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Principal Investigator: Robert Christopher Pierce
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $531,579
Funding agency: National Institute on Drug Abuse
Project Summary
The focus of this research program, which has been NIH-funded since 2012, is the influence of paternal
psychostimulant self-administration on the physiology and behavior of subsequent generations (i.e. offspring
and grand-offspring) using rat models. Our work previously demonstrated that sire cocaine self-administration
reprogramed the germline epigenome resulting in decreased cocaine reinforcing efficacy in the male progeny.
The current application expands our focus on cocaine alone to encompass the transgenerational effects of
paternal methamphetamine (meth), which will be compared and contrasted with cocaine. The proposed
research will examine the mechanisms whereby information is passed to meth-sired offspring (and potentially
grand-offspring) through epigenetic changes in sperm. We also will define epigenetic and transcriptional
profiles in the nucleus accumbens of cocaine- and meth-sired offspring that may underlie the respective
influences on psychostimulant self-administration. Specific Aim 1 will examine the behavioral consequences of
paternal meth self-administration on psychostimulant self-administration in male and female offspring (F1) and
grand-offspring (F2). Intriguingly, our preliminary results indicate that meth and cocaine produce opposite
effects on psychostimulant reinforcing efficacy in male offspring. In contrast to our prior results with cocaine,
preliminary data indicate that paternal meth self-administration results in increased self-administration of, and
motivation for, this psychostimulant selectively in male offspring. Drug naïve F1 rats will be used to generate
an F2 generation, where the acquisition, maintenance and reinforcing efficacy of meth will be assessed just as
in F1 offspring. In Specific Aim 2 we will assess epigenetic changes in sperm through which paternal
psychostimulant self-administration may influence the behavior of offspring. Potential transgenerational
cocaine- and meth-induced epigenetic alterations (small noncoding RNAs and DNA methylation) in sperm will
be evaluated. Finally, genome-wide assessments of psychostimulant transgenerational effects have not yet
been performed on neurons in the nucleus accumbens, a brain region that plays a critical role in modulating
psychostimulant-induced behaviors. The experiments in Specific Aim 3 are designed to interrogate the
landscape of accessible chromatin and gene expression by coupling single-nuclei ATAC-seq and single-nuclei
RNA-seq analyses in the accumbens of experimentally naive meth-sired, cocaine-sired and saline-sired rats.
Collectively, the experiments described in this application will use state-of-the-art cellular, molecular and
behavioral methodologies to examine epigenetic mechanisms whereby psychostimulant-associated
information can be transmitted from sires to offspring and grand-offspring. These cross-generational studies
represent a novel strategy to identify transcripts related to risk or protective factors for psychostimulant self-
administration, which will illuminate new targets for therapeutic development.
Terms: <21+ years old><ATAC sequencing><ATAC-seq><ATACseq><Adult><Adult Human><Ammon Horn><Animal Model><Animal Models and Related Studies><Anxiety><Assay for Transposase-Accessible Chromatin using sequencing><BS-seq><Behavior><Behavioral><Bisulfite-based sequencing><Brain><Brain Nervous System><Brain region><Breeding><Cell Nucleus><Characteristics><Chromatin><Cocaine><Common Rat Strains><Cornu Ammonis><Coupling><Crystal Meth><Crystal methamphetamine><DNA Methylation><Data><Deoxyephedrine><Desoxyephedrine><Drugs><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Expression Signature><Female><Functional RNA><Funding><Gene Expression><Gene Expression Profile><Generations><Genes><Germ Lines><Grant><Health><Hereditary><Heritability><Hippocampus><Human><Impairment><Inherited><L-Serine><Learning><Maintenance><Measurement><Mediating><Medication><Messenger RNA><Methamphetamine><Methodology><Methylamphetamine><Methylation><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Motivation><N-Methyl-D-Aspartate Receptors><N-Methylamphetamine><N-Methylaspartate Receptors><NIH><NMDA Receptor-Ionophore Complex><NMDA Receptors><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleus><Nucleus Accumbens><Partner in relationship><Paternal Exposure><Pharmaceutical Preparations><Phenotype><Physiology><Play><Proteins><RNA Seq><RNA methylation><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Receptor Signaling><Reinforcement Schedule><Research><Resistance><Risk Factors><Role><Saccharose><Saline><Saline Solution><Self Administered><Self Administration><Serine><Single-Nucleus Sequencing><Specificity><Sperm><Spermatozoa><Sucrose><Synaptic plasticity><Transcript><Transfer RNA><Transmission><Triplet Codon-Amino Acid Adaptor><United States National Institutes of Health><Untranslated RNA><Viral><Work><addiction><addiction to psychostimulants><addiction to stimulants><addictive disorder><adulthood><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><behavior influence><behavioral influence><bisulfite sequencing><bisulfite-seq><cocaine exposure><cocaine self-administration><cocaine-exposed><design><designing><drug/agent><epigenetically><epigenome><experiment><experimental research><experimental study><experiments><exposed to cocaine><exposure to cocaine><exposure to meth><exposure to methamphetamine><gene expression pattern><gene expression signature><genome scale><genome-wide><genomewide><hippocampal><interest><knock-down><knockdown><mRNA><male><mate><meth><meth exposure><methamphetamine exposure><miRNA><miRNAs><model of animal><neuronal><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><noncoding><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><offspring><overexpress><overexpression><programs><protective factors><psychostimulant><psychostimulant addiction><psychostimulant dependence><reinforcer><resistant><sNuc-Seq><self-administer cocaine><sex><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><sperm cell><stimulant addiction><stimulant dependence><tRNA><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transfer Ribonucleic acids><transgenerational epigenetic inheritance><transgenerational inheritance><transmission process><zoosperm>