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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-MXL-F (07))
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Calvigioni, Daniela; Hurd, Yasmin L; Harkany, Tibor et al. (2014) Neuronal substrates and functional consequences of prenatal cannabis exposure. Eur Child Adolesc Psychiatry 23:931-41
Brahmachary, Manisha; Guilmatre, Audrey; Quilez, Javier et al. (2014) Digital genotyping of macrosatellites and multicopy genes reveals novel biological functions associated with copy number variation of large tandem repeats. PLoS Genet 10:e1004418
Garg, Paras; Ludwig, Kerstin U; Bohmer, Anne C et al. (2014) Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts. Eur J Hum Genet 22:822-30
Watson, Corey T; Marques-Bonet, Tomas; Sharp, Andrew J et al. (2014) The genetics of microdeletion and microduplication syndromes: an update. Annu Rev Genomics Hum Genet 15:215-44
Szutorisz, Henrietta; DiNieri, Jennifer A; Sweet, Eric et al. (2014) Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology 39:1315-23
Tyson, Christine; Sharp, Andrew J; Hrynchak, Monica et al. (2014) Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2. Eur J Hum Genet 22:458-63
Huynh, Jimmy L; Garg, Paras; Thin, Tin Htwe et al. (2014) Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci 17:121-30
Hurd, Yasmin L; Michaelides, Michael; Miller, Michael L et al. (2014) Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology 76 Pt B:416-24
Hernando-Herraez, Irene; Prado-Martinez, Javier; Garg, Paras et al. (2013) Dynamics of DNA methylation in recent human and great ape evolution. PLoS Genet 9:e1003763
Guilmatre, Audrey; Highnam, Gareth; Borel, Christelle et al. (2013) Rapid multiplexed genotyping of simple tandem repeats using capture and high-throughput sequencing. Hum Mutat 34:1304-11

Showing the most recent 10 out of 11 publications