Abstract: Maintaining average activity level within a set-point range constitutes a fundamental property of central neural circuits. Accumulated evidence suggests that mean firing rate (MFR), reflecting an average level of spontaneous spiking activity over extended timescales, represents a physiological variable regulated by homeostatic systems in central neural circuits. However, some central questions have remained open. What are the mechanisms that establish the specific values of MFR set-points? Are MFR set-points depend on brain states? Are set-points dysregulated in Alzheimer’s disease (AD) and whether this dysregulation is state-dependent? Integrating large-scale in vivo imaging of neuronal calcium dynamics and electrophysiology in distinct mouse models bearing familial AD mutations, we identified silent features of hippocampal circuits at the presymptomatic stage of the disease, before cognitive dysfunctions become evident. I will present our new data on the role of brain states in physiological regulation of CA1 activity set-points and their dysregulation at the early stages in AD models.