be an important substrate of learning and memory. However, regular 2-photon microscopy does not have enough spatial resolution to properly visualize functionally crucial details of spine and dendrite anatomy; in many instances it even fails to distinguish individual spines, leading to serious errors in reporting their density and dynamics. Hence, our insights into the complexity and plasticity of these nanoscale structures, let alone their impact on synaptic signalling, circuit function and ultimately animal behaviour, remain fragmentary and circumstantial. While the concept of dendritic spines as distinct anatomical and biochemical compartments is firmly established, there is little consensus on whether and how spines influence electrical signaling. Evidence indicates that spine size correlates with quantal synaptic currents, but very little is known about the amplitude and time course of the voltage deflection in the spine during a synaptic event and how this voltage might be boosted by the activation of ion channels as it spreads into the dendrite and towards the soma. However, such knowledge is absolutely essential for understanding how synaptic activity from across many synapses is integrated by the dendritic tree and converted into postsynaptic spiking. Even less is known about how spine and dendrite morphology, in particular the spine neck, exerts electrotonic amplification and filtering of synaptic voltages, which has been a long-standing question in the plasticity field, because structural changes may represent a powerful mechanism for tuning synaptic potentials, encoding synaptic memory and influencing higher integrative functions of dendrites and circuits. Our objective is to close the knowledge gap between nanoscale neuronal morphology and postsynaptic integration of synaptic potentials within a relevant behavioral context using an array of cutting-edge experimental techniques and mathematical modeling. Our approach will overcome the technical bottlenecks that impeded the measurement of rapid voltage signals inside small compartments and visualization of neuronal morphology with sufficiently high spatial resolution in live tissue. The consortium brings together research teams with strong and complementary expertise in STED microscopy and synaptic plasticity (Partner 1: Nägerl), dendritic integration and voltage-sensitive dye (VSD) imaging (Partner 2: DiGregorio), in vivo electrophysiology of hippocampal neurons (Partner 2: Schmidt-Hieber), and biophysical modeling and numerical simulations (Partner 3: Cattaert), using acute slices and intact brains in vivo as experimental preparations. Our overarching hypothesis is that nanoscale features of neuronal morphology (like spine necks and dendritic constrictions) and their spatial distribution in the dendritic tree exert a powerful influence on postsynaptic electrical signalling, shaping postsynaptic potentials in the spine head and their dendritic integration, which ultimately influence the neuronal representations of space. Specifically, through this proposal (NanoDend) we will 1) identify the nano-anatomical dendritic motifs that might underlie non-linear dendritic integration, 2) investigate the influence of spine morphology on spine and dendritic potentials and plasticity, and 3) establish the anatomical principles that influence nonlinear dendritic integration and place field formation.

Alzheimer's disease (AD) is a devastating disease and there is an urgent need to better understand the factors which promote this disease and to develop novel ways of prevention. Infectious agents, among them viruses, may foster the development of the main hallmarks of AD, including the promotion of neuroinflammation, amyloid deposit and phosphorylated Tau. Several viruses have already been implicated in AD pathology, among them the Herpes viruses are promising candidates. However, the mechanisms by which viral infections increase AD are still poorly understood. Beyond, only few viruses have been investigated. A global approach, without focus on a specific virus, may help identifying other viruses, allowing opening new ways of prevention. We hypothesize that, as the immune system weakens with age, viruses could migrate to the central nervous system and trigger or favor the development of AD. Our project aims at investigating the viral hypothesis in AD: 1/ by targeting specific herpes viruses that have been previously suspected (HSV1 and HHV6); 2/ and by studying all the viruses that an individual may have encountered in his/her lifetime. This project will use an agnostic approach studying numerous potential viruses and their interactions, thanks to the innovative Virscan technology, which allows detecting the exposition to more than 200 viral species with 1000 different strains. It will leverage large population-based cohorts: the 3C-Bordeaux cohort with up to 14 years of follow-up of an elderly population (n=1300, 65y +) with repeated clinical assessments; and the Biobank and Brain Health in Bordeaux (B3), with multi-sequence brain MRI among 500 senior adults aged 55-70y, including innovative brain imaging technology for neuroinflammation. The long follow-up period in 3C will allow the identification of viral infections long prior to clinical signs. The younger population in B3 will allow exploring the link between viral infections and early neuropathological stages, long before the appearance of clinical signs, when lesions may still be reversed by early treatment. Moreover, thanks to the wealth of data available in these cohorts we will explore the individual susceptibility factors to infections that could explain why only some infected people will develop AD pathology. This project is organized in 5 Work Packages. The WP1 aims at assessing viral exposure history of participants from the 3C and B3 cohorts. The WPs 2 and 3 aim at evaluating the associations between viral exposure history and neuropsychological and clinical markers of AD (in WP2) and brain imaging markers (in WP3), in the 3C cohort. In WP4 we will perform multi-modal brain MRI, with multi-compartment diffusion imaging indices from quantitative magnetization transfer for neuroinflammation, in participants from the B3 cohort; it will allow identifying new viral exposures involved in early brain alterations and neuroinflammation. WP5 will be devoted to the management of this project. To our knowledge, this project will be the first to evaluate the involvement of numerous viral infections on clinical and imaging outcomes of AD using prospective data over a very long period. It will allow establishing whether, when, and among whom viruses affect AD risk, and which viruses are involved. Thus, by deciphering the infectious mechanisms in AD, the VirAlz project may allow opening new ways of prevention of cognitive decline and dementia, by targeting at-risk individuals and fighting viral agents and/or their consequences.

