Cerebellar biobehavioral markers in cannabis users

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Cannabis use represents a significant and increasing public health concern as social acceptance accompanies legalization of this drug for medicinal and recreational purposes. These factors make understanding the health consequences of cannabis (CB) urgent and critical. For example, a recent study found university students age 19-22 had the highest rate of CB use in the last 30 years, with 39% having used in the last year. The prevailing view is that CB is a significant public health risk factor because (1) use is associated with increased risk for health and accidents, (2) adolescent use likely disturbs crucial brain maturation processes; (3) chronic use has been associated with cognitive deficits and (4) people who use CB are at increased risk for psychotic and mood disorders. However, the assessment of risks associated with cannabis is currently incomplete and equivocal. The proposed research strongly advocates that understanding the risks (or lack thereof) depends critically on a neural circuit-informed approach to testing the integrity of brain systems known to be richly endowed with CB-relevant receptors that are altered in response to CB exposure. The principal psychoactive ingredient of CB is delta-9-tetrahydrocannabinol (THC), which acts as a ligand for widely distributed CB1 receptors in the human brain. CB1R density in cerebellum is one of the highest in the brain. Although measures of cerebellar function could provide sensitive probes for the neurobehavioral effects of CB use, they have rarely been tested in CB users, nor have they been explicitly linked to behavioral deficits. Specific Aim 1 will measure resting state functional connectivity (rsFC) between cerebellum sub-regions and established cortical resting state brain networks (RSNs). Specific Aim 2 will test: a) whether cerebellar fMRI activation during cerebellar-dependent delay eyeblink conditioning (dEBC) is reduced in CB users; and b) whether task-based cerebellar activations produce different patterns of RSN connectivity (using the 10 RSNs from Aim 1) that are differentially sensitive to CB use. Specific Aim 3 will test the sensitivity of a set of cerebellar-dependent behavioral tasks to CB use. Findings from the proposed research will likely identify the cerebellar paradigms and measures which are most affected in current CB users. If the strongly founded predictions are borne out, this set of measures could then be utilized in a wide range of studies, including 1) longitudinal studies of high risk groups and CB users which would be critical for future research projects, 2) direct administration of cannabis compounds in humans, 3) studies of comparable measures in animal models of cannabis use and consequences, 4) genetically informed familial and twin studies and 5) field studies of cannabis intoxication. Additionally, these protocols could be highly informative in parsing cerebellar circuits which have been implicated in a broad range of addictive behaviors.