The endocannabinoid system has recently been established as a major feedback circuitry controlling synaptic plasticity at multiple neurochemically distinct synapse populations in the meosocorticolimbic system of the adult. However, the functions of endocannabinoid signaling during patterning of the central nervous system, in particular instructing the migration and phenotypic morphometric differentiation of neuronal precursors, in the embryonic brain are unknown. Our lack of knowledge on the cellular specification of endocannabinoid signaling during brain development is surprising given that cannabinoid receptors are the preferred cellular targets of 9-tetrahydrocannabinol (THC), the active component from cannabis, and cannabis smoking during pregnancy causes life-long motor and cognitive deficits, controlled centrally by mesocorticolimbic neuronal circuitries, in the affected offspring. We have previously found that CB1 cannabinoid receptors are selectively localized to the limbic system of the human embryo as early as week 14 of gestation, endocannabinoids and phytocannabinoids are instructive for neuronal migration and cortical interneuron specification, and identified endocannabinoids as a novel class of repulsive axon guidance cues for GABAergic interneurons. In the present project we will focus on: (1) defining the cellular consequences of THC exposure during critical periods of neuronal precursor migration and neuronal synaptogenesis with particular emphasis on their association with GABAergic and dopaminergic (DAergic) neurons in the mesocorticolimbic system and (2) identifying cellular regulatory mechanisms on the transcriptome level that are relevant to THC-induced developmental changes. An integrative, multidiscplinary series of studies will be performed in green fluorescent protein-expressing reporter mice that allow selective visualization of genetically-tagged target neurons. Subsequently, transcriptome analysis from animal model studies of prenatal THC administration will be combined with identifying developmentally-regulated gene sets in mesocorticolimbic neurons whose expression is differentially regulated by prenatal THC in a unique material of cannabis-exposed human fetal brain specimens. Expanding our knowledge of the basic developmental and signaling principles controlled by the endocannabinoid system will provide significant insights about pathological mechanisms of prenatal cannabis exposure that is of significant concern in society considering the continued frequent use of marijuana by pregnant women. The results of this project will expand our current understanding of the functional significance of the endogenous cannabinoid signaling system during brain development and the pathological mechanisms associated with prenatal cannabis exposure. Such insights are of significant importance considering that marijuana is the most commonly used illicit drug by pregnant women and young women of childbearing age.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Wu, Da-Yu
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Alpár, Alán; Di Marzo, Vincenzo; Harkany, Tibor (2016) At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring. Biol Psychiatry 79:e33-45
Malenczyk, Katarzyna; Keimpema, Erik; Piscitelli, Fabiana et al. (2015) Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci U S A 112:E6185-94
Parsons, Loren H; Hurd, Yasmin L (2015) Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16:579-94
Michaelides, Michael; Hurd, Yasmin L (2015) DREAMM: a biobehavioral imaging methodology for dynamic in vivo whole-brain mapping of cell type-specific functional networks. Neuropsychopharmacology 40:239-40
Alpár, Alán; Tortoriello, Giuseppe; Calvigioni, Daniela et al. (2014) Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 5:4421
Tortoriello, Giuseppe; Morris, Claudia V; Alpar, Alan et al. (2014) Miswiring the brain: ?9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33:668-85
Maccarrone, Mauro; Guzmán, Manuel; Mackie, Ken et al. (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15:786-801
Keimpema, Erik; Hökfelt, Tomas; Harkany, Tibor et al. (2014) The molecular interplay between endocannabinoid and neurotrophin signals in the nervous system and beyond. Eur J Neurosci 39:334-43
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
Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram et al. (2014) GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain. Cereb Cortex 24:3277-88

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