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Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b -specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1 -associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease. [Display omitted] • Expression of c ircHomer1 is inversely associated with relative HOMER1B mRNA levels • CircHomer1 and Homer1b bind to each other and inhibit each other's synaptic expression • In vivo KD of Homer1b improves OFC-mediated chance reversal learning • Co-KD of Homer1b and circHomer1 restores chance reversal learning Through in vivo circRNA and mRNA isoform-specific knockdown in mouse orbitofrontal cortex (OFC), Hafez et al. elucidate the antagonistic interaction between the psychiatric-disease-associated circHomer1 and Homer1b mRNA and their opposing effects on OFC-mediated reversal learning. [ABSTRACT FROM AUTHOR]

Discrimination thresholds were obtained using a delayed spatial frequency discrimination task. In Experiment 1, we found that presentation of a mask 3 s before onset of a reference Gabor patch caused a selective, spatial frequency dependent interference in a subsequent discrimination task. However, a 10 s interval abolished this masking effect. In Experiment 2, the mask was associated with a second spatial frequency discrimination task so that a representation of the mask had to be coded into short-term perceptual memory. This experiment was performed to assess whether absence of masking in the 10 s condition of Experiment 1 might be due to decay of the mask information in the perceptual or the memory representational domain. The presence of this second discrimination task now caused similar interference effects on the primary discrimination task at both the 3 s and 10 s interstimulus intervals (ISI) conditions. Finally, to test the robustness of the masking effect, the nature of the secondary masking task was changed from a spatial frequency discrimination task to an orientation discrimination task in Experiment 3. The masking effect was now abolished in both the 3 and 10 s ISI conditions. Together, the results from these experiments are consistent with the idea of a two-level perceptual memory mechanism. The results also suggest that stimulus representations during a perceptual discrimination task are shared between the perceptual and memory representation domains in a task-dependent manner. [Copyright &y& Elsevier]

Estrogens rapidly facilitate learning and memory, including social recognition – the ability of an animal to recognize another. In ovariectomized female mice, systemic or dorsal hippocampal administration of 17β-estradiol (E2) facilitates short-term social recognition memory within 40 min. Within the same timeframe, E2 increases dendritic spine density in CA1 dorsal hippocampal neurons of behavioural task-naïve mice and in hippocampal sections. Mechanisms underlying these effects remain unclear. Estrogens rapidly modulate actin cytoskeletal dynamics through actin polymerization and the translation of key synaptic proteins. We first determined doses of actin polymerization inhibitor latrunculin A (LAT) and protein synthesis inhibitor anisomycin (ANI) that would block short-term social recognition memory when infused into the dorsal hippocampus of ovariectomized female mice 15 min prior to testing. The highest doses that did not block social recognition prevented the facilitating effects of E2, whereas DNA transcription inhibitor, actinomycin D, could not block social recognition. As task performance may interfere with E2-facilitated increases in dendritic spine density, dendritic spine density and length were examined in task-performing and task-naïve mice. E2 increased dendritic spine density 15 but not 40 min following treatment, regardless of whether the animal had performed the social recognition task. This effect was blocked by LAT, but not ANI. Thus, both actin polymerization and protein synthesis are necessary for E2 to rapidly facilitate social recognition, whereas actin polymerization, but not protein synthesis, is required for the rapid increase in dendritic spine density brought on by E2. • Dorsal hippocampal actin polymerization or protein synthesis inhibition blocks short-term social recognition memory (SRM). • Dorsal hippocampal actin polymerization and protein synthesis inhibition blocks E2-facilitated short-term SRM. • Dorsal hippocampal E2 increases dendritic spine density 15- but not 40-minutes following treatment. • Actin polymerization, but not protein synthesis, inhibition blocks E2-facilitated dendritic spine density increases. [ABSTRACT FROM AUTHOR]