The concept that astrocytes are actively involved in neural development, synapse formation and synaptic activity in the healthy brain has emerged during the last 15 years. In the diseased brain, such as in Alzheimer’s Disease (AD), we are just starting to probe whether dysregulated astrocytes significantly contribute to the pathology. Neurofibrillary tangles, made of hyperphosphorylated and aggregated Tau proteins, are an essential pathological neuronal feature of the AD brain. In the latter, progression of neuronal « Tau pathology », scored as the Braak stages, from entorhinal cortex to hippocampus and lastly neocortex, is associated with progression of clinical symptoms supporting a pivotal contribution of neuronal Tau pathology to cognitive deficits. Mechanisms for Tau pathology-induced cognitive deficits in AD remain poorly understood and most studies focus on neuron-autonomous dysregulations. Conversely, relationships between neuronal Tau pathology and astrocytes remain largely unknown. Our preliminary observations raise the hypothesis that neuronal Tau pathology induces astrocyte dysfunctions, possibly through a Tau transfer from neurons to astrocytes. In addition, we recently identified adenosine A2A receptors (A2ARs), G-protein-coupled receptors whose endogenous ligand is adenosine, as a mediator of these interactions between neuronal Tau pathology and astrocytes. In this context, our overall objective is to uncover the impact of neuronal Tau pathology towards astrocyte function and establish astroglial A2ARs as druggable regulators of the development of Tau pathology and associated memory deficits. We will explore this link using several mouse models combined with innovative viral methods and functional tools to specifically address several questions in FACS-sorted acstrocytes, regarding astrocyte morphology and activity, as well as modifications of astrocytic transcriptome and epigenome. Specifically, we will 1) evaluate whether and how neuronal Tau pathology affects astrocyte function including chromatin structure and gene profiles and 2) establish astrocyte A2A receptors as a druggable switch of Tau-induced astrocyte dysfunction. To achieve our goals, we have assembled the unique ADORASTrAU consortium which brings together three research teams sharing a common interest towards AD pathophysiology, with highly complementary, non-overlapping and non-interchangeable scientific expertise. Our project will provide original insights in the mechanisms by which Tau pathology impacts the function of astrocytes and determine to which extent adenosine A2A receptors could be a molecular switch of Tau-induced cognitive dysfunctions.

Coherent oscillations of neuronal activity, ubiquitous across brain scales, would play core roles in information transfer and processing. Oscillatory coordination is implicated in the formation of sensory or behavioral representations, or in the flexible routing of information between neuronal populations as suggested by both experiments and theory. In the hippocampal formation, theta (θ) oscillations during exploration behavior provide a reference for phase-coding of place sequences while coherence in different gamma (γ) frequency sub-bands temporally segregates information originating from different sources. Furthermore, behavior also correlates with dynamic coherence between hippocampus and other cortical regions. Altogether, these and other findings establish θ-γ oscillatory dynamics in the hippocampus and its broader networks as a signature for computations underlying spatial navigation and, more generally, episodic and spatial memory. Beyond the healthy brain, these key cognitive functions are particularly disrupted in pathologies like neurodegenerative diseases and dementias, with disruptions of hippocampal oscillatory dynamics correlating with behavioral and cognitive degradation before any detectable classical histopathological alterations in animal models of AD. In humans as well, hippocampal functional connectivity is disrupted at early preclinical stages in relation with cognitive decline, revealing alterations of long-range oscillatory coordination linked to pathology. It remains an open question whether these changes in coordinated neural dynamics are a consequence of neurodegeneration or one of its causes. Beyond the advancement of neurodegeneration, it is likely that the degradation of structured neural dynamics has a direct mechanistic impact on the emergence of functional impairments. This hypothesis has major implications. First, designing neuromarkers which faithfully track deviations from “healthy” neural dynamics may lead to earlier predictions about the evolution of deficits. Second, being able to intervene on dynamics could eventually slow or even invert the evolution of cognitive and behavioral impairments, by acting on the “software” –local neural codes and global routing/interfacing processes (mediated by multi-scale oscillatory coordination, refitted to be closer to non-pathological trajectories)– rather than on the “hardware”, i.e. the integrity of structural circuits. HippoComp will rely on a synergy between electrophysiological recordings (single units and LFPs at the meso-scale of hippocampus; EEG at the macro-scale of whole cortex), machine-learning approaches and non-linear time-series and temporal multiplex network analyses to fulfill the following general aims: i) deepen our general understanding of how complex oscillatory dynamics at multiple scales mediate coding and computations relevant to behavior and memory function; ii) to identify alterations of oscillatory-mediated information processing that translate since early AD pathology stages into functional impairments; and, iii) to show that manipulations (visual gamma stimulation, vGENUS) that preserve/restore function in AD do so by acting to restore a “healthy” oscillatory dynamics (and the associated organization of neural computations). Explicitly pursuing these aims requires a radical redefinition of analyses approaches to the study of the relations between oscillations, oscillatory coherence and behavior and cognition. Notably, we will shift emphasis from well-behaved average oscillatory properties to the haphazard and apparently random-like spectrum of transient oscillatory events, ongoing “in real time” in parallel with actual behavior, to show that such complexity, usually averaged out as noise, may be a needed resource for efficient neural information processing.

