Shifting transcriptional machinery is required for long-term memory maintenance and modification in Drosophila mushroom bodies

Abstract

Accumulating evidence suggests that transcriptional regulation is required for maintenance of long-term memories (LTMs). Here we characterize global transcriptional and epigenetic changes that occur during LTM storage in the Drosophila mushroom bodies (MBs), structures important for memory. Although LTM formation requires the CREB transcription factor and its coactivator, CBP, subsequent early maintenance requires CREB and a different coactivator, CRTC. Late maintenance becomes CREB independent and instead requires the transcription factor Bx. Bx expression initially depends on CREB/CRTC activity, but later becomes CREB/CRTC independent. The timing of the CREB/CRTC early maintenance phase correlates with the time window for LTM extinction and we identify different subsets of CREB/CRTC target genes that are required for memory maintenance and extinction. Furthermore, we find that prolonging CREB/CRTC-dependent transcription extends the time window for LTM extinction. Our results demonstrate the dynamic nature of stored memory and its regulation by shifting transcription systems in the MBs.

Deregulation of CRTCs in Aging and Age-Related Disease Risk

“…These observations contrast with the requirement of CRTC-1 inhibition in AMPK mediated longevity in C. elegans [3], suggesting that CRTCs might display opposite roles in the regulation of lifespan or metabolism, and in neuronal functions and memory. Lastly, in addition to being involved in the formation of memory in Drosophila , the CRTC/CREB complex is also involved in early maintenance of Long Term Memory (LTM), targeting genes required for memory maintenance and extinction in mushroom bodies [100]. …”

Epigenetic regulation of Fgf1 transcription by CRTC1 and memory enhancement

“…Given that deregulation of H4K12 acetylation is involved in age-associated memory loss (Peleg et al, 2010), it is possible that aberrant CRTC1-CREB-KAT5-mediated regulation of H4K12 acetylation may be involved in the pathophysiology of age-related cognitive disorders. Another study has also shown that the transition from memory formation to maintenance is mediated by H4K16 acetylation and shifting the transcriptional complex from CREB/CBP to CREB/CRTC1 in Drosophila (Hirano et al, 2016). This study also reported that KAT5-dependent histone acetylation is required for memory maintenance.…”

“…Some reports have shown recently that CRTC1 plays a key role in synaptic plasticity and memory formation in rodents (Nonaka et al, 2014; Sekeres et al, 2012; Uchida et al, 2017a; Zhou et al, 2006a). Moreover, CRTC1 is associated with memory enhancement and memory maintenance via epigenetic regulation of gene transcription (Hirano et al, 2016; Uchida and Shumyatsky, 2017; Uchida et al, 2017a). …”

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…Recent studies show that molecular processes involved in LTM consolidation and plasticity involve additional gene regulatory mechanisms. Epigenetic mechanisms such as DNA methylation and histone acetylation as well as the role of cofactors are gaining importance. Moreover, recent evidence suggests that CREB initiates a gene regulatory cascade, which appears to be critical for long‐lasting memories .…”

“…Epigenetic mechanisms such as DNA methylation and histone acetylation as well as the role of cofactors are gaining importance. Moreover, recent evidence suggests that CREB initiates a gene regulatory cascade, which appears to be critical for long‐lasting memories . Thus, CREB provides an early entry point and a critical link to a gene regulatory program in LTM.…”