Cell-type and sex-specific rhythmic gene expression in the nucleus accumbens.

Circadian rhythms are critical for human health and are highly conserved across species. Disruptions in these rhythms contribute to many diseases, including psychiatric disorders. Previous results suggest that circadian genes modulate behavior through specific cell types in the nucleus accumbens (NAc), particularly dopamine D1-expressing medium spiny neurons (MSNs). However, diurnal rhythms in transcript expression have not been investigated in NAc MSNs. In this study we identified and characterized rhythmic transcripts in D1- and D2-expressing neurons and compared rhythmicity results to homogenate as well as astrocyte samples taken from the NAc of male and female mice. We find that all cell types have transcripts with diurnal rhythms and that top rhythmic transcripts are largely core clock genes, which peak at approximately the same time of day in each cell type and sex. While clock-controlled rhythmic transcripts are enriched for protein regulation pathways across cell type, cell signaling and signal transduction related processes are most commonly enriched in MSNs. In contrast to core clock genes, these clock-controlled rhythmic transcripts tend to reach their peak in expression about 2-h later in females than males, suggesting diurnal rhythms in reward may be delayed in females. We also find sex differences in pathway enrichment for rhythmic transcripts peaking at different times of day. Protein folding and immune responses are enriched in transcripts that peak in the dark phase, while metabolic processes are primarily enriched in transcripts that peak in the light phase. Importantly, we also find that several classic markers used to categorize MSNs are rhythmic in the NAc. This is critical since the use of rhythmic markers could lead to over- or under-enrichment of targeted cell types depending on the time at which they are sampled. This study greatly expands our knowledge of how individual cell types contribute to rhythms in the NAc.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome.

Polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). Presently, no treatments exist for this rare disease that manifests with a spectrum of symptoms including intellectual disability, developmental delay, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in patients. Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation in Sms gene that results in a glycine-to-serine substitution at position 56 (G56S) of the SMS protein. Mice harboring this mutation exhibit a complete loss of SMS protein and elevated spermidine/spermine ratio in skeletal muscles and the brain. In addition, the G56S mice demonstrate increased anxiety, impaired learning, and decreased explorative behavior in fear conditioning, Morris water maze, and open field tests, respectively. Furthermore, these mice failed to gain weight over time and exhibit abnormalities in brain structure and bone density. Transcriptomic analysis of the cerebral cortex revealed downregulation of genes associated with mitochondrial oxidative phosphorylation and ribosomal protein synthesis. Our findings also revealed impaired mitochondrial bioenergetics in fibroblasts isolated from the G56S mice, indicating a correlation between these processes in the affected mice. Collectively, our findings establish the first in-depth characterization of an SRS preclinical mouse model that identifies cellular processes that could be targeted for future therapeutic development.

Resolving Phylogenetic Relationships for Streptococcus mitis and Streptococcus oralis through Core- and Pan-Genome Analyses.

Taxonomic and phylogenetic relationships of Streptococcus mitis and Streptococcus oralis have been difficult to establish biochemically and genetically. We used core-genome analyses of S. mitis and S. oralis, as well as the closely related species Streptococcus pneumoniae and Streptococcus parasanguinis, to clarify the phylogenetic relationships between S. mitis and S. oralis, as well as within subclades of S. oralis. All S. mitis (n = 67), S. oralis (n = 89), S. parasanguinis (n = 27), and 27 S. pneumoniae genome assemblies were downloaded from NCBI and reannotated. All genes were delineated into homologous clusters and maximum-likelihood phylogenies built from putatively nonrecombinant core gene sets. Population structure was determined using Bayesian genome clustering, and patristic distance was calculated between populations. Population-specific gene content was assessed using a phylogenetic-based genome-wide association approach. Streptococcus mitis and S. oralis formed distinct clades, but species mixing suggests taxonomic misassignment. Patristic distance between populations suggests that S. oralis subsp. dentisani is a distinct species, whereas S. oralis subsp. tigurinus and subsp. oralis are supported as subspecies, and that S. mitis comprises two subspecies. None of the genes within the pan-genomes of S. mitis and S. oralis could be statistically correlated with either, and the dispensable genomes showed extensive variation among isolates. These are likely important factors contributing to established overlap in biochemical characteristics for these taxa. Based on core-genome analysis, the substructure of S. oralis and S. mitis should be redefined, and species assignments within S. oralis and S. mitis should be made based on whole-genome analysis to be robust to misassignment.