Our survival depends on motivated states that underlie defensive, ingestive and reproductive behaviour. A critical ingredient of motivated states is arousal. It is not clear, however, through which circuits arousal is recruited to enable motivated behaviours. We are studying the systems regulating food intake to characterize this network. Ascending neurones in the hypothalamic arcuate nucleus (Arc) act as sensors of the supply and demand of energy of the body. One of the targets of the Arc are the hypocretin/orexin (H/O) neurones in the lateral hypothalamus (LH), which are critical for maintaining the awake state. In order for H/O cells to regulate vigilance state, they need to influence network activity in the cerebral cortex, the electrophysiological correlate of sleep and wakefulness. While such effects can be relayed through brainstem and hypothalamic arousal systems, the possibility of direct, cortical H/O actions has received relatively little attention, even though there is a prominent innervation from the LH to the cortex. This issue was investigated electrophysiologically in ferret prefrontal cortex slices that spontaneously express the sleep-associated slow oscillation, a < 1Hz EEG rhythm, characterized by alternating depolarized UP and hyperpolarized DOWN states. In the presence of H/O, the frequency of the slow oscillation increased reversibly, dose-dependently, and in many cases transformed into the continuous, tonic firing, typical of the awake state. The cellular mechanisms underlying the network effects included broad presynaptic excitation of pyramidal cells, but postsynaptic actions were seen only in layer 6b neurones (similar to Bayer et al., J. Neurosci; 2004). Thus, global, intra-cortical effects of H/O may directly influence core phenomena of sleep and will be discussed in relationship to our recent findings of similar actions by the neuropeptide thyrotropin-releasing hormone.