Extended Data Fig. 10: Hypodermal DAF-2 degradation improves memory with age similar to daf-2 mutants.
From: Body-to-brain insulin and Notch signaling regulates memory through neuronal CREB activity
(a) Chemotaxis Index plots (top) and Learning Index (bottom) plots for hypodermal Day 6 DAF-2-AID worms treated with or without auxin. (b) Memory was evaluated by calculating the rate of change in CI between the learning and 1 h time points across replicates. (c) Chemotaxis Index plots (top) and Learning Index (bottom) plots for Day 6 neuronal DAF-2-AID worms treated with or without auxin. (d) Memory was evaluated by calculating the rate of change in CI between the learning and 1 h time points across replicates. (e) 1 h memory in Day 6 worms was compared across wild-type worms, daf-2 mutants, and neuronal and hypodermal DAF-2 AID worms ± auxin. Two-tailed unpaired t-test. Box plots: center line = median, box range is 25th - 75th percentile; whiskers denote minimum–maximum values. (f) Additional biological replicates shown for Day 6 control or osm-11-overexpressing worms. (g) Additional biological replicates shown for Day 6 daf-2 and daf-2;crh-1 worms. (a, c, e, f, g) Mean ± SEM. Two-way repeated measures ANOVA, Bonferroni post-hoc tests. n ≥ 4 per time point. n represents the number of chemotaxis plates at each time point. Each plate contains ~80 worms for all memory experiments. ns = not significant, *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.0001. (b, d,g, Two-tailed unpaired t-test. All biological replicates are shown. Source data available in supplement. h, A Model of Non-autonomous regulation of memory through Hypodermal IIS and Notch signaling to neuronal CREB activity. Young animals exhibit memory extension after a single training session that is partially CREB-dependent, and partially CREB-independent. The neuronal-IIS pathway controls CREB-independent, DAF-16-dependent gene expression that regulates CREB-independent short-term associative memory. Aged animals exhibit memory extension after a single training session that is CREB-dependent. The reduction of DAF-2 in the hypodermis induces osm-11 gene expression; OSM-11 signals to neurons and activates neuronal Notch signaling by binding to the Notch receptor LIN-12. The activated Notch receptor is cleaved33,69,70, and the intracellular domain transfers into the nucleus71,72, forming a complex with the transcription factor LAG-1 and the coactivator SEL-8 to regulate downstream Notch target gene transcription73 (for example, ins-19). CREB transcriptional activation of memory genes contributes to hypodermal DAF-2 degradation-induced associative memory.
