The major goal of our NIDA-funded (R01DA041208) grant is to determine the molecular mechanisms of the interaction between genetic predisposition and adolescent cannabis exposure in producing long-term cognitive impairment in adulthood. The main focus of our study is the cell type-specific inflammatory pathways that mediate deleterious effects of adolescent treatment with ?9-tetrahydrocannabinol (?9-THC), a psychoactive cannabis constituent. We have recently reported that astrocyte-selective expression of a mutant form of disrupted in schizophrenia 1 (DISC1), a gene involved in neurodevelopment and synaptic plasticity, and adolescent ?9-THC treatment synergistically up-regulate inflammatory signaling in astrocytes, leading to impaired recognition memory (Jouroukhin et al., Biological Psychiatry 2018). These results suggest that genetic risk factors expressed in astrocytes may play a key role in moderating adverse effects of adolescent ?9-THC exposure. However, recent studies demonstrate that a chronic low dose of ?9-THC was able to reverse age-related cognitive decline and prevent neurodegenerative processes via protection from inflammation-induced cognitive damage in animal models of Alzheimer's disease. Considering these biphasic age-dependent effects of ?9-THC on cognition, we propose to extend our NIDA-funded studies to test the hypothesis that the opposite cognitive effects of ?9-THC in adolescent vs. aged mice could be explained by age-dependent changes in cannabinoid receptor 1 (CNR1)-mediated molecular cascades in astrocytes. To test this hypothesis, we will determine the role of astrocyte CNR1 in age-dependent (i.e., opposite) effects of ?9- THC on cognition by selectively deleting expression of CNR1 in astrocytes of adolescent and aged mice.
This aim will establish the impact of aging on CNR1 signaling in astrocytes and its contribution to the ?beneficial? effects of low doses of ?9-THC on cognition in aged mice as compared to adolescent mice. We will also identify astrocyte-specific transcriptome signatures to underpin age-dependent effects of ?9-THC using cell type specific RNA-sequencing approach.
This aim will determine the age-dependent and cell type-specific molecular mechanisms that underlie the ?beneficial? effects of low doses of ?9-THC on cognition in aged mice as compared to adolescent mice. The supplemental proposal will provide critical information for understanding the molecular mechanisms underlying adverse and beneficial age-dependent effects of ?9-THC on cognitive function, and will stimulate discovery treatment approaches for cognitive dysfunction in normal or pathological aging.

Public Health Relevance

The grant application aims to determine the convergent mechanisms of genetic predispositions and adolescent cannabis exposure on neuronal function and long-term cognitive changes in adulthood. The proposed work will provide important knowledge about the cell type-specific molecular mechanisms of deleterious effects of adolescent cannabis use on cognitive behaviors in adults. Supplemental proposal will identify age-dependent biphasic effects of ?9-THC on cognitive function and molecular landscapes in the astrocyte.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA041208-04S1
Application #
9874833
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wu, Da-Yu
Project Start
2016-09-15
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Xu, Zhexue; Zhang, Shu; Huang, Liyuan et al. (2018) Altered Resting-State Brain Activities in Drug-Naïve Major Depressive Disorder Assessed by fMRI: Associations With Somatic Symptoms Defined by Yin-Yang Theory of the Traditional Chinese Medicine. Front Psychiatry 9:195
Leishman, Emma; Murphy, Michelle; Mackie, Ken et al. (2018) ?9-Tetrahydrocannabinol changes the brain lipidome and transcriptome differentially in the adolescent and the adult. Biochim Biophys Acta Mol Cell Biol Lipids 1863:479-492
Jouroukhin, Yan; Kageyama, Yusuke; Misheneva, Varvara et al. (2018) DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders. Transl Psychiatry 8:76
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Terrillion, Chantelle E; Abazyan, Bagrat; Yang, Zhongxi et al. (2017) DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice. Neuropsychopharmacology 42:2242-2251
Shevelkin, Alexey V; Terrillion, Chantelle E; Abazyan, Bagrat N et al. (2017) Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice. Neurobiol Dis 103:144-153