Investigating how neuronal activity state governs the decline of plasticity with age in C. elegans
Item statusRestricted Access
Embargo end date30/11/2021
Neural plasticity, which is the basis or learning and memory formation, declines continuously and progressively over the course of life. However, the molecular mechanisms underlying neuronal ageing and the decline of neural plasticity with age are not well understood. Sensory input and neural excitation have been shown to regulate organismal ageing processes and control lifespan, but how they drive the ageing of cognitive function and plasticity remains obscure. To study the mechanisms of how neuronal activity affects the decline of neural plasticity with age, I have established an assay in C. elegans based on its robust and reproducible behavioral responses to O2. Animals show O2 experience-dependent behavioral plasticity, where an overnight shift of the O2 concentration in the culture environment reprograms worms’ O2-evoked speed responses. I show that long-term high neural activity of the O2-sensing neurons accelerates the decline of plasticity with age at both the neuronal and behavioral level. By gene expression profiling of O2- sensing neurons in ageing animals, I show that neuronal activity alters age-related changes in transcription, and the data suggest that neuronal resources undergo a redistribution during ageing that depends on the neuronal activity state. In particular, the differential expression of neuronal genes that modulate Ca2+ homeostasis plays a central role in mediating activity-dependent decline. Low activity neurons require the K+-dependent Na+/Ca2+ (NCKX) exchanger to remove intracellular Ca2+ in order to sustain plasticity with age, whereas the decline of plasticity associated with high neuronal activity acts through calmodulin and the scaffold protein Kidins220 (also known as ARMS). These findings demonstrate directly that the activity of neurons alters neuronal homeostasis to govern the age-related decline of neural plasticity and throw light on the mechanisms involved.