Despite the presence of various behavioural/cognitive activities during wakefulness (W), this vigilance state has long been regarded as relatively homogeneous and defined on the cortical EEG as a low voltage and fast activity. Recent studies have shown, however, that cortical oscillation and neuronal properties undergo major changes from quiet to active W. We hypothesize that each brain arousal system exerts a distinct control of different behavioural contexts of W and have investigated using knockout (KO) mouse models the role of histamine (HA) and orexins (Ox), two W-promoting systems of the posterior hypothalamus, in controlling W during different behavioural situations such as locomotion, exploration, motivation, anticipation and sexual arousal.
We found that 1) Ox KO but not HA-deficient mice showed impaired W when they were subjected to a voluntary wheel test, indicating that Ox but not HA promotes W by enhancing locomotion. 2) HA-deficient mice were unable to remain awake in a new environment while Ox KO mice preserved their W enhancement. 3) In a test of motivation, wild type (WT) and Ox KO mice were motivated enough to catch difficult-to-reach palatable food and maintained highly awake, while HA deficient mice, though interested by the food, made no effort to catch it and slept as usual. The two last tests show that as compared to Ox, HA is more involved in the cognitive aspects of W. 4) When WT mice were fed with a predictable restricted schedule (11am-17pm) instead of ad libitum, they developed an anticipatory W of 70±9 min before the meal time. This anticipatory W was significantly reduced in Ox KO or HA- deficient mice. Moreover, Ox KO, but not HA-deficient mice exhibited W deficit during the feeding period. Finally, anticipatory W disappeared in double KO mice lacking both HA and Ox; 5) In sexual arousal test, defined as an increased W in a male mouse facing a female, acute inhibition of HA synthesis or antagonism of Ox1-receptor abolished sexual arousal while this function was maintained in Ox KO or HA-deficient mice, indicating a compensation under long term loss of HA or Ox. This compensation became ineffective when both HA and Ox were deficient as sexual arousal was absent in KO mice lacking both HA and Ox.
These data indicate that the regulation of W is context- dependent and support our hypothesis according to which, W is a heterogeneous state with multiple faces. Each arousal system contributes complementarily and synergistically to the maintenance of cortical activation during W, while in different behavioural and cognitive contexts, their individual participation and specific functional role are distinct.

Jian-Sheng LIN, CRNL/Waking