Project Grant R01DA059378

EFFECTS OF EARLY-LIFE CANNABINOID EXPOSURE ON PREFRONTAL CIRCUITRY AND COGNITIVE BEHAVIOR ACROSS DEVELOPMENT - PROJECT SUMMARY CANNABIS CONSUMPTION DURING PREGNANCY AND LACTATION HAS REACHED 7-15% IN PREGNANT WOMEN AND NURSING MOTHERS IN RECENT YEARS, AND WILL LIKELY RISE DUE TO WIDESPREAD LEGALIZATION. INCREASED AVAILABILITY OF CANNABIS HAS LED TO THE PUBLIC PERCEPTION THAT IT IS A SAFE NATURAL REMEDY FOR PREGNANCY-RELATED AILMENTS AND POSTPARTUM MOOD DISORDERS. YET, GROWING CLINICAL AND PRECLINICAL DATA SUGGEST PRENATAL AND PERINATAL CANNABIS EXPOSURE IS ASSOCIATED WITH LONG-TERM NEURODEVELOPMENTAL CONSEQUENCES IN CHILDREN, INCLUDING SENSORIMOTOR, EMOTIONAL, AND COGNITIVE DEFICITS, AS WELL AS INCREASED RISK FOR ILLICIT DRUG USE IN ADOLESCENCE AND ADULTHOOD. THE NEURAL MECHANISMS AND SENSITIVE PERIODS UNDERLYING THESE LONG-TERM EFFECTS ARE STILL POORLY UNDERSTOOD, MAKING IT CHALLENGING TO PROVIDE ACCURATE MEDICAL ADVICE FOR RISK ASSESSMENT OF CANNABIS USE IN MOTHERS. TO ADDRESS THIS CHALLENGE, OUR OVERALL GOAL IS TO IDENTIFY THE DEVELOPMENTAL PROCESSES AND CIRCUIT-SPECIFIC MECHANISMS UNDERLYING THE EFFECTS OF EARLY-LIFE CANNABINOID EXPOSURE ON THE EMERGENCE OF COGNITIVE BEHAVIORS. WE WILL FOCUS ON THE MEDIAL PREFRONTAL CORTEX (MPFC) DUE TO ITS HIGH LEVELS OF CANNABINOID RECEPTOR EXPRESSION DURING DEVELOPMENT, AND ITS CRITICAL ROLE IN COGNITIVE PROCESSING. WE WILL ASSESS THE CIRCUIT AND NETWORK EFFECTS OF EARLY- LIFE EXPOSURE TO THE TWO MOST WIDELY USED AND FREQUENTLY COMBINED CANNABINOIDS, 9-TETRAHYDROCANNABINOL (THC) AND CANNABIDIOL (CBD), IN MOUSE PUPS ACROSS DEVELOPMENT. WE WILL TEST THE CENTRAL HYPOTHESIS THAT EARLY-LIFE CANNABINOID EXPOSURE DISRUPTS MPFC MATURATION BY INTERFERING WITH NETWORK SYNCHRONIZATION DURING A CRITICAL DEVELOPMENTAL WINDOW, RESULTING IN ABNORMAL NEURONAL ACTIVATION DURING COGNITIVE BEHAVIORS IN ADOLESCENCE AND ADULTHOOD. WE WILL LEVERAGE OUR NOVEL LONGITUDINAL 2-PHOTON IMAGING TECHNIQUE IN DEVELOPING MICE TO ASSESS THE IMPACT OF THC, CBD, AND THC+CBD EXPOSURE THROUGH THREE AIMS. IN AIM 1, WE WILL REVEAL THE SPATIAL AND TEMPORAL PATTERNS OF IN VIVO NETWORK ACTIVITY AND ECB DYNAMICS ACROSS DEVELOPMENT AND DETERMINE CRITICAL WINDOWS DURING WHICH ALTERED ECB SIGNALING AFFECTS THESE NETWORK DYNAMICS. IN AIM 2, WE WILL ASSESS HOW EARLY-LIFE THC, CBD, OR THC+CBD EXPOSURE IMPACTS ECB AND CALCIUM DYNAMICS DURING DEVELOPMENT USING LONGITUDINAL 2-PHOTON IMAGING. WE WILL ALSO EXAMINE THE EFFECTS OF CANNABINOID EXPOSURE ON SYNAPTIC CONNECTIVITY AND THE BALANCE BETWEEN EXCITATION AND INHIBITION IN THE MPFC. IN AIM 3, WE WILL ASSESS THE IMPACT OF EARLY-LIFE CANNABINOID EXPOSURE ON THE NEURAL CORRELATES OF COGNITIVE BEHAVIORS IN THE MPFC ACROSS ADOLESCENCE AND ADULTHOOD. WE WILL ALSO SYSTEMATICALLY ASSESS THE BEHAVIORAL OUTCOMES AFTER EARLY-LIFE CANNABINOID EXPOSURE LONGITUDINALLY ACROSS NEONATAL, ADOLESCENCE AND EARLY ADULTHOOD. TOGETHER, OUTCOMES OF THIS PROJECT WILL IDENTIFY NEURAL MECHANISMS UNDERLYING LATER-LIFE BEHAVIORAL DEFICITS AS A RESULT OF EARLY-LIFE CANNABINOID EXPOSURE. AS SUCH, THIS PROJECT IS EXPECTED TO HAVE A SIGNIFICANT TRANSLATIONAL IMPACT ON CLINICAL EFFORTS TO PROVIDE GUIDELINES ON CANNABIS USE IN MOTHERS AND TIMELY INTERVENTIONS FOR AFFECTED CHILDREN.