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.

MicroRNAs (miRNAs) are endogenous small (18–25 nt), single-stranded, non-coding RNAs that play key roles in post-transcriptional gene expression regulation. The expression profiles of miRNAs in biofluids and tissues change in various diseases. Multiple system atrophy (MSA) and Parkinson’s disease (PD) are both categorized as α-synucleinopathies and often present with similar clinical manifestations. This study aimed to identify miRNAs that are differently expressed in plasma samples of PD patients, MSA patients, and healthy controls. We used microarray analysis to screen for miRNAs that are up- and down-regulated in these patients and analyzed the relative-quantitative expression levels of the identified miRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p showed significantly different expression levels among patients with MSA-C, MSA-P, or PD, and healthy controls. Hsa-miR-671-5p levels were lower in the MSA-P and PD than the MSA-C and control groups, hsa-miR-19b-3p levels were higher in the PD than the other groups, and hsa-miR-24-3p levels were higher in the PD than the MSA-C group. Hsa-miR-671-5p was the first miRNA shown to be expressed differently between MSA-C and MSA-P in plasma. Interestingly, the expression levels of hsa-miR-19b-3p and hsa-miR-24-3p were positively correlated, indicating that these miRNAs may be involved in the same processes in PD pathogenesis. Our findings suggest that hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p may reflect the pathophysiology or symptoms of PD and MSA. Electronic supplementary material The online version of this article (10.1186/s13041-019-0471-2) contains supplementary material, which is available to authorized users.

Memory consolidation is augmented by repeated learning following rest intervals, which is known as the spacing effect. Although the spacing effect has been associated with cumulative cellular responses in the neurons engaged in memory, here, we report the neural circuit-based mechanism for generating the spacing effect in the memory-related mushroom body (MB) parallel circuits in Drosophila. To investigate the neurons activated during the training, we monitored expression of phosphorylation of mitogen-activated protein kinase (MAPK), ERK [phosphorylation of extracellular signal-related kinase (pERK)]. In an olfactory spaced training paradigm, pERK expression in one of the parallel circuits, consisting of γm neurons, was progressively inhibited via dopamine. This inhibition resulted in reduced pERK expression in a postsynaptic GABAergic neuron that, in turn, led to an increase in pERK expression in a dopaminergic neuron specifically in the later session during spaced training, suggesting that disinhibition of the dopaminergic neuron occurs during spaced training. The dopaminergic neuron was significant for gene expression in the different MB parallel circuits consisting of α/βs neurons for memory consolidation. Our results suggest that the spacing effect-generating neurons and the neurons engaged in memory reside in the distinct MB parallel circuits and that the spacing effect can be a consequence of evolved neural circuit architecture.

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Genetic Creutzfeldt-Jakob disease (gCJD) with a mutation in codon 180 of the prion protein gene (V180I gCJD) is the most common form of gCJD in Japan, but only a few cases have been reported in Europe and the United States. It is clinically characterized by occurring in the elderly and presenting as slowly progressive dementia, although it generally shows less cerebellar and pyramidal symptoms than sporadic CJD. Here, we report a patient with V180I gCJD who initially presented with slowly progressive spastic paralysis with neither cerebrospinal fluid (CSF) nor magnetic resonance imaging (MRI) abnormalities. His symptoms progressed gradually, and after 9 years, he displayed features more typical of CJD. Diffusion-weighted MRI revealed high-intensity signals in the cortical gyrus, and there was a marked increase of 14-3-3 protein and total tau protein in the CSF, but he was negative for the real-time quaking-induced conversion assay. Although the time course was more consistent with Gerstmann-Sträussler-Scheinker disease than CJD, genetic testing revealed V180I gCJD. This is the first report of a patient with V180I gCJD who initially presented with spastic paralysis, and also the first to reveal that it took 9 years from disease onset for cortical dysfunction to develop and for MRI and CSF abnormalities to be detectable. In conclusion, we should screen for V180I gCJD in elderly patients presenting with slowly progressive spastic paralysis.