Epigenetics in learning and memory - Wikipedia

If BDNF is a PRP, a natural question is whether TrkB, the receptor for BDNF, can serve as a synaptic tag. A synaptic tag has to satisfy several criteria (): 1) the tag can be activated by weak tetanus that induces only E-LTP; 2) the lifetime of the tag is about 1–2 hours; 3) the activation of the tag does not require protein synthesis; 4) the tag is induced in an input-specific and physically immobile manner; and 5) the tag interacts with PRP for L-LTP. A twist of the “tagging” model here is that the PRP (BDNF) needs to be secreted before it can be captured by the tag (TrkB). Demonstrating that TrkB is a “synaptic tag” represents the ultimate challenge in the hypothesis that BDNF-TrkB is a PRP-tag pair in synaptic tagging.

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Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.

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Investigating the role of BDNF during retention or recall of hippocampal dependent memory also requires an inducible or transient disruption of BDNF signaling. As discussed above, this cannot be determined using conventional BDNF or TrkB knockouts since deletion of these genes compromise initial acquisition. It has been shown that recall of some forms of hippocampal dependent memory increase BDNF mRNA expression, namely following contextual fear conditioning and Morris water maze training (; ). Several studies have been designed to address the role of BDNF in the consolidation or recall of more remotely formed memories. Infusion of antisense BDNF oligonucleotides in rats that had been trained for the reference memory task for 28 days in the radial arm maze disrupts recall of a well-established spatial memory (). In an inhibitory avoidance test, infusion of BDNF into the hippocampus 1 hr or 4 hrs after training facilitates, whereas that of anti-BDNF antibody at the same time after training impairs, LTM tested 24 hrs later (). Interestingly, infusion of BDNF antibodies or antisense oligonucleotide 6 hrs post-training no longer affects memory retention tested at 24 hrs (; ). However, one recent study showed that intra-hippocampal infusion of BDNF antisense oligonucleotide 12 hours after inhibitory avoidance training impairs memory retention 7 days later (). Thus, there are two time windows for LTM that require BDNF: one at 1-4 hours after encoding and this is critical for LTM lasting for 1-2 days, whereas the other at 12 hours after memory formation and is important for persistence of LTM 7 days later. Previous work has demonstrated the existence of two critical periods for memory consolidation, both of which require protein synthesis (; ; ). By extending the investigation of LTM beyond 24 hours, the authors revealed a previously unknown, time-delayed effect of BDNF expression on memory recall. This should encourage further investigation into the temporal parameters of BDNF-mediated plasticity and its role in LTM retention.

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How could BDNF synthesis be induced 12 hours after memory acquisition when there is no obvious trigger? Replay of synaptic activity during consolidation (such as that during sleep) may be sufficient to elicit activity-dependent expression of BDNF (; ). In fact, it is possible that the BDNF antisense oligos interrupted this replay of learning-related activity (). On the other hand, there may be distinct phases of consolidation mediated by BDNF activity that are independent of experience and synaptic replay and are instead contingent on the induction of BDNF-dependent L-LTP. In other words, there are at least two distinct possibilities for post-acquisition involvement of BDNF signaling in the hippocampus: 1) BDNF synthesis and signaling is triggered by subsequent synaptic activity similar to that induced by initial learning or 2) the initial upregulation of BDNF during acquisition triggers a cascade of events resulting in subsequent BDNF-mediated consolidation processes that itself may recapitulate the learning-related activity. Further work is necessary to distinguish these possibilities.

Synthesis, Trafficking and Release of BDNF | SpringerLink

Extinction of previously acquired memories is a new form of learning and a potential target of BDNF-mediated plasticity. It has been shown that extinction of conditioned fear is accompanied by a significant increase in BDNF gene expression, particularly transcription mediated by BDNF promoters I and III in the prefrontal cortex () and amygdala (). Moreover, extinction of fear-potentiated startle was impaired in mice with a site-specific knockout of the BDNF gene in the dorsal hippocampus through targeted injections of a cre-recombinase lentivirus (). Although it has not been tested, another potential target of BDNF modulation is the context-specific acquisition or retrieval of extinction memory (). Many questions remain to be addressed. First, the role of BDNF in the encoding versus consolidation of extinction memory has not been determined and requires temporally restricted and inducible manipulations of BDNF signaling. As with initial learning, if BDNF plays a role in both, it will be difficult to observe the effect on consolidation if acquisition is compromised. Second, it is unclear whether BDNF transcription, or other aspects of BDNF signaling (trafficking, secretion, etc) is required, and if so, whether specific BDNF transcripts (exon I or III) are involved. Third, BDNF may contribute to specific aspect(s) of memory extinction by modulating synaptic function in specific brain regions. For example, amygdala-specific expression of a dominant-negative truncated TrkB receptor impairs consolidation but not encoding of conditioned fear extinction (). It is possible that hippocampal BDNF is required for acquisition of extinction memory. In contrast, BDNF in the amygdala or prefrontal cortex may be necessary for the consolidation and retention of extinction memory ().

BDNF neuroplasticy | Chemical Synapse | Neuroplasticity

AB - It is generally believed that late-phase long-term potentiation (L-LTP) and long-term memory (LTM) require new protein synthesis. Although the full complement of proteins mediating the long-lasting changes in synaptic efficacy have yet to be identified, several lines of evidence point to a crucial role for activity-induced brain-derived neurotrophic factor (BDNF) expression in generating sustained structural and functional changes at hippocampal synapses thought to underlie some forms of LTM. In particular, BDNF is sufficient to induce the transformation of early to late-phase LTP in the presence of protein synthesis inhibitors, and inhibition of BDNF signaling impairs LTM. Despite solid evidence for a critical role of BDNF in L-LTP and LTM, many issues are not resolved. Given that BDNF needs to be processed in Golgi outposts localized at the branch point of one or few dendrites, a conceptually challenging problem is how locally synthesized BDNF in dendrites could ensure synapse-specific modulation of L-LTP. An interesting alternative is that BDNF-TrkB signaling is involved in synaptic tagging, a prominent hypothesis that explains how soma-derived protein could selectively modulate the tetanized (tagged) synapse. Finally, specific roles of BDNF in the acquisition, retention or extinction of LTM remain to be established.

Reviews: BDNF and Memory Formation and Storage - …

Based on the investigations of BDNF regulation of L-LTP, there are several hypotheses that remain to be tested behaviorally. One of these is that BDNF-TrkB signaling may serve as a PRP-synaptic tag pair (). As discussed above, synaptic tagging allows for synapse specificity of plasticity and, under appropriate conditions, can generate heterosynaptic L-LTP if weak stimulation, sufficient to produce a synaptic tag, can capture PRPs induced by stimulation of an independent pathway. Evidence for “behavioral tagging” was recently reported in a study designed to test whether novelty exposure before or after weak training could provide the PRPs necessary to convert STM to LTM (). Weak inhibitory avoidance conditioning (IA) normally results in a STM memory detectable at 15 minutes, but not 1 or 24 hrs, after training. The same training produces LTM if coupled with novelty exposure. This effect was dependent on protein synthesis as infusion of anisomycin, a protein synthesis inhibitor, immediately after the pretraining exposure to novelty blocked the formation of LTM (). Because BDNF has been suggested to be a critical PRP, it would be interesting to test the sufficiency of this protein to induce LTM by replacing novelty exposure with a transient increase in BDNF expression. Likewise, the role of TrkB in synaptic tagging could be evaluated with a temporally restricted disruption of the receptor at the time of the weak training.