Low brain allopregnanolone levels mediate flattened circadian activity associated with memory impairments in aged rats.

摘要

BACKGROUND: Sleep and cognitive impairments are two of the most prevalent neuropsychiatric disorders in the aged population. Age-related memory dysfunctions can result from alterations in sleep/wake circadian rhythm. However, the underlying mechanism of these alterations is unknown. Here, we demonstrate the role of alterations in brain steroid levels in age-related sleep-dependent memory impairment in rats. METHODS: Sleep/wake circadian activity and spatial memory performance were evaluated in adult, middle-aged, and aged rats, and steroid levels were measured in brain structures involved in mediating sleep-dependent memory processes using gas chromatography/mass spectrometry. The causal relationship between circadian activity and allopregnanolone levels was assessed using an inhibitor of allopregnanolone synthesis (indomethacin). RESULTS: Similar to observations in humans, a subpopulation of middle-aged and aged rats show flattened amplitude of circadian activity associated with impaired spatial long-term memory performance. Sleep-dependent memory dysfunction was associated with a low level of allopregnanolone in the hypothalamus, pedunculopontine nucleus, and ventral striatum. Inhibition of allopregnanolone synthesis in young rats decreased allopregnanolone in the hypothalamus and produced flattened amplitude of circadian activity similar to aged rats. CONCLUSIONS: These findings identify brainstem and basal forebrain allopregnanolone as an essential endogenous substrate involved in mediating sleep-dependent memory function in young and aged rats. Allopregnanolone may play a critical role in preserving individuals from age-induced alterations in sleep and memory processes and may represent a novel target for attenuating age-related declines in sleep and memory.