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.
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.
