Nervous systems maintain information internally using persistent activity changes. The mechanisms by which this activity arises are incompletely understood. We study prefrontal cortex (PFC) in mice performing behaviors in which stimuli predicted rewards at different delays with different probabilities. We measure membrane potential (Vm) from pyramidal neurons across layers. Reward-predictive persistent firing increases arise due to sustained increases in mean and variance of Vm and are terminated by reward or via centrally generated mechanisms based on reward expectation. Other neurons show persistent decreases in firing rates, maintained by persistent hyperpolarization that is robust to intracellular perturbation. Persistent activity is layer (L)- and cell-type-specific. Neurons with persistent depolarization are primarily located in upper L5, whereas those with persistent hyperpolarization are mostly found in lower L5. L2/3 neurons do not show persistent activity. Thus, reward-predictive persistent activity in PFC is spatially organized and conveys information about internal state via synaptic mechanisms.