PMC

IGF-II enhances memory without altering its flexibility. (a–c) Schematic representation of the behavioral schedule; Tr: Training; T1:Test 1; E1–E8: Extinction trials 1–8. (a) CFC memory retentions in IGF-II- or vehicle (Veh)-injected (↑) mice extinguish at similar rates. Data are expressed as the mean (±SEM) % freezing (n=8). (b) No difference in the rate of extinction (%) expressed as the mean (±SEM) rate of freezing change: [E−T1]/T1 (c) or as the % freezing of E8/T1. (d) IGF-II enhances working memory (% alternation) in the spontaneous alternation task, expressed as the mean (±SEM) % alternation. Mice were injected with Veh or IGF-II 20 min before being placed into the Y-Maze (n=7–8). (e) Spatial reference task in Y-Maze. Data are expressed as the mean (±SEM) % correct arm entry of mice in the Y-Maze (baited arm). A1–A2: acquisition sessions 1–2; R1–R2: reversal sessions 1–2; each acquisition or reversal session refers to a block of five trials (n=7–8) (e). *P<0.05, **P<0.01, ***P<0.001.

IGF-II increases strength and/or persistence of non-aversive memories. Experimental schedules are shown above each panel. (a) IGF-II enhances nOR memory, expressed as mean (±SEM) % preference for a novel object (n=9–10) and (b) enhances OP memory, expressed as mean (±SEM) % preference for a displaced object (n=6–8) in mice injected (↑) with vehicle (Veh) or IGF-II 20 min before training. (c) IGF-II does not affect social recognition 20 min after injection (Test 1) or immediate social memory tested 5 min later (Test 2). However, it enhances social learning memory tested at 24 h (Test 3). Data are expressed as mean (±SEM) % preference for a novel mouse (n=10). (d–f). Schematic representation of the behavioral extinction protocol. Tr: Training; T1: Test 1; E1–E4: Extinction trials 1–4. (d) IGF-II facilitates contextual fear extinction, expressed as mean (±SEM) % freezing (n=9–10). (e) IGF-II increases the rate of extinction, expressed as mean (±SEM) % rate of change from Test 1. Mice were injected with Veh or IGF-II 20 min before each extinction trial. (f) E4 is expressed as mean (±SEM) % freezing of T1 (100%). (g) Mean % (±SEM) preference for the novel object in mice injected with either Veh or IGF-II 20 min before a reactivation given 4 h after Tr. (n=6). noR, no reactivation. *P<0.05, **P<0.01, ***P<0.001.

Systemic treatment with IGF-II enhances memory via hippocampal IGF-IIR and increases the expression of immediate early genes (IEGs) in the brain. (a) Experimental schedule is shown above the panel. Tr: Training. Data are expressed as mean (±SEM) percentage (%) freezing. Mice were injected (↑) with IgG or anti-IGF-IIR intrahippocampally and, immediately after, with vehicle (Veh) or IGF-II s.c. Twenty min later they underwent CFC training, and were tested 24 h later. (b–e) Examples and quantification of western blots of hippocampal and prefrontal cortex extracts obtained from naive and trained mice injected (↑) with either vehicle (Veh) or IGF-II 20 min before CFC training and euthanized 1 h after training. Values were normalized against actin. Data are expressed as mean percentage (±SEM) of naive mice injected with Veh (Naive-Veh). In naive mice, compared with Veh, IGF-II injection (Naive-IGF-II) increases the levels of (b) Arc and (c) Zif268 in the hippocampus, but not in the prefrontal cortex (d, Arc: e, Zif268). Training significantly increases the levels of Arc in the hippocampus and prefrontal cortex and of Zif268 in the hippocampus (Trained-Veh); IGF-II treatment does not further increase the levels of either IEGs following training (Trained-IGF-II). (n=7–10), *P<0.05, **P<0.01.

Systemic IGF-II enhances contextual fear but not auditory fear memory. Experimental schedules are shown above each panel. Tr: Training. (a–f) Data are expressed as mean (±SEM) percentage (%) freezing. Mice were injected (↑) with vehicle (Veh) or IGF-II 20 min before or immediately after training. (a) 15, 30, and 45 μg/kg, but not other doses, of IGF-II enhances contextual fear conditioning memory (n=6–9). (b) 15 μg/kg IGF-II enhances memory at 1 day, but not at 7 days, after training (n=7–8). (c) 30 μg/kg enhances memory at both 1 and 7 days after training (n=8–11). (d) IGF-II enhances short-term memory, 1 h after training (n=7). (e) IGF-II injected immediately after training enhances memory at 24 h, but not at 7 days, after training (n=7–8). (f) IGF-II injected immediately after training does not enhance short-term memory (n=6). (g) IGF-II has no effect on auditory fear conditioning memory (n=6). IGF-II has no effect on (h) locomotor activity, expressed as mean (±SEM) beam breaks of mice injected with vehicle (Veh) or IGF-II 24 h before testing (n=5–6), (i) open field test, expressed as mean (±SEM) center entries (Left) or time spent in the center (in s) (Middle) or number of total line crossings (Right) in the open field arena at 24 h after injection of vehicle or IGF-II (n=6), (j) mean (±SEM) of blood glucose concentration (mg/dl) 30 min, 12 h, 24 h, and 7 days after injection of Veh or IGF-II (n=6), or (k) mean (±SEM) weight (g) of mice injected with either Veh or IGF-II 20 min before CFC training and tested 24 h before (Pre), immediately after (Tr), 24 h and 7 days after training (Post, n=7). *P<0.05, **P<0.01, ***P<0.001.