The autonomic nervous system (ANS), that regulates involuntary body functions divides into the parasympathetic (PANS) and sympathetic nervous system (SANS). The output from the SANS is through sympathetic preganglionic neurons (SPNs) lying in the thoracolumbar part of the spinal cord (SC). Highly specialized neurons, the cerebrospinal fluid-contacting neurons (CSF-cNs), present around the central canal in the spinal cord, have been recently described as a novel sensory system intrinsic to the central nervous system. Based on our preliminary data unrevealing synaptic connections between SPNs and thoracic CSF-cNs, we propose to shed light on a possible complex circuitry between CSF-cNs and SANS neurons involved in sensing metabolic changes and maintaining homeostasis. For this purpose, we will combine electrophysiological recordings, optogenetic stimulations and in vivo non-invasive recordings of blood pressure and heart rate in mice.

Context- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motoneuron (MN) disease. ALS is considered as a protein misfolding disorder, accompanied by neuroinflammation that accelerates MN cell death and disease progression. To date, the absence of both biomarker discovery and key cellular mechanism identification impairs the elaboration of effective treatments of ALS. Alterations of the purinergic signaling are involved in the pathogenesis of several neurological diseases with a pivotal role for P2X4 receptors. P2X4 is an ATP-gated cation expressed in CNS neurons and glial cells as well as in peripheral tissues such as macrophages, monocytes in mammals including humans. In the healthy organism, P2X4 is constitutively internalized and as a result, is found preferentially in intracellular compartments where it may have intracellular functions. In contrast, in various diseases such as chronic pain, ischemia and neurodegenerative diseases including Alzheimer Disease (AD) and ALS, surface P2X4 receptors are upregulated by mobilization of intracellular pools and/or de novo expression in glia or neurons. We have recently shown using P2X4 knock-out or our novel upregulated P2X4 knock-in mice, that P2X4 are instrumental for ALS pathogenesis and lifespan in a murine model of ALS, the SOD1 mice. In addition, we found that P2X4 surface trafficking is increased in both spinal MNs and microglia but also in peripheral macrophages in SOD1 mice compared to wild-type animals at pre- and symptomatic phases. Hypotheses- Our data suggest that ATP and P2X4 receptors are attractive novel targets for understanding and fighting the ALS disease. Our innovative hypothesis, validated by our data is that misfolded protein accumulation in ALS such as mutant SOD1 proteins interferes with the internalization of P2X4 and leads to an increase in surface P2X4, first in spinal MNs and second in microglia during ALS. The increase in surface P2X4 in peripheral macrophages of SOD1 mice at pre-symptomatic phase leads to our second hypothesis: aberrant P2X4 expression in blood cells may represent a marker of ALS before the symptom onset. Our data show that surface/total ratio of human P2X4 can be measured by FACS analysis from peripheral blood of ALS patients. Objectives- We propose using innovative transgenic mice and blood samples from ALS patients by behavioral, cellular, functional and biochemical approaches to: 1) unravel the cell-specific function of P2X4 in ALS pathogenesis, vulnerability of MNs, and neuroinflammation in SOD1 mice expressing conditional either knock-in non-internalized P2X4 (cP2X4KI) or knock-out for P2X4 selectively in macrophage/microglia or neurons and to determine how and when P2X4 can serve as therapeutic targets. 2) to make the proof of concept that detection of aberrant surface expression of human P2X4 in serum-derived macrophages from patients with ALS can serve as an early biomarker of the disease. 3) generalize the mechanism of P2X4 upregulation in several ALS models. 4) screen by functional assay in vitro the impact of several nanobodies on the function of human P2X4 or murine P2X4. Nanobodies modulating human P2X4 function may represent novel innovative drugs that could improve the patients’ quality of life by delaying the progression of ALS. Impact- Our project fits very well within the orientation of CE 17- translational research in Health and the priority axis towards rare diseases. The medical and scientific complementary expertise of our consortium belonging to Bordeaux Neurocampus and the ALS reference center of Bordeaux should allow us to i) provide attractive novel strategy and cellular targets to fight against this devastating neurodegenerative disorder; ii), define P2X4 as a useful biomarker for ALS patients and develop a method for P2X4 detection from human peripheral blood; iii) identify new innovative drugs with the screening of camelid nanobodies.