DOSE DEFINES FUNCTION: IL-1 SIGNALING DIFFERENTIALLY REGULATES ADULT HIPPOCAMPAL NEUROGENESIS MODULATING POTENTIAL THERAPEUTIC OUTCOMES IN NEURODEGENERATIVE DISEASES

Adult hippocampal neurogenesis (AHN) is the process by which neural stem cells (NSCs) in the dentate gyrus (DG) generate new granule neurons that integrate into hippocampal circuitry and support learning and memory. AHN is highly sensitive to inflammatory signals, including interleukin-1 (IL-1), a proinflammatory cytokine implicated in both normal brain function and neurodegenerative disease. IL-1 signals through interleukin-1 receptor type 1 (IL-1R1) and contributes to neuroprotection and synaptic remodeling, yet its role in AHN remains incompletely understood. Using transgenic mouse models with cell type–specific IL-1R1 expression, we examined how IL-1 signaling regulates AHN. Adeno-associated viral vectors encoding IL-1 or GFP were stereotaxically delivered to the DG of ten-week-old male and female mice, enabling precise spatial and dose control. One week after injection, mice with global IL-1R1 expression exhibited a dose-dependent response: low-dose IL-1 enhanced NSC proliferation, whereas high-dose IL-1 suppressed neurogenesis and induced neuroinflammation, modeling features of neurodegenerative pathology. Inhibition of IL-1 signaling via adeno-viral delivery of an IL-1 receptor antagonist reduced NSC proliferation, confirming the requirement for physiological IL-1 activity. In contrast, IL-1R1 knockout mice showed no changes in NSC proliferation following IL-1 administration. Strikingly, selective expression of IL-1R1 in astrocytes was sufficient to restore the pro-neurogenic effects of low-dose IL-1, identifying astrocytes as key regulators of the neurogenic niche. Retroviral labeling revealed increased numbers of newborn neurons one month after IL-1 treatment, with ongoing analyses assessing dendritic complexity and functional integration. Our findings position IL-1 as a relevant modulator of AHN, underscoring its therapeutic relevance in neurodegeneration.