p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2.

Proper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded b

Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation

Abstract Memory consolidation involves discrete patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, mapping the transcriptomic signature across subregions of the hippocampus has remained challenging. Here, we utilized unbiased spatial sequencing to delineate transcriptome-wide gene expression changes across subregions of the dorsal hippocampus of male mice following learning. We find that each subregion of the hippocampus exhibits distinct yet overlapping transcriptomic signatures. The CA1 region exhibited increased expression of genes related to transcriptional regulation, while the DG showed upregulation of genes associated with protein folding. Importantly, our approach enabled us to define the transcriptomic signature of learning within two less-defined hippocampal subregions, CA1 stratum radiatum, and oriens. We demonstrated that CA1 subregion-specific expression of a transcription factor subfamily has a critical functional role in the consolidation of long-term memory. This work demonstrates the power of spatial molecular approaches to reveal simultaneous transcriptional events across the hippocampus during memory consolidation

Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

<div><p>Objective</p><p>Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.</p><p>Methods</p><p>To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.</p><p>Results</p><p>An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of ‘binge-like’ eating.</p><p>Conclusions</p><p>These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.</p></div

Endoplasmic reticulum chaperone genes encode effectors of long-term memory

The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia

Exendin-4 administration in a model of ‘binge-like’ eating.

<p>Twelve-week-old wild-type female mice were placed on a protocol with intermittent access to HFD. After stable episodes of ‘binge-like’ feeding were achieved, mice received acute administration of exendin-4 (2.4 micrograms/kg) or vehicle 30 minutes prior to access to HFD. Two-hour HFD intake is significantly reduced after exendin-4 administration (n = 8, p = 0.0497 by Student’s t-test). Data presented as mean ± SEM with *p < 0.05 considered significant.</p

Network of genetically-associated genes having additional evidence for involvement in appetite or feeding behaviors.

<p>Genes showing significantly increased burden (FDR < 0.1 for either binge or restricting phenotypes) were projected onto the STRING functional network, and nodes were shaded according to their expression/GO evidence supporting their role as a putative ED gene (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181556#sec006" target="_blank">Methods</a> for details on Random Forest classifier). Square-shaped nodes were shown to have supporting evidence in an automated analysis of the literature (i.e., they are training set genes for the Random Forest classifier).</p

Schematic representation of select peptide neurotransmitters.

<p>(A) proneurotensin, (B) proglucagon, and (C) proopiomelanocortin. Proteolytic cleavage sites highlighted with arrows. Variants observed in our sample are labeled in red. NN- neuromedin N, NT- neurotensin, GLP-1- glucagon-like peptide 1, GLP-2- glucagon-like peptide 2, GRPP- glicentin-related polypeptide, ACTH- adrenocorticotrophic hormone, β-LPH- beta lipotrophin, γ-MSH- gamma melanocyte stimulating hormone, α-MSH- alpha melanocyte stimulating hormone, CLIP- corticotrophin-like intermediate peptide, γ-LPH- gamma lipotrophin, β-end- beta endorphin, ME- met-enkephalin.</p