The idea that the performance of complex behaviors depends on arousal levels was formulated fifty years ago

The idea that the performance of complex behaviors depends on arousal levels was formulated fifty years ago by Donald Hebb [1] in a landmark paper of behavioral neuroscience. As Hebb wrote: “Physiologically, we may assume that cortical synaptic function is facilitated by the diffuse bombardment of the arousal system. When this bombardment is at a low level an increase will tend to strengthen or maintain the concurrent cortical activity. But when arousal is at a high level, the greater bombardment may interfere with the delicate adjustments involved in cue function, perhaps by facilitating irrelevant responses. Thus there will be an optimal level of arousal for effective behavior, as Schlosberg has suggested” (Figure 1A). In the vertebrate cortex, such a ‘bombardment’ is ensured by diffuse afferent inputs from dopaminergic and other biogenic amine neuromodulatory neurons [2]. A new study in Drosophila melanogaster by Ralph Greenspan and colleagues [3], reported in this issue of Current Biology, shows that dopamine transmission similarly controls arousal states in the insect brain. They present evidence that, in fruit flies as in humans, an optimal level of arousal and dopamine release is required to perform complex behaviors (Figure 1B). This suggests that general features of brain functioning appeared very early in the course of animal evolution. The starting point for this study [2] was a pharmacological analysis of the lowest state of arousal — sleep. Sleep appears to be a common feature in brainendowed animals. But nobody knows for sure why this unconscious state of rest is essential for life, and what exactly its physiological function is at the cellular level. Even smaller animals, like the fruit fly, sleep for many hours in a day [4–6], principally during the night for this species. Drugs that reduce sleep need in humans also affect sleep in Drosophila. This is the case for caffeine [4,5] and the wakepromoting agents modafinil [7] and, as shown now by Andretic et al. [3], methamphetamine. Methamphetamine is a potent psychostimulant, commonly named ‘speed’ and too widely used among college students. Long-term use has dramatic consequences, including addiction, tolerance, dementialike behavior and brain damage. Methamphetamine acts principally by increasing dopamine release and preventing its reuptake into cells, thus strongly enhancing the effects of the neurotransmitter on target cells. Although the mechanism of action of modafinil is less clearly known, this drug may also interfere with dopamine transmission [8]. Feeding methamphetamine [3] or modafinil [7] to flies decreased both their sleep bout and cumulative sleep durations. Conversely, pharmacological inhibition of dopamine biosynthesis led to a narcolepticlike behavior, with the flies spending a lot more time than normal sleeping during the day [3]. These observations point to an important role for dopaminergic signaling in fly arousal. Sleep-deprived flies feel increased need for rest and tend to sleep more the next day [4,5,9]. This homeostatic regulation is characteristic of sleep in all animals. They also show reduced performance in behavior tests and heightened arousal thresholds. Andretic et al. [3] found that, in flies as in humans, sleep deprivation did not abolish the wake-promoting effect of methamphetamine: instead, methamphetamine feeding partially suppressed the need for sleep and rebound following rest deprivation. A recent mutagenesis study in Drosophila [10] identified several short-sleeper lines as well as lines that show no sleep rebound after rest deprivation. One of the strongest phenotypes turned out to be caused by a loss-of-function mutation in Shaker, a gene encoding a voltage-dependent potassium channel. Lack of Shaker is known to increase neuronal excitability. In light of the 9. Miller, M.G. , and Johnson, A.D. (2002). White-opaque switching in Candida albicans is controlled by mating type (MTL) locus homeodomain proteins and allows efficient mating. Cell 110, 293–302. 10. Lockhart, S.R. , Zhao, R. , Danielsa, K.J., and Soll, D.R. (2003). a-Pheromoneinduced ‘shmooing’ and gene regulation require white-opaque switching during Candida albicans mating. Euk. Cell 2, 847–855. 11. Daniels, K.J., Lockhart, S.R. , Staab, J.F. , Sundstrom, P., and Soll, D.R. (2003). The adhesin Hwp1 and the first daughter cell localize to the a/a portion of the conjugation bridge during Candida albicans mating. Mol. Biol. Cell 14, 4920–4930. 12. Johnson, A. (2003). The biology of mating in Candida albicans. Nat. Rev. Microbiol. 1, 106–116. 13. Tzung, K. -W. , Williams, R.M. , Scherer, S. , Federspiel, N. , Jones, T. , Hansen, N. , Bivolarevic, V. , Huizar, L. , Komp, C. , Surzycki, R. , et al. (2001). Genomic evidence for a complete sexual cycle in Candida albicans. Proc. Natl. Acad. Sci. USA 98, 3249–3253. 14. Murtagh, G.J., Dyer, P.S. , and Crittenden, P.D. (2000). Sex and the single lichen. Nature 404, 564.