Marijuana (Cannabis sativa) is the most commonly abused illicit drug by teens and young adults of childbearing age in the USA with significant social and public health implications. While research efforts have begun to characterize the behavioral and neurobiological consequences of direct repeated exposure to cannabis, the possible impact across multiple generations is not known. Preliminary data obtained in our lab suggests that adult rats from parents with adolescent exposure to D-tetrahydrocannabinol (THC; primary psychoactive component of cannabis) exhibit reduced motivation and a depression-like phenotype, as well as anxiety-related behaviors that develop in response to their tendency for increased heroin intake. In addition, both male and female F1 offspring show decreased striatal expression of genes that encode several components of the dopamine, opioid and glutamate neurotransmitter systems. Female F1 offspring tended to have more significant disturbances, emphasizing the importance of gender that could potentially be relevant to sex differences seen in psychiatric disorders. The goal of this proposal is to characterize the whole population of mRNAs in the nucleus accumbens (NAc) of F1 offspring from parents with a history of THC exposure by transcriptome sequencing, as well as to study whole genome DNA methylation and chromatin modifications to identify the epigenetic milieu underlying the cross- generational disturbances in this mesolimbic brain region. The molecular studies will be combined with behavioral tests to assess reward-, depression- and anxiety-like behaviors in F1 males and females. We will address the causality between gene expression impairments and specific behavioral phenotypes using in vivo gene manipulations in the NAc. In order to determine whether there is persistent transgenerational transmission, phenotypic and epigenetic marks shown to be impaired in the F1 generation will be followed into the F2 progeny. Overall, these studies will provide fundamental mechanistic insights into the cross-generational impact of cannabis exposure that could guide the development of therapeutic interventions for the spectrum of behavioral phenotypes associated with vulnerability to addiction and psychiatric disorders.

Public Health Relevance

Marijuana is the illicit drug most used in the USA. Understanding the possible cross-generational impact of parental marijuana exposure on neurobiological events and behavior in their adult offspring and subsequent generations could provide insight into neurobiological mechanisms that underlie the spectrum of behavioral traits linked to the vulnerability to psychiatric and addiction disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033660-04
Application #
8828645
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Wu, Da-Yu
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Miller, Michael L; Chadwick, Benjamin; Dickstein, Dara L et al. (2018) Adolescent exposure to ?9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol Psychiatry :
Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153
Szutorisz, Henrietta; Hurd, Yasmin L (2018) High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 85:93-101
Michaelides, Michael; Miller, Michael L; DiNieri, Jennifer A et al. (2017) Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic-Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement. Neuropsychopharmacology 42:2365-2376
Miller, Michael L; Hurd, Yasmin L (2017) Testing the Gateway Hypothesis. Neuropsychopharmacology 42:985-986
Szutorisz, Henrietta; Egervári, Gabor; Sperry, James et al. (2016) Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. Neurotoxicol Teratol 58:107-114
Peter, Cyril J; Fischer, Laura K; Kundakovic, Marija et al. (2016) DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition. Biol Psychiatry 80:765-774
Gymrek, Melissa; Willems, Thomas; Guilmatre, Audrey et al. (2016) Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet 48:22-9
Szutorisz, Henrietta; Hurd, Yasmin L (2016) Epigenetic Effects of Cannabis Exposure. Biol Psychiatry 79:586-94
Joshi, Ricky S; Garg, Paras; Zaitlen, Noah et al. (2016) DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome. Am J Hum Genet 99:555-566

Showing the most recent 10 out of 29 publications