Endogenous BDNF is required for long-term memory formation in the rat parietal cortex

Abstract

Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.

Figure 1.

(A) Schematic drawing showing a dorsal view of the rat cortex in stereotaxic coordinates prepared from coronal and horizontal sections by orthogonal projection (Zilles 1985). The extent of the area reached by the infusion in the PCx (stippled) is illustrated. (Par 1) Primary somatosensory cortex; (Par 2) supplementary somatosensory cortex. (B) Representative brain with methylene blue stain depicting correct infusion placement.

Figure 2.

Cortical BDNF is required for memory formation. Medians (interquartile range) of latencies to step down from the platform of the inhibitory avoidance box in the test session 1.5 h (STM) and 24 h (LTM) after training. Animals were infused with saline, BDNF (0.25 μg/side), or anti-BDNF (0.5 μg/side) (A) immediately after avoidance training, (B) 1 h after training, (C) 6 h after training, or (D) 15 min before retrieval. (^***) p < 0.001; (^**) p < 0.01; (^*) p < 0.05 versus saline group; Mann-Whitney U test, n =9-10 per group.

Figure 3.

Inhibitory avoidance training is associated with CREB activation in the PCx. (A) Representative Western blots and densitometric analysis of the data using anti-activated CREB (pCREB) and total CREB in the nuclear fraction obtained from the area of the PCx in which the infusion cannulae were placed, 30 min after animals were injected with saline or BDNF (0.25 μg/side) or anti-BDNF (0.5 μg/side). Data are expressed as the mean ±SEM of the logarithm of the pCREB/total CREB ratio; (^**) p < 0.01; (^*) p < 0.05; Newman-Keuls test after ANOVA, n =5-6 per group. (B) Representative Western blots and densitometric analysis of the data using anti-activated CREB (pCREB) and total CREB in the nuclear fraction obtained from the PCx in trained (closed bars; T) and shocked (hatched bars; S) groups, immediately after training (0 min) and 1 h after training. Data are expressed as the mean ±SEM of the logarithm of the pCREB/total CREB ratio; (^*) p < 0.05; Newman-Keuls test after ANOVA, n = 5 per group. The dotted line represents the mean naive value (0.1893 ± 0.1398). (N) Naive group.