Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice

Abstract

Numerous animal and clinical studies have described memory deficits following sleep deprivation. There is also evidence that the absence of sleep increases brain oxidative stress. The present study investigates the role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Mice were sleep deprived for 72 h by the multiple platform method—groups of 4–6 animals were placed in water tanks, containing 12 platforms (3 cm in diameter) surrounded by water up to 1 cm beneath the surface. Mice kept in their home cage or placed onto larger platforms were used as control groups. The results showed that hippocampal oxidized/reduced glutathione ratio as well as lipid peroxidation of sleep-deprived mice was significantly increased compared to control groups. The same procedure of sleep deprivation led to a passive avoidance retention deficit. Both passive avoidance retention deficit and increased hippocampal lipid peroxidation were prevented by repeated treatment (15 consecutive days, i.p.) with the antioxidant agents melatonin (5 mg/kg), N-tert-butyl-α-phenylnitrone (200 mg/kg) or vitamin E (40 mg/kg). The results indicate an important role of hippocampal oxidative stress in passive avoidance memory deficits induced by sleep deprivation in mice.

Introduction

There is considerable evidence that sleep plays an important role in memory processes (for review, see Maquet, 2001). Clinical data have shown that the deprivation of sleep causes deficits in several forms of learning/memory (Tilley and Empson, 1978, Cochran et al., 1994, Karni et al., 1994, Fluck et al., 1998, Harrison and Horne, 2000, Mednick et al., 2002). In addition, numerous studies have demonstrated that sleep deprivation in laboratory animals produces memory deficits in several behavioral models, such as avoidance tasks (Harris et al., 1982, Smith and Kelly, 1998, Bueno et al., 1994, Guart-Masso et al., 1995), Morris water maze task (Smith and Rose, 1996, Youngblood et al., 1997, Youngblood et al., 1999) and radial maze task (Smith et al., 1998).

The mechanisms responsible for the occurrence of memory deficits following sleep deprivation are not clearly understood. In this respect, one of the theories to explain the changes in the cerebral function that follow sleep deprivation proposes that normal sleep would revert oxidative stress by removing the reactive oxygen species that were produced during the wake period. In short, sleep deprivation would reduce the antioxidant defenses (Reimund, 1994). Indeed, increases in hypothalamic and thalamic oxidative stress levels were found in sleep-deprived rats (D’Almeida et al., 1998, D’Almeida et al., 2000). Furthermore, Maquet et al. (2002) suggested that the proposed restorative function of sleep might involve the elimination of toxic compounds (e.g. free radicals) and the replenishment of energy stores.

Increased brain oxidative stress seems to have an important role in cognitive impairment caused by normal aging and neurodegenerative diseases. Administration of antioxidant agents has been shown to improve such deficits (Carney et al., 1991, Carrillo et al., 1993, Knoll et al., 1994, Markesbery, 1997, Small, 1998, Kontush, 2001). However, the participation of brain oxidative stress in sleep-induced memory deficiency has not yet been investigated. Thus, the aim of the present study is to investigate this possibility, by verifying: (1) whether the same protocol of sleep deprivation would produce increased oxidative stress in hippocampus and memory deficits assessed in a passive avoidance task (demonstrated to be related to the hippocampal function; Kim and Fanselow, 1992, Izquierdo and Medina, 1993) and (2) the effects of the administration of different antioxidant agents on memory deficits and hippocampal oxidative stress induced by sleep deprivation.