Abstract: Aim: Sleep disorders are common in Alzheimer’s disease (AD) and assumed to directly influence cognitive function and progression of the disease. The present study evaluated sleep characteristics in a rat model of AD that was induced by intracerebroventricular administration of streptozocin, and we assessed the possible underlying mechanisms. Methods: The cognition ability of rats was assessed by Morris water maze (MWM) trails. Sleep parameters were analyzed by electroencephalographic (EEG) and electromyographic (EMG) recordings. The neuronal activity in sleep-wake regulating brain areas was evaluated by double-staining immunohistochemistry test. High performance liquid chromatograph- electrochemical detection (HPLC-ECD) was used for the detection of neurotransmitters. Results: On day 14 after STZ injection, the rats exhibited sleep disorders that are similar to those in AD patients as evidenced by significant increase in wakefulness and decrease in rapid-eye movement sleep (REMS) and non-REMS. The c-Fos expression analysis indicated that neuronal activity and the number of neurons in the dorsal raphe nucleus and locus coeruleus decreased in STZ rats. In the ventrolateral preoptic nucleus (VLPO), the activity of γ-aminobutyric acid (GABA) neurons was suppressed. In the arousal-driving parabrachial nucleus (PBN), GABAergic activity was suppressed, whereas glutamatergic activity was promoted. The neurotransmitter analysis revealed a reduction of GABA in the VLPO and PBN and elevations of glutamate in the PBN. A direct injection of the GABAA receptor antagonist bicuculline in the PBN in normal rats induced a similar sleep disorder pattern as in STZ rats. Furthermore, a microinjection of GABA in the PBN improved sleep disorders induced by STZ. Conclusion: These results suggest that the reduction of GABAergic inhibition in the PBN and VLPO may be involved in sleep disorders induced by STZ. Our novel findings encourage further study aimed at investigating the new mechanisms of sleep regulation in sporadic AD.

Key words: Alzheimer&rsquo, s disease, Sleep disorders, GABA, Streptozocin, Parabrachial nucleus