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Principal Investigator: Kuei-Yuan Tseng
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $359,775
Funding agency: National Institute on Drug Abuse
Abstract
Converging human association studies link cannabis abuse during adolescence with an increased likelihood of
developing cognitive and emotional regulation deficits later in life, many of which are refined and dependent on
prefrontal cortex (PFC) maturation during adolescence. However, the neurobiology underlying this adolescent
vulnerability remains unclear due to our limited knowledge on how adolescent cannabis exposure impacts the
maturation of neural circuits. Our long-term goal is to identify sensitive neurodevelopmental processes that are
vulnerable to repeated cannabis exposure, with emphasis on PFC neuronal circuits that undergo functional
remodeling during adolescence. Data from our recent studies revealed that a hallmark of PFC maturation is the
re-calibration of an excitatory-inhibitory (E-I) balance during adolescence that is required for sustaining proper
PFC-mediated behaviors in adulthood. Our data also indicate that it is the maturation of GABA function that
renders the PFC labile during adolescence, a developmental process that is intimately linked to the activity of
afferent transmission from the ventral hippocampus. Similarly, adolescent, but not adult, exposure to THC
impaired the maturation of PFC GABA function. This raises the exciting possibility that the PFC deficit resulting
from adolescent THC exposure is mechanistically linked to the disruption of specific inputs driving PFC
maturation. Based on our preliminary data, we will test the central hypothesis that the developing PFC GABA
circuit during adolescence is highly sensitive to the negative impact of cannabis through a ventral hippocampal
-mediated mechanism. Thus, the rationale for undertaking this research is that if PFC GABA maturation is
compromised by adolescent THC exposure, the normal facilitation of PFC inhibitory control will be arrested,
which in turn could lead to an enduring state of PFC disinhibition resulting in behavioral deficits in adulthood. We
will fill this gap in knowledge through the pursuit of 3 Specific Aims. We will use a recently developed
combustion/smoking chamber to deliver THC at 3 non-overlapping adolescent windows to establish the precise
period during which changes in PFC GABA function (Aim 1) and PFC-sensitive behaviors (Aim 2) are susceptible
to repeated THC exposure. Currently available input-specific DREADD manipulations will be used in Aim 3 to
establish whether the enduring PFC GABA deficit elicited by THC is causally linked to disruption of ventral
hippocampal-to-PFC transmission.
Terms: <12-20 years old><21+ years old><4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><9-ene-Tetrahydrocannabinol><Adolescence><Adolescent><Adolescent Youth><Adult><Adult Human><Affective><Age><Aminalon><Aminalone><Ammon Horn><Attenuated><Automobile Driving><Behavior><Behavior Control><Behavioral><Behavioral Manipulation><CB1><CB1 Receptor><CB1R><CNR1 gene><Calibration><Cannabinoid Receptor CB1><Cannabis><Cannabis Abuse><Cell Communication and Signaling><Cell Signaling><Cognitive><Cognitive deficits><Common Rat Strains><Cornu Ammonis><D9-tetrahydrocannabinol><DREADDs><