Developmental Decline in Neuronal Regeneration by the Progressive Change of Two Intrinsic Timers

navigation requires more than the hippocampal spatial signal: It also entails decision-making, goal-directed behaviors, sensory-motor integration , and other cognitive processes (mediated by brain structures such as the striatum, cerebellum, and prefrontal and parietal cortices). Thus, to elucidate the neural basis of real-life navigation in bats (27, 29), it would be essential to record neu-ral activity from the hippocampal formation (and additional brain structures) in bats navigating over distances of kilometers. 19. Materials and methods are avaliable as supplementary materials on Science Online. 20. This telemetry system did not allow recording of low-frequency local field potentials because of inherent high-pass limitations (19). The bat's wings hitting on the telemetry transmitter caused some recording artifacts (Fig. 1G and fig. S11), but these artifacts constituted only a small fraction of the flight time (3.6 T 0.91% of the total flight time per day, mean T SD). This fraction decayed to 0.11% after 9 recording days (fig. S11D), enabling us to collect neural spiking data with almost no movement-related interference. M. Geva-Sagiv for the 3D trajectory reconstruction system; C. Stengel for the neural telemetry system; B. Pasmantirer and G. Ankaoua for mechanical designs; A. Rubin and A. Averkin for assistance with neural recordings and video calibrations; and A. Tuval for veterinary oversight; C. Ra'anan and R. Eilam for histology; and M. P. Witter for advice on reconstruction of tetrode-track locations. Like mammalian neurons, Caenorhabditis elegans neurons lose axon regeneration ability as they age, but it is not known why. Here, we report that let-7 contributes to a developmental decline in anterior ventral microtubule (AVM) axon regeneration. In older AVM axons, let-7 inhibits regeneration by down-regulating LIN-41, an important AVM axon regeneration–promoting factor. Whereas let-7 inhibits lin-41 expression in older neurons through the lin-41 3′ untranslated region, lin-41 inhibits let-7 expression in younger neurons through Argonaute ALG-1. This reciprocal inhibition ensures that axon regeneration is inhibited only in older neurons. These findings show that a let-7–lin-41 regulatory circuit, which was previously shown to control timing of events in mitotic stem cell lineages, is reutilized in postmitotic neurons to control postdifferentiation events. W e use Caenorhabditis elegans to study developmental decline in neuronal re-generation (Fig. 1A) (1). As in vertebrates , advancing development leads to decreased axon regenerative capacity in C. elegans (Fig. 1C) (2–4). The timing mechanism that controls developmental decline in neuronal regeneration is poorly understood (2–5). Because heterochronic genes are implicated in …