A Positive Autoregulatory BDNF Feedback Loop via C/EBPβ Mediates Hippocampal Memory Consolidation

Abstract

Little is known about the temporal progression and regulation of the mechanisms underlying memory consolidation. Brain-derivedneurotrophic-factor (BDNF) has been shown to mediate the maintenance of memory consolidation, but the mechanisms of this regulation remain unclear. Using inhibitory avoidance (IA) in rats, here we show that a hippocampal BDNF-positive autoregulatory feedback loop via CCAAT-enhancer binding protein ␤ (C/EBP␤) is necessary to mediate memory consolidation. At training, a very rapid, learninginduced requirement of BDNF accompanied by rapid de novo translation controls the induction of a persistent activation of cAMPresponse element binding-protein (CREB) and C/EBP␤ expression. The latter, in turn, controls an increase in expression of bdnf exon IV transcripts and BDNF protein, both of which are necessary and, together with the initial BDNF requirement, mediate memory consolidation. The autoregulatory loop terminates by 48 h after training with decreased C/EBP␤ and pCREB and increased methyl-CpG binding protein-2, histone-deacetylase-2, and switch-independent-3a binding at the bdnf exon IV promoter.

Memory retrieval of inhibitory avoidance requires histamine H 1 receptor activation in the hippocampus

“…Because molecular changes specific for IA-LTM in rat hippocampus begin immediately after the training session and progress for less than 20 h (35, 36), the amnesia resulting from a-FMHis infusion 24 h posttraining is likely caused by an impairment of retrieval rather than consolidation. This view is supported by the observation that intra-CA1 infusion of anisomycin 12 h after training failed to disrupt IA-LTM tested 2 d posttraining (35,37). Indeed, the requirement of de novo protein synthesis to consolidate IA memory is crucial only during the immediate phase after training (35,37).…”

“…This view is supported by the observation that intra-CA1 infusion of anisomycin 12 h after training failed to disrupt IA-LTM tested 2 d posttraining (35,37). Indeed, the requirement of de novo protein synthesis to consolidate IA memory is crucial only during the immediate phase after training (35,37). Delayed processes, such as gene expression-dependent phases, are necessary specifically for long-term maintenance of the memory but not for its formation (36,38).…”

Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus

“…The IA training activates molecular changes with different temporal progression in multiple brain areas, such as amygdala, hippocampus, entorhinal cortex, and parietal cortex (36,37). However, experimental evidence indicates that CA1 and BLA operate also in parallel (9).…”

Transforming growth factor β recruits persistent MAPK signaling to regulate long-term memory consolidation in Aplysia californica

“…The importance of post-training growth factor signaling in LTM consolidation and maintenance has also been established for brain derived neurotrophic factor (BDNF) (Bekinschtein et al 2007;Katche et al 2013;Bambah-Mukku et al 2014). In rodents, BDNF is important for LTM consolidation at multiple time points following training and this is regulated through a BDNF autoregulatory feedback loop (Bambah-Mukku et al 2014).…”

“…In rodents, BDNF is important for LTM consolidation at multiple time points following training and this is regulated through a BDNF autoregulatory feedback loop (Bambah-Mukku et al 2014). In Aplysia, a well-established downstream target of growth factor signaling is CREB-dependent gene expression, which supports the consolidation of LTF at sensorimotor synapses through a positive CREB autoregulatory feedback loop lasting for several hours following training (Mohamed et al 2005;Liu et al 2008).…”