High-amplitude theta wave bursts during REM sleep and cataplexy in hypocretin-deficient narcoleptic mice STEFANO BASTIANINI*, ALESSANDRO SILVANI*, CHIARA BERTEOTTI, VIVIANA LO MARTIRE and GIOVANNA ZOCCOLI Department of Human and General Physiology, Alma Mater Studiorum – Universita ` di Bologna, Bologna, Italy Keywords arterial blood pressure, electroencephalography, heart, orexin, sleep, spindle Correspondence Giovanna Zoccoli, MD, PhD, Dipartimento di Fisiologia Umana e Generale, Alma Mater Studiorum – Universita ` di Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy. Tel.: +39 051 2091726; fax: +39 051 2091737; e-mail: giovanna.zoccoli@unibo.it *These authors contributed equally to this work. *S. B. and A. S. contributed equally to this work. Accepted in revised form 9 July 2011; received 26 January 2011 DOI: 10.1111/j.1365-2869.2011.00945.x SUMMARY Neurons that release hypocretin (HCRT; orexin) peptides control wake– sleep states and autonomic functions, and are lost in patients with narcolepsy with cataplexy. Bursts of high-amplitude electroencephalo- graphic (EEG) activity have been reported during behavioural arrests and rapid eye movement sleep (REMS) episodes at sleep onset in HCRT- deficient narcoleptic mice. Quantitative information on these EEG phenomena is lacking. We aimed to quantify EEG frequency, occurrence rate, daily rhythm and cardiovascular correlates of high-amplitude EEG bursts during REMS and cataplexy. Twenty HCRT-deficient mice and 15 congenic wild-type controls were instrumented with electrodes for sleep recordings and a telemetric blood pressure transducer. Short (1–2 s) high-amplitude bursts of pointed theta waves (7 Hz) occurred during either REMS or cataplexy in 80% of HCRT-deficient mice without any significant accompanying modification in systolic blood pressure or heart period. Theta bursts were significantly more likely to occur during the dark period and in the last third of REMS episodes. Similar EEG events were detected in a significantly lower fraction (27%) of wild-type mice and with a significantly lower occurrence rate (0.8 versus 5 per hour of REMS). These data demonstrate that occurrence of high-amplitude theta bursts is facilitated during REMS and cataplexy in narcoleptic mice. Analysis of EEG frequency and daily and intra-episode patterns of event occurrence do not support interpretation of theta bursts as temporally displaced pre-REMS spindles. Facilitation of high-amplitude theta bursts may thus represent a novel neurophysiological abnormality associated with chronic HCRT deficiency. INTRODUCTION Neurons that release hypocretin (HCRT) ⁄ orexin peptides control wake–sleep states and autonomic functions, and are functionally lost in patients with narcolepsy with cataplexy (Sakurai, 2007). HCRT knockout mice (KO) lacking HCRT peptides (Chemelli et al., 1999) and HCRT-ataxin3 trans- genic mice (TG) lacking HCRT-releasing neurons (Hara et al., 2001) show a narcoleptic phenotype, which includes fragmentation of waking behaviour and abrupt behavioural arrests resembling human cataplexy (Scammell et al., 2009). The first report on KO described phasic high-amplitude electroencephalographic (EEG) events on a non-rapid eye movement sleep (NREMS) background at the onset of abrupt behavioural arrests (Chemelli et al., 1999). The most abrupt behavioural arrests in KO were later found to appear as sleep-onset rapid eye movement sleep (REMS) episodes (Willie et al., 2003). In TG, phasic high-amplitude EEG events also occur during cataplexy episodes of this latter type (Hara et al., 2001). In these studies (Chemelli et al., 1999; Hara et al., 2001; Willie et al., 2003), phasic EEG events were interpreted as displacement of sleep spindles, which physiologically characterize the intermediate (pre- REMS) sleep stage (Glin et al., 1991). This interpretation was, however, not supported by a quantitative analysis of these phasic EEG phenomena. We have recently shown that chronic HCRT deficiency blunts the physiological sleep-related decrease in blood pressure in narcoleptic mice (Bastianini et al., 2011). While performing sleep scoring in HCRT-deficient mice for this J. Sleep Res. (2012) 21, 185–188 Theta waves in narcoleptic mice ª 2011 European Sleep Research Society 185