Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. Chronic stress modify microglia cell morphology enhancing their phagocytic activity and pro-inflammatory phenotype. Hampering neuron-microglia communication, (i.e via the CX3CR1-CX3CL1 pathway) prevents the effects of chronic unpredictable stress on microglial function, neuronal plasticity and depressive-like behaviour suggesting that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression (MD). However, the role of these brain immune cells in mediating the effects of stress is still unclear. The present project aim to elucidate the role of microglia in mediating the effects of stress on synaptic dysfunction and vulnerability to MD through a multidisciplinary and integrated approach, ranging from electrophysiological and molecular to behavioral and imaging phenotyping, across various levels of analysis, from cell to mouse models and human sample. To this purpose microglia responses to chronic stress will be investigated by: (i) analyzing the interplay between the hypothalamic-pituitary adrenal (HPA) axis and microglia cells using a new mouse line engineered to display a specific silencing of the glucocorticoid receptor (GR) gene in microglia and (ii) a pharmacological approach based on minocycline treatment to inhibit microglia cells. In addition, microglia human cell obtained by adult patients who will undergo surgery operation will be characterized, cultured and tested for their ability to respond to cortisol. Overall, the proposed experiments will highlight the microglia involvement in stress responses and in synaptic dysfunction that leads to vulnerability to psychopathologies, such us MD.
The project exploits a multidisciplinary approach and has a potential translational relevance. The added value of the collaboration lies in the complementary expertise of the researchers involved, in terms of technical and conceptual approaches, ranging from electrophysiological and molecular to behavioral and imaging phenotyping, across various levels of analysis, from cell to mouse models and human sample. Preclinical studies have been planned according to statistical considerations about power analysis to maximize the achievement of reliable results. In addition, the project is designed to minimize risks and enable collaboration across partners from the beginning; i.e. the research is truly integrated from conception and not just bringing together individual projects at the end. The different groups involved in the proposal already have ongoing collaborations, (i.e. Maggi, Tremblay and Branchi; Maggi and Di Castro; Maggi and Fucile) and already produced results published in international scientific journal. At present, all partners possess the Ministerial authorization to use the mouse line indicated in the proposal. This will give them the possibility to conduct parallel experiments and to facilitate data and discussion exchanges.
By performing building a knowledge chain from molecular/cellular/electrophysiological and imaging techniques to the analysis of the behavior and the characterization of phenotypic human microglia, the project will help in the identification of new promising leads for pharmacological treatment of MDD. They will also be a step of major importance for the future development of innovative cell therapies controlling the effector functions of microglia and their consequences on synaptic function, first in mice, subsequently in human. By preventing the substantial elimination of non-targeted (or mis-targeted) brain circuits during stress, such therapies will allow to bypass the default progression of pathology or immune reaction to stress, when a more oriented, information-based, and personalized intervention is medically required.
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