Sunday, May 4, 2025
5/4/2025
Impact of Cannabinoid Across the Lifespan (ICAL) - IMPACT OF CANNABINOIDS ACROSS THE LIFESPAN (ICAL): SUMMARY Teenagers use cannabis more than any other recreational drug. Their developing brains may also be especially vulnerable to its effects, as epidemiological and experimental evidence suggests that frequent cannabis use in adolescence is associated with impairments in cognitive and affective functioning that continue in adult life. Excessive stimulation of the endocannabinoid (ECB) system – the target of cannabis’s intoxicating constituent, Δ9-tetrahydrocannabinol (THC) – is a plausible but still poorly understood mechanism for the lasting consequences of cannabis use. The NIDA Center Impact of Cannabinoids Across Lifespan (ICAL), whose renewal is proposed in this revised application, combines molecular, synaptic, and behavioral approaches to determine whether adolescent THC exposure (‘ado-THC’) alters ECB signaling in a persistent manner thus causing impairments in adult brain function and behavior. In the first funding period, which lasted 4 years, we made substantive progress on our research and service goals. Research: (1) We systematically characterized pharmacokinetics and metabolism of THC in adolescent and adult mice and rats of both sexes and validated a THC treatment protocol that models daily cannabis consumption (an increasingly common use pattern among teenagers). (2) We found that this protocol produces enduring neurobehavioral alterations, most (but not all) of which appear to be rooted in persistent disruption of microglial homeostasis. (3) We uncovered unexpected modifications in the adult metabolic and immune phenotype of male and female ado-THC mice. (4) We published 29 articles in peer-reviewed journals, including Cell Metabolism, Biological Psychiatry, Nature Communications, and Nature Neuroscience. Service: we (1) organized 2 international symposia (>1600 participants), 5 research seminars, and 4 workshops/webinars; (2) created and launched a public biobank, which in ~12 months of service distributed >500 ado-THC tissue samples to 6 laboratories worldwide; (3) trained 9 graduate students (5 from underrepresented minorities, URM), 5 post-docs (2 from URM), and 51 undergraduate students (26 from URM); and (4) funded 7 pilot research projects. In this renewal, we propose to test the highly innovative hypothesis that ado-THC alters ECB signaling in microglia and, by doing so, disrupts both their homeostasis and their interactions with neurons, ultimately causing persistent (but possibly correctable) alterations in neuroplasticity, episodic memory, and vulnerability to opioids. This hypothesis, which is supported by rigorous preliminary data generated by the close cooperation of ICAL’s three Projects, will be tested in Aim 1 using emerging molecular techniques (e.g., single-nuclei RNAseq, imaging mass cytometry) along with state-of- the-art electrophysiological and behavioral methods. In Aim 2, we will continue our service mission by (1) organizing symposia and workshops to strengthen the cannabinoid research community and increase public access to cannabis-related information; (2) expanding the public reach of ICAL’s biobank; and (3) attracting early-career scientists to cannabinoid research by offering training opportunities and pilot funds.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).