A cerebellar granule cell-climbing fiber computation to learn to track long time intervals.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.

Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia.

Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as "high-risk" (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or "low-risk" (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somatic mutations detected at 6 months after IST predicted high-risk evolution.

Cognition-Enhancing Vagus Nerve Stimulation Alters the Epigenetic Landscape.

Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. Here, we present evidence that epigenetic modulation underlies VNS-induced improvements in cognition. We show that VNS enhances novelty preference (NP); alters the hippocampal, cortical, and blood epigenetic transcriptomes; and epigenetically modulates neuronal plasticity and stress-response signaling genes in male Sprague Dawley rats. Brain-behavior analysis revealed structure-specific relationships between NP test performance (NPTP) and epigenetic alterations. In the hippocampus, NPTP correlated with decreased histone deacetylase 11 (HDAC11), a transcriptional repressor enriched in CA1 cells important for memory consolidation. In the cortex, the immediate early gene (IEG) ARC was increased in VNS rats and correlated with transcription of plasticity genes and epigenetic regulators, including HDAC3. For rats engaged in NPTP, ARC correlated with performance. Interestingly, blood ARC transcripts decreased in VNS rats performing NPTP, but increased in VNS-only rats. Because DNA double-strand breaks (DSBs) facilitate transcription of IEGs, we investigated phosphorylated H2A.X (γH2A.X), a histone modification known to colocalize with DSBs. In agreement with reduced cortical stress-response transcription factor NF-κB1, chromatin immunoprecipitation revealed reduced γH2A.X in the ARC promoter. Surprisingly, VNS did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. However, TNFRSF11B (osteoprotegerin) correlated with NPTP as well as plasticity, stress-response signaling, and epigenetic regulation transcripts in both hippocampus and cortex. Together, our findings provide the first evidence that VNS induces widespread changes in the cognitive epigenetic landscape and specifically affects epigenetic modulators associated with NPTP, stress-response signaling, memory consolidation, and cortical neural remodeling.SIGNIFICANCE STATEMENT Recent studies have implicated vagus nerve stimulation (VNS) in enhanced learning and memory. However, whereas epigenetic modifications are known to play an important role in memory, the particular mechanisms involved in VNS-enhanced cognition are unknown. In this study, we examined brain and behavior changes in VNS and sham rats performing a multiday novelty preference (NP) task. We found that VNS activated specific histone modifications and DNA methylation changes at important stress-response signaling and plasticity genes. Both cortical and hippocampal plasticity changes were predictive of NP test performance. Our results reveal important epigenetic alterations associated with VNS cognitive improvements, as well as new potential pharmacological targets for enhancing cortical and hippocampal plasticity.