LOCAL ENERGY DEPLETION IN THE BASAL FOREBRAIN AND SLEEP

Kalinchuk Anna, Urrila Anna-Sofia, Alanko Lauri, Heiskanen Silja
Wigren Henna-Kaisa, Suomela Maricel, Stenberg Dag, Porkka-Heiskanen Tarja
Institute of Biomedicine, University of Helsinki, Helsinki, Finland
e-mail: anna.kalinchuk@helsinki.fi

Restoration of energy metabolism is one of the major functions of sleep. In contrast to wakefulness, when utilization of energy is continuous, during sleep brain energy expenditure is reduced. Prolonged wakefulness is accompanied by accumulation of extracellular adenosine in the basal forebrain indicating discrepancy between energy demand and availability, while during recovery sleep adenosine concentration gradually decreases. Sleep saves energy and restores energy deficit induced by prolonged wakefulness, but can energy depletion induce sleep? To test this hypothesis we induced local energy depletion in the brain of rats by infusion of 2,4-dinitrophenol (DNP) - a drug which uncouples oxidative phosphorilation from ATP synthesis in mitochondria. Changes in sleep and concentrations of adenosine, lactate and pyruvate were compared with those induced by prolonged wakefulness.

Rats were implanted with electrodes for EEG/EMG recording and guide cannulae. Microdialysis probes were inserted into basal forebrain (BF group) or adjacent non-cholinergic areas for control (non-BF group). Experimental schedule included either prolonged wakefulness for 3h followed by 2h of recovery sleep or infusion of DNP in three doses (0.5mM, 1mM and 1.5mM) for 3h, which was proceeded by 3h baseline. Samples were collected every 30 min and analysed for adenosine, lactate and pyruvate content using HPLC coupled with UV detector. The EEG was recorded for 24h and scored to wakefulness, non-REM and REM sleep. After the experiments the locations of probe tips were verified histologically.

Prolonged wakefulness induced significant increase in non-REM sleep by 53.4±16.4% in all animals, but concentrations of adenosine, lactate and pyruvate were significantly raised only in the BF group. DNP infusion increased the extracellular concentrations of adenosine, lactate and pyruvate in both the BF and the non-BF group. In contrast, non-REM sleep after DNP infusion was significantly increased only in the BF group (by 43.0±17.4% at the 0.5mM dose, 68.0±18.0 at the 1.0mM dose and by 105.6±27.0% at the 1.5mM dose). In the non-BF group changes in sleep were not significant.

Thus, infusion of DNP into the basal forebrain mimicked the effects of prolonged wakefulness. We propose that continuous activity of the basal forebrain neurons during prolonged wakefulness induces local energy depletion which enhances concentrations of lactate, pyruvate and adenosine and subsequently elevates non-REM sleep. Thus, local energy depletion in the basal forebrain can be a mechanism that promotes sleep.