Transgenerational Inheritance of a Cocaine Resistance Phenotype

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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.