Spatial, transcriptomic, and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition.

Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology.

Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains.

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current, frontline addiction treatment strategies fail to produce lasting abstinence in most users. This underscores the lasting effects of chronic opioid exposure and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal.

Regression convolutional neural network models implicate peripheral immune regulatory variants in the predisposition to Alzheimer's disease.

Alzheimer's disease (AD) involves aggregation of amyloid β and tau, neuron loss, cognitive decline, and neuroinflammatory responses. Both resident microglia and peripheral immune cells have been associated with the immune component of AD. However, the relative contribution of resident and peripheral immune cell types to AD predisposition has not been thoroughly explored due to their similarity in gene expression and function.

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder.

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD.

Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes.

Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor that is implicated in a variety of psychiatric disorders including autism spectrum disorder (ASD), major depression, and schizophrenia. Autosomal dominant mutations in TCF4 are causal for a specific ASD called Pitt-Hopkins Syndrome (PTHS). However, our understanding of etiological and pathophysiological mechanisms downstream of TCF4 mutations is incomplete.

Integrative multi-dimensional characterization of striatal projection neuron heterogeneity in adult brain.

Striatal projection neurons (SPNs) are traditionally segregated into two subpopulations expressing dopamine (DA) D-like or D-like receptors. However, this dichotomy is challenged by recent evidence. Functional and expression studies raise important questions: do SPNs co-express different DA receptors, and do these differences reflect unique striatal spatial distributions and expression profiles? Using RNAscope in mouse striatum, we report heterogenous SPN subpopulations distributed across dorsal-ventral and rostral-caudal axes.

Relating enhancer genetic variation across mammals to complex phenotypes using machine learning.

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low sequence conservation. We developed the Tissue-Aware Conservation Inference Toolkit (TACIT) to associate candidate enhancers with species' phenotypes using predictions from machine learning models trained on specific tissues.

Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.

Machine learning sequence prioritization for cell type-specific enhancer design.

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic strain or virus screening. Here, we present Specific Nuclear-Anchored Independent Labeling (SNAIL), an improved virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue.

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder.

Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction.

Induction of Bdnf from promoter I following electroconvulsive seizures contributes to structural plasticity in neurons of the piriform cortex.

Background: Electroconvulsive therapy (ECT) efficacy is hypothesized to depend on induction of molecular and cellular events that trigger neuronal plasticity. Investigating how electroconvulsive seizures (ECS) impact plasticity in animal models can help inform our understanding of basic mechanisms by which ECT relieves symptoms of depression. ECS-induced plasticity is associated with differential expression of unique isoforms encoding the neurotrophin, brain-derived neurotrophic factor (BDNF).

Addiction-Associated Genetic Variants Implicate Brain Cell Type- and Region-Specific Cis-Regulatory Elements in Addiction Neurobiology.

Recent large genome-wide association studies have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in noncoding regions of the genome, likely disrupting -regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction.

Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder.

Background: Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on the dorsolateral prefrontal cortex and nucleus accumbens, regions heavily implicated in OUD, from postmortem brains in subjects with OUD.

SPEAQeasy: a scalable pipeline for expression analysis and quantification for R/bioconductor-powered RNA-seq analyses.

Background: RNA sequencing (RNA-seq) is a common and widespread biological assay, and an increasing amount of data is generated with it. In practice, there are a large number of individual steps a researcher must perform before raw RNA-seq reads yield directly valuable information, such as differential gene expression data. Existing software tools are typically specialized, only performing one step-such as alignment of reads to a reference genome-of a larger workflow.

dotdotdot: an automated approach to quantify multiplex single molecule fluorescent in situ hybridization (smFISH) images in complex tissues.

Multiplex single-molecule fluorescent in situ hybridization (smFISH) is a powerful method for validating RNA sequencing and emerging spatial transcriptomic data, but quantification remains a computational challenge. We present a framework for generating and analyzing smFISH data in complex tissues while overcoming autofluorescence and increasing multiplexing capacity. We developed dotdotdot (https://github.

A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Pten and Mecp2).

Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs.

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across 9 time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells. We identify widespread changes in the expression of both individual features and global patterns of transcription.

Salvage Stereotactic Radiosurgery in Breast Cancer Patients with Multiple Brain Metastases.

Background: The overall survival rates for breast cancer are increasing due to controlled brain disease and improved systemic treatments. This study examined neurologic outcomes, tumor control, and survival data in breast cancer patients with multiple brain metastases and who required salvage stereotactic radiosurgery (SRS) for recurrent breast cancer brain metastases.

Methods: The study included 231 patients with a primary diagnosis of breast cancer who underwent SRS for more than 1 brain metastases from May 1993 and July 2007.