Cognitive rigidity, aberrant energy metabolism, and accelerated brain aging following cranial irradiation: gene to behavior

Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but often leads to progressive and debilitating cognitive impairments. Growing evidence has linked irradiation of the CNS to impaired cognitive flexibility, an inability to extinct fear memory, and cognitive decline. Past work from us and others has found that radiation-induced depletion of neural stem and precursor cell populations likely contribute to the inhibition of neurogenesis and the onset of cognitive impairment. Our research has established the irradiation induced genomic instability, DNA double strand break, and mitochondrial bioenergetics. Irradiation produces lasting changes in the endocannabinoid system, leading to decreased levels of two principal endocannabinoids (2AG and anandamide) and reduced density of endocannabinoid receptors (CB1 and CB2) in the hippocampus of irradiated mice. Moreover, an integrated analysis of the transcriptome and proteome demonstrated that genes encoding glycolytic enzymes, mitochondrial energetics, glucose transporters, and cognitive functions are differentially expressed in the irradiated mouse brain at both the mRNA and protein levels. Furthermore, our findings indicate that irradiation has the ability to reduce the number of glucose transporters in neurons (GLUT3, p<0.05), microglia (GLUT5, p<0.05), and astrocytes (GLUT1, p<0.01), resulting in neurotoxicity and degeneration. To evaluate if changes in dendritic architecture might be behind the neurocognitive sequelae seen after irradiation, we studied the influence of cranial irradiation on a range of micromorphometric parameters in mice. Our findings demonstrated dramatic reductions in dendritic complexity, with dendritic branching, length, and area consistently reduced in a dose-dependent manner. At the same doses and periods, we discovered significant reductions in the number and density of dendritic spines on hippocampal neurons Therefore, the dysregulation of genes and their respective proteins regulating glycolysis, mitochondrial energetics, neuroimmune interaction, and endocannabinoid signaling play a causative role in irradiation-induced mood and memory deficits, and accelerated brain aging. (author)