Brain glycogen metabolism: A possible link between sleep disturbances, headache and depression

The functions of sleep and its links with neuropsychiatric diseases have long been questioned. Among the numerous hypotheses on sleep function, early studies proposed that sleep helps to replenish glycogen stores consumed during waking. Later studies found increased brain glycogen after sleep deprivation, leading to “glycogenetic” hypothesis, which states that there is a parallel increase in synthesis and utilization of glycogen during wakefulness, whereas decrease in the excitatory transmission creates an imbalance causing accumulation of glycogen during sleep. Glycogen is a vital energy reservoir to match the synaptic demand particularly for re-uptake of potassium and glutamate during intense glutamatergic transmission. Therefore, sleep deprivation-induced transcriptional changes may trigger migraine by reducing glycogen availability, which slows clearance of extracellular potassium and glutamate, hence, creates susceptibility to cortical spreading depolarization, the electrophysiological correlate of migraine aura. Interestingly, chronic stress accompanied by increased glucocorticoid levels and locus coeruleus activity and leading to mood disorders in which sleep disturbances are prevalent, also affects brain glycogen turnover via glucocorticoids, noradrenaline, serotonin and adenosine. These observations altogether suggest that inadequate astrocytic glycogen turnover may be one of the mechanisms linking migraine, mood disorders and sleep.