Stimulation of hippocampal adenylyl cyclase activity dissociates memory consolidation processes for response and place learning

Abstract

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.

Figure 1.

Effects of a bilateral intrahippocampal injection of aCSF (controls, n = 13) (shaded bar) or FK (0.3 μg/0.2 μl) (solid bars) on retention performance in the bar-pressing task. Animals received FK at different delays after the acquisition (for each delay, n = 9). Bar graphs represent mean (±SEM) number of bar-press responses per minute. (**) Significantly different from controls (P < 0.01).

Figure 2.

Effects of bilateral intrahippocampal injections of aCSF (controls, n = 13) (○) or FK (0.3 μg/0.2μl) on the time needed to perform five bar-press responses at the beginning or at the end of the retention session. Animals received intrahippocampal injection of FK 3 h (n = 9) (▴) or 6 h (n = 9) (●) after the acquisition. Data are expressed as mean (±SEM) time of 5 bar-press responses. (*) Significantly different from controls for both FK groups (P < 0.05).

Figure 3.

Effects of bilateral intrahippocampal injections of aCSF (controls, n = 10) (○) or FK (0.3 μg/0.2 μl) on cued-response memory or place memory in the water-maze task. Animals received FK 5 min (n = 10) (●) or 3 h (n = 10) (◼) after the acquisition. Data are expressed as mean (±SEM) latency to find the platform. (*) Significantly different from controls (P < 0.05).

Figure 4.

Swim distances during spatial retention and in the cued test for the three groups (n = 10 for each group). Animals received intrahippocampal injections of aCSF (○) or FK (0.3 μg/0.2 μl) 5 min after the acquisition (●), or FK 3 h after the acquistion (◼). (*) Significantly different from controls (P < 0.05).

Figure 5.

Effects of a bilateral intrahippocampal injection of aCSF or FK (0.3 μg/0.2 μl) on competition between place and cue responses. (A) Representative swim paths of each group recorded during the cue test. (B) Bar graph represents mean (±SEM) number of crossing over the virtual place where the platform was previously located. (C) Bar graph represents means (±SEM) of the time spent within the virtual place area. Animals (n = 10 per group) received intrahippocampal injections of aCSF or FK (0.3 μg/0.2 μl) 5 min or 3 h after acquisition. (*) Significantly different from controls (P < 0.05).

Figure 6.

(A) Bar graphs represent means (±SEM) of the number of pCREB positive neurons/mm² in the CA1, CA3, or primary somato-sensori cortex (PSS cortex) at 0 min (n = 2), 30 min (n = 4), 1 h (n = 5), 2 h (n = 3), or 3 h (n = 4) after bilateral intrahippocampal injections of FK (0.3 μg/0.2 μl). (*) Significantly different from the group 0 min (P < 0.05). (B) Photomicrographs illustrating pCREB immunoreactivity in the dorsal hippocampus of mice injected with FK and killed either 0 min (left) or 1 h (right) later.

Figure 7.

Histological controls showing representative placements of guide cannulae and cannulae in the dorsal hippocampus.