In CHARM, we will characterize the role of the thalamic reuniens and rhomboid nuclei (ReRh) in systems consolidation of a spatial memory by establishing 1) When, during the consolidation period, ReRh are involved, 2) How ReRh regulate the reorganization of the memory trace between the hippocampus (HPC) and the medial prefrontal cortex (mPFC), and 3) Which pathways within the HPC-ReRh-mPFC circuit are specifically recruited. The system consolidation of episodic memories is a dynamical process that requires a dialogue between the HPC and the mPFC, mostly during sleep. Although the HPC establishes direct anatomical contacts with the mPFC, there is no direct return pathway. Thus, other brain regions appear necessary for the HPC-mPFC dialogue to occur. The ReRh are ideally placed to enable such a dialogue since these nuclei are an anatomical hub reciprocally connected to the HPC and mPFC, and their lesion/inactivation prevents memory persistence. However, when and how ReRh enable the transfer of information is not yet known. We will address these questions using a combination of behavioural, viral vector-mediated disconnections, pharmacogenetics, and state-of-the-art in vivo electrophysiological approaches in rats. We will reach three objectives: 1) Establish when the hippocampal-cortical dialogue comes into play in order to consolidate a memory at the systems level, and the temporal window during which the ReRh intervene using pharmacogenetics. 2) Evaluate how ReRh regulate the hippocampal-cortical dialogue through the synchronization of oscillations and the recruitment of neuronal assemblies using in vivo recordings. 3) Determine which pathway(s )in the hippocampal-thalamo-cortical network is (are) involved in the consolidation process with selective disconnections. CHARM is designed to elucidate how the ReRh enable the consolidation of episodic memory supported by a hippocampal-cortical dialogue. This information will be instrumental for the study of episodic memory deficits, which are common to most, if not all, neurological disorders, as well as during normal aging.

Chronic eye pain causes a real deterioration in the quality of life of patients, since it is estimated that nearly 60% of patients are hampered in their daily activities. The burden of ocular pain is generally associated with emotional comorbidities and psychosocial alterations. In patients with Dry eye disease (DED), clinical observations demonstrate higher immune cell density and severe alterations in corneal nerves, leading to peripheral sensitization that may induce central sensitization mechanisms responsible for the chronicization of ocular pain. To date, there is no effective medication for chronic eye pain. Thus, a better understanding of the inflammatory and neurogenic mechanisms involved in chronic ocular pain resulting from DED is a crucial issue for the development of new therapeutic strategies. The aim of this proposal is to evaluate the therapeutic relevance of blocking chemokine receptors (Ccr2 and/or Cx3cr1) to relieve chronic corneal neuralgia. This interdisciplinary project brings together two areas of research: neuroscience and immunopathology. The objective is to define the functional role of chemokines in the interactions between immune cells (macrophages, microglia) and sensory neurons and their implications in the mechanisms of initiation and chronicization of pain. Ultimately, this project using state-of-the-art technologies (FACS and multicolor flow cytometry, confocal microscopy, multi-photon, electrophysiological recording) will provide justification for the use of Ccr2 and Cx3cr1 antagonists as a treatment for chronic ocular pain.