The nervous and the immune systems undergo a continuous cross talk, starting from early development and continuing throughout adulthood and aging. Defects in this cross-talk contribute to neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the brain and are primarily involved in this bidirectional communication. During brain development, microglia control several key processes, including neurogenesis, myelin formation and synapse homeostasis. We have obtained indications that during the early postnatal period, microglia direct the genetic signature of specific subgroups of hippocampal neurons, shifting them toward defective metabolic and developmental patterns. This process is controlled by the microglial Triggering receptor expressed on myeloid cells 2 (Trem2), a gene associated to Alzheimer’s Disease. We hypothesized that, by causing imbalances during early maturation phases, dysfunctional Trem2 may have a striking impact on the adult brain, making it a more sensitive target for insults occurring during adulthood and aging. The present project, MATILDA, aims to address this possibility. We will map the hippocampal energetic profile on a single-cell basis, in the presence of proper or defective Trem2 expression and we will define through which mechanisms microglia and Trem2 control the neuronal transcriptomic phenotype. Once settled all methods, we will move to the hypothalamus, where the brain areas orchestrating the body energy homeostasis reside. Owing to the presence of transcriptionally heterogeneous neuronal subtypes and to a vast range of non-neuronal cells regulating systemic metabolism, food intake, and body weight, the hypothalamus represents a key structure to investigate the functional interaction of microglia with specific cell types and the outcomes of its dysregulation. We expect to identify novel mechanisms potentially contributing to metabolic decline, offering potential for new therapeutic strategies that could reverse immune-metabolic dysfunctions by modulation of hypothalamic microglial function.
