Role of brain glycogen and glucose regulation in migraine susceptibility

Genetic disorders affecting glucose transport and fasting as a trigger suggest that disruptions in brain glucose metabolism may contribute to migraine susceptibility. The activation of the peripheral sympathetic nervous system plays a critical role in responding to declines in blood sugar. Beyond its role in glucose regulation, sympathetic activity driven by locus coeruleus also influences astrocytes, the glial cells responsible for supporting neuronal function. During periods of fasting, stress, and sleep deprivation, sustained sympathetic activation from locus coeruleus may contribute to reduced availability of glycosyl units derived from glycogen in peri-synaptic astrocyte processes. This is attributed to transcriptional shifts favoring glycogen synthesis over utilization, in contrast to the transient low-level locus coeruleus activity that typically promotes glycogen breakdown. The metabolism of glycogen within astrocyte processes is tightly coupled to excitatory synaptic activity, helping to meet the high energetic demands of synaptic transmission, as well as supporting the uptake of glutamate and potassium released during neuronal firing. Disruptions in glycogen metabolism, which impair these processes, may contribute to migraine pathophysiology by compromising the uptake of glutamate and potassium. This environment reduces the cortical spreading depolarization threshold and facilitates the activation of parenchymal inflammatory signaling, both of which increase susceptibility to migraine headaches. The locus coeruleus is closely connected to several hypothalamic nuclei, including the suprachiasmatic nucleus, which helps synchronize circadian rhythms. The hypothalamus can also be activated by nociceptive input as well as external triggers. These reciprocal interactions may give rise to loop activity that fluctuates throughout migraine attacks and interictal periods, potentially influencing glycogen and glucose metabolism in cortical astrocytes. In conclusion, disruptions in astrocyte energy supply to synaptic activity, which is modulated by the extensive projections of locus coeruleus, may contribute to the initiation and progress of certain migraine forms.