Delta power, a measure of EEG activity in the 1-4 Hz range, in slow-wave sleep (SWS) is in a quantitative and predictive relationship with prior wakefulness. Thus, sleep loss evokes a proportional increase in delta power, and excess sleep a decrease. Therefore, delta power is thought to reflect SWS need and its underlying homeostatically regulated recovery process. The neurophysiological substrate of this process is unknown and forward genetics might help elucidate the nature of what is depleted during wakefulness and recovered during SWS. We applied a mathematical method that quantifies the relationship between the sleep-wake distribution and delta power to sleep data of six inbred mouse strains. The results demonstrated that the rate at which SWS need accumulated varied greatly with genotype. This conclusion was confirmed in a "dose-response" study of sleep loss and changes in delta power; delta power strongly depended on both the duration of prior wakefulness and genotype. We followed the segregation of the rebound of delta power after sleep deprivation in 25 BXD recombinant inbred strains by quantitative trait loci (QTL) analysis. One "significant" QTL was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. Interestingly, the rate at which SWS need decreases did not vary with genotype in any of the 31 inbred strains studied. These results demonstrate, for the first time, that the increase of SWS need is under a strong genetic control, and they provide a basis for identifying genes underlying SWS homeostasis. Key words: EEG delta power; slow-wave activity; sleep deprivation; homeostatic regulation of non-REM sleep; simulation of Process S; BXD recombinant-inbred mouse strains; QTL;Dps1; Dps2; Dps3; forward genetics Slow oscillations in the delta frequency range (1-4 Hz) are characteristic of the EEG during slow-wave sleep (SWS) (i.e., non-REM sleep in humans). Delta oscillations reflect synchronized burst-pause firing patterns of hyperpolarized thalamocortical and corticothalamic neurons (Steriade et al., 1993;McCormick and Bal, 1997;Steriade, 1999). Activity in the delta frequency range can be quantified as delta power by Fourier analysis. Delta power is negatively correlated with the response to arousing stimuli (Neckelmann and Ursin, 1993) and SWS fragmentation (Franken et al., 1991a) and thus can be seen as a measure of SWS intensity. Delta power is also in a quantitative and predictive relationship with prior sleep and wakefulness in mammals, including humans. Sleep loss evokes an increase in delta power during subsequent SWS that is proportional to the loss (Tobler and Borbély, 1986;Dijk et al., 1987), excess sleep results in an attenuation of delta power (Werth et al., 1996), and delta power decreases over the course of a sleep period, independent of the circadian phase at which sleep is initiated (Dijk and Czeisler, 1995). These and other observations have been interpreted as evidence that SWS is a restorative and homeostatically regulated behavior and that delta ...

The genetic variation in spontaneous rhythmic electroencephalographic (EEG) activity was assessed by the quantitative analysis of the EEG in six inbred mice strains. Mean spectral EEG profiles (0–25 Hz) over 24 h were obtained for paradoxical sleep (PS), slow-wave sleep (SWS), and wakefulness. A highly significant genotype-specific variation was found for theta peak frequency during both PS and SWS, which strongly suggests the presence of a gene with a major effect. The strain distribution of theta peak frequency during exploratory behavior differed from that during sleep. In SWS, the relative contributions of delta (1–4 Hz) and sigma (11–15) power to the EEG varied with genotype and power in both frequency bands was negatively correlated. In addition, the EEG dynamics at state transitions were analyzed with a 4-s resolution. The onset of PS, but not that of wakefulness, was preceded by a pronounced peak in high-frequency (>11 Hz) power. These findings are discussed in terms of the neurophysiological mechanisms underlying rhythm generation and their control and modulation by the brain stem reticular-activating system.

Narcolepsy is a chronic sleep disorder caused by the loss of neurons that produce hypocretin. The close association with HLA-DQB1*06:02, evidence for immune dysregulation and increased incidence upon influenza vaccination together suggest that this disorder has an autoimmune origin. However, there is little evidence of autoreactive lymphocytes in patients with narcolepsy. Here we used sensitive cellular screens and detected hypocretin-specific CD4 T cells in all 19 patients that we tested; T cells specific for tribbles homologue 2-another self-antigen of hypocretin neurons-were found in 8 out of 13 patients. Autoreactive CD4 T cells were polyclonal, targeted multiple epitopes, were restricted primarily by HLA-DR and did not cross-react with influenza antigens. Hypocretin-specific CD8 T cells were also detected in the blood and cerebrospinal fluid of several patients with narcolepsy. Autoreactive clonotypes were serially detected in the blood of the same-and even of different-patients, but not in healthy control individuals. These findings solidify the autoimmune aetiology of narcolepsy and provide a basis for rapid diagnosis and treatment of this disease.

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Our findings indicate that sleep complaints should not be viewed as part of normal aging but should prompt the identification of underlying causes.