FALSELIFE addresses what is often described as one of the most fundamental issues in cognitive psychology, namely the relations between working memory (WM) and long-term memory (LTM). The WM-LTM relations are at the heart of human cognition because they sustain how we are able to learn new knowledge and skills, to use previously acquired knowledge, and to maintain autonomous daily life functioning. FALSELIFE addresses this challenge from an innovative perspective by examining the role of WM in the formation of false memories. False memory is well-established LTM phenomenon in which semantically related associates are confidently and falsely remembered as studied items (e.g., Roediger & McDermott, 1995). However, this false memory effect was observed at short delays as well (e.g., Atkins & Reuter-Lorenz, 2008). Recently, we put forward a new theoretical account emphasizing the crucial role of WM maintenance in the emergence of short and long-term false memories (Abadie & Camos, 2018). FALSELIFE’s objective is to better understand the mechanisms underlying false memories by examining how they change across the lifespan. Drawing on our theoretical account, I propose an ambitious and original programme of lifespan studies investigating the role of WM maintenance mechanisms in short and long term false memories. FALSELIFE’s first aim is to examine the formation of false memories from a developmental perspective by comparing false memories in older children that spontaneously use WM maintenance mechanisms and younger children that do not yet use any maintenance strategies (Work Package 1). FALSELIFE’s second aim is to investigate the effect of age-related decline in WM maintenance on the occurrence of false memories (Work Package 2). FALSELIFE has the potential to offer new methods to help people at all stages in childhood and adulthood to resist memory distortions by improving WM maintenance and maximizing verbatim accessibility.

Heart failure with preserved ejection fraction (HFpEF) is the most rapidly increasing form of heart failure in the Western world. Despite high public-health importance, no treatment strategy has yet been established to reduce morbidity and mortality. MINOTAUR is a multidisciplinary consortium of cardiologists, cardiac surgeons, systems biologists, biophysicists, biochemists and physiologists aimed at expanding our original observations that a natural caloric restriction mimetic (CRM) improves diastolic function in two different animal models with independent HFpEF risk factors, namely age and hypertension. To investigate the broader applicability of CRM treatment and its translational potential, we will extend our investigations to an animal model of HFpEF induced by metabolic syndrome, the most prevalent cause and comorbidity of HFpEF. We will concentrate our efforts on the mechanistic details by which CRMs counteract the development of HFpEF with metabolic dysfunction. Using a wide range of state-of-the-art techniques, we will provide a comprehensive in-depth characterisation of the CRM-treated HFpEF cardiac phenotype at the molecular, cellular and whole organism level, and considering the gender aspect. Gender-based correlation analysis of key biochemical parameters (polyamine levels and post-translational modification of titin) and diastolic dysfunction in humans will reveal new diagnostic and prognostic tools in HFpEF. This novel information will feed future clinical trials to evaluate the potential of CRM-rich diets as an effective therapy for managing HFpEF.

Lymph nodes (LN) are prototypical lymphoid organs where adaptive immune responses against local infections are initiated. It has become well established that peripheral dendritic cells (DC) arriving from afferent lymphatic vessels in the subcapsular sinus (SCS) migrate via the interfollicular areas (IFA) into the paracortical T cell zone. There, DC present processed protein antigen in the form of peptide-major histocompatibility complex (pMHC) to naive T cells for the initiation of cellular responses. This process has been exhaustively studied. Yet, IFA are strongly enriched for cells of the innate immune system such as gamma-delta T cells, innate-like CD8+ T cells, natural killer T cells (NKT), innate lymphoid cells (ILC), natural killer (NK) cells, macrophages and neutrophils. The physiological function of this multicellular innate system has been assigned to limit pathogen spread by fostering antimicrobial activity of macrophages and stromal cell-mediated repair processes. To date, however, it is unknown how the specific IFA niche for innate immune cells is created and maintained by the stromal microenvironment. Further, it remains unclear whether and how a microbial challenge impacts on innate cells of the IFA-resident multicellular immune system and their cross-talk with cells of the adaptive immune system. The team of C. Mueller, partner in this project, has recently demonstrated that LN stromal mesenchymal cells located just beneath the SCS express the TNF family member TNFSF11 (also known as RANKL) to activate the overlaying TNFRSF11a+ (RANK+) lymphatic endothelial cells (LEC). This creates a specific niche for the recruitment and retention of sinusoidal macrophage (SM) populations. Deletion of mesenchymal RANKL or lymphatic RANK precipitates the loss of SM, with a concomitant impairment of humoral immune responses. In addition, LEC lose their activated phenotype, which leads to altered expression of numerous immunoregulatory genes. These include chemokine scavenging receptors and the chemoattractants CXCL4 and CCL20, which are known to attract and/or retain cells of the innate immune system. An attractive hypothesis is therefore that the RANKL-RANK signaling axis linking LN mesenchymal cells and LEC orchestrates the establishment and maintenance of the multicellular innate immune system of the IFA. Here, we will combine transgenic mouse lines with disrupted RANK and CSF-1 signaling in combination with reporter mouse lines for innate immune cells to critically examine the role of LEC in establishing the innate immune system in IFA. To this end, we will employ multiplex immunofluorescence in combination with whole-organ and intravital imaging, flow cytometry, as well as single cell and spatial transcriptomics of the IFA niche in the steady state and after microbial challenge. We will use this knowledge to examine how activated LEC and the innate immune system of the IFA regulate adaptive immunity during a microbial challenge. From these data, we anticipate to unravel the complex cross-talk balancing innate and adaptive immune responses in reactive LN, which may eventually lead to specifically-tailored vaccination strategies.