scholarly journals 4141 Molecular Signatures of Cocaine Toxicity in Postmortem Human Brain and Neurons

2020 ◽  
Vol 4 (s1) ◽  
pp. 140-140
Author(s):  
Emily Frances Mendez ◽  
Laura Stertz ◽  
Gabriel Fries ◽  
Ruifeng Hu ◽  
Thomas Meyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Subjects ◽  
Induced Pluripotent Stem Cell ◽  
Synaptic Proteins ◽  
Specific Gene ◽  
Cocaine Exposure ◽  
Postmortem Human Brain ◽  
Neuronal Nuclei ◽  
Clinical Biomarkers ◽  
Cocaine Toxicity

OBJECTIVES/GOALS: The goal of this project is to identify new therapeutic targets and biomarkers to treat or prevent cocaine toxicity by investigating proteomic, transcriptomic and epigenetic signatures of cocaine exposure in human subjects. METHODS/STUDY POPULATION: Cocaine is a highly addictive neurotoxic substance, and it is estimated that 1.9 million Americans are current users of cocaine. To study the molecular effects of cocaine, we generated preliminary proteomics and next-generation RNA sequencing (RNAseq) data from human postmortem dorsolateral prefrontal cortex (Broadmann area 9 or BA9) of 12 cocaine-exposed subjects and 17 controls. Future directions for this project include RNAseq and DNA methylation analysis of neuronal nuclei sorted from human postmortem BA9 and a human induced pluripotent stem cell-derived neuron (hiPSN) model of cocaine exposure from the same postmortem subjects from whom we have brain samples. RESULTS/ANTICIPATED RESULTS: We found alterations in neuronal synaptic protein levels and gene expression, including the serotonin transporter SLC6A4, and synaptic proteins SNAP25, SYN2, SYNGR3. Pathway analysis of our results revealed alterations in specific pathways involved with neuronal function including voltage-gated calcium channels, and GABA receptor signaling. In the future, we expect to see an enhancement in neuron-specific gene expression signatures in our sorted neuronal nuclei and our hiPSN model of cocaine exposure. The hiPSN model will help elucidate which effects are due to acute versus chronic exposure of cocaine. DISCUSSION/SIGNIFICANCE OF IMPACT: Neuronal signatures found with this analysis can help us understand mechanisms of cognitive decline in long-term cocaine users as well as the acute effects on the brain of cocaine taken in overdose. With this work and future proposed studies, we can discover novel clinical biomarkers for cocaine neurotoxicity in patients with cocaine use disorder and determine readouts for future therapeutic development on cocaine addiction and overdose.

scholarly journals Egr2 induction in SPNs of the ventrolateral striatum contributes to cocaine place preference in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Diptendu Mukherjee ◽  
Ben Jerry Gonzales ◽  
Reut Ashwal-Fluss ◽  
Hagit Turm ◽  
Maya Groysman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Exposure ◽  
Dorsal Striatum ◽  
Gene Induction ◽  
Early Gene ◽  
Specific Gene ◽  
Cocaine Exposure ◽  
Neuronal Ensembles ◽  
Cocaine Seeking ◽  
Cell Type Specific

Drug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG Egr2 in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.

scholarly journals Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

2019 ◽  
Vol 3 (2) ◽  
pp. 468-487 ◽  
Author(s):  
Taylor P LaRese ◽  
Bruce A Rheaume ◽  
Ron Abraham ◽  
Betty A Eipper ◽  
Richard E Mains
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Specific Gene ◽  
Cocaine Exposure ◽  
Specific Gene Expression ◽  
Before And After

scholarly journals Integrative inference of brain cell similarities and differences from single-cell genomics

2018 ◽  
Author(s):  
Joshua Welch ◽  
Velina Kozareva ◽  
Ashley Ferreira ◽  
Charles Vanderburg ◽  
Carly Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Single Cell ◽  
Human Subjects ◽  
Cell Types ◽  
Joint Analysis ◽  
Specific Gene ◽  
Cell Type ◽  
Type Definition ◽  
Cell Type Specific

SummaryDefining cell types requires integrating diverse measurements from multiple experiments and biological contexts. Recent technological developments in single-cell analysis have enabled high-throughput profiling of gene expression, epigenetic regulation, and spatial relationships amongst cells in complex tissues, but computational approaches that deliver a sensitive and specific joint analysis of these datasets are lacking. We developed LIGER, an algorithm that delineates shared and dataset-specific features of cell identity, allowing flexible modeling of highly heterogeneous single-cell datasets. We demonstrated its broad utility by applying it to four diverse and challenging analyses of human and mouse brain cells. First, we defined both cell-type-specific and sexually dimorphic gene expression in the mouse bed nucleus of the stria terminalis, an anatomically complex brain region that plays important roles in sex-specific behaviors. Second, we analyzed gene expression in the substantia nigra of seven postmortem human subjects, comparing cell states in specific donors, and relating cell types to those in the mouse. Third, we jointly leveraged in situ gene expression and scRNA-seq data to spatially locate fine subtypes of cells present in the mouse frontal cortex. Finally, we integrated mouse cortical scRNA-seq profiles with single-cell DNA methylation signatures, revealing mechanisms of cell-type-specific gene regulation. Integrative analyses using the LIGER algorithm promise to accelerate single-cell investigations of cell-type definition, gene regulation, and disease states.

scholarly journals Egr2 induction in Drd1+ ensembles of the ventrolateral striatum supports the development of cocaine reward

2020 ◽  
Author(s):  
Diptendu Mukherjee ◽  
Ben Jerry Gonzales ◽  
Reut Ashwal-Fluss ◽  
Hagit Turm ◽  
Maya Groysman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Exposure ◽  
Dorsal Striatum ◽  
Gene Induction ◽  
Early Gene ◽  
Specific Gene ◽  
Cocaine Exposure ◽  
Neuronal Ensembles ◽  
Cell Type Specific ◽  
Cocaine Reward

AbstractDrug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG Egr2 in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.Impact statementVLS ensembles are dynamically recruited by cocaine experiences to mediate cocaine reward.

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