Maintaining average activity level within a set-point range constitutes a fundamental property of central neural circuits. Accumulated evidence suggests that firing rate distributions and their means represent physiological variables regulated by homeostatic systems. Utilizing basic concepts of control theory, we developed a theoretical and experimental framework for identifying the core members of homeostatic machinery. I will describe an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations in local microcircuits, synaptic transmission and plasticity, sleep and memory functions. I will show our new data on a state-dependent regulation of firing rate set-points, their dysregulation at the presymptomatic stage of Alzheimer’s disease, and the role of mitochondria in these processes.