BDNF is essential to promote persistence of long-term memory storage

Abstract

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage.

Fig. 1.

BDNF is necessary and sufficient for memory persistence. (A) Human recombinant BDNF (hrBDNF) rescues the impairment in memory persistence caused by inhibition of protein synthesis. Anisomycin (Ani; 80 μg per side) caused amnesia 7 days after training when infused 12 h after learning (dark gray). This effect was reversed by infusion of hrBDNF (0.25 μg per side) 15 min later (light gray). *, P < 0.05, n = 8. (B) Intrahippocampal infusion of BDNF antisense oligonucleotide (BDNF ASO) late after IA training blocks memory retention at 7, but not at 2, days after training. BDNF ASO, but not BDNF missense oligonucleotide (BDNF MSO), infusion 10 h after training hinders memory persistence at 7 days but leaves memory intact 2 days after training. Animals were infused into the dorsal hippocampus with BDNF MSO (2 nmol per side) (white bars) or BDNF ASO (2 nmol per side) (gray bars) 10 h after training. Data are expressed as mean (±SEM) of training (TR, black bars) or test session step-down latency 2 or 7 days after IA training. **, P < 0.01; ASO vs. MSO at 7 days; Student's t test, n = 8–10.

Fig. 2.

BDNF promotes persistence of LTM storage. (A) A strong (0.7 mA), but not a weak (0.4 mA), foot shock during IA training creates a persistent LTM, lasting for at least 7 days. Data are expressed as mean (±SEM) of training (TR, black bars) or test session step-down latency at 2, 4, or 7 days after training. ***, P < 0.001; *, P < 0.05 vs. TR; n = 10. (B) (Upper) A strong, but not a weak, training is associated with an increase in BDNF in the dorsal hippocampus. Bars show normalized mean percentage level of BDNF with respect to the naïve group. Data are expressed as mean ± SEM. *, P < 0.05; **, P < 0.01 vs. naïve in Newman–Keuls test after ANOVA, n = 6. (Lower) Representative blots showing BDNF and actin levels. (C and D) Infusion of hrBDNF 12 h, but not 24 h, after training prevents memory decay. Rats were infused into the dorsal hippocampus with vehicle (Veh) or hrBDNF (0.25 μg per side) after a weak training and tested for retention 2 or 7 days afterward. Data are expressed as mean ± SEM of training (TR, black bars), Veh (white bars), or hrBDNF (gray bars) test session step-down latency at 2 or 7 days after training. **, P < 0.01 vs. Veh group; Student's t test, n = 10. (E) Infusion of hrBDNF 12 h after strong IA training does not enhance memory retention at 7 days. Rats were bilaterally infused into the dorsal hippocampus with vehicle (Veh) or hrBDNF (0.25 μg per side) after strong IA training and tested for retention 7 days afterward. Data are expressed as mean ± SEM of training (TR, black bars) or test session step-down latency 7 days after training.

Fig. 3.

ERK activation is necessary for BDNF induction of persistence of LTM storage. (A) (Upper) Strong, but not weak, IA training is associated with an increase in phospho-ERK2 (p-ERK2) in the dorsal hippocampus 12 h after training. Bars show normalized mean percentage level (±SEM) of p-ERK2 with respect to the naïve group. ***, P < 0.05 in Newman–Keuls test after ANOVA, n = 6. (Lower) Representative blots showing p-ERK2 and ERK2 levels. (B) U0126, but not Veh, infusion 12 h after strong IA training hindered memory at 7 days but left memory intact 2 days after training. Animals were infused into the dorsal hippocampus with U0126 (0.38 μg per side) or Veh 15 min before or 12 h after training. Data are expressed as mean ± SEM of training (TR, black bars) or test step-down latency, 2 (white bars) or 7 days (gray bars) after training. ***, P < 0.001 in Student's t test, n = 8–10. (C) (Upper) Intrahippocampal BDNF ASO infusion 10 h after training prevented the learning-associated increase in p-ERK2 12 h after training. Naïve or trained rats received bilateral infusions of BDNF MSO (white bars) or BDNF ASO (gray bars). Two hours later, the dorsal hippocampus was dissected out and used for Western blot analysis of p-ERK. Bars show the normalized mean percentage levels (±SEM) with respect to the naïve animals injected with MSO. *, P < 0.05 in Newman–Keuls test after ANOVA, n = 5. (Lower) Representative blots showing p-ERK2 and ERK2 levels. (D) ERK activation is required for BDNF induction of memory persistence. Intrahippocampal hrBDNF infusion 12 h after weak IA training induced persistence of LTM (hrBDNF, light gray) that was abolished by U0126 injection (0.38 μg per side) 15 min before (U0126+hrBDNF, dark gray). Data are expressed as mean ± SEM of training (TR, black bars) or test session step-down latency 7 days after IA training. **, P < 0.01, Student's t test, n = 8.