Microglial control of synaptic function in stress response and vulnerability to depression

Proponente Laura Maggi - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Sergio Fucile Componenti il gruppo di ricerca
Maria Amalia Di Castro Dottorando/Assegnista/Specializzando componente il gruppo di ricerca
Componente Qualifica Struttura Categoria
Igor Branchi ricercatore ISS, Roma, Italia Altro personale Sapienza o esterni
Marie-Eve Tremblay ricercatore Centre Hospitalier de l'Université Laval (CHUL) , Québec CANADA Altro personale Sapienza o esterni
Giusi Chece tecnico scientifico Dip. Fisiologia e Farmacologia, Sapeinza Altro personale Sapienza o esterni

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.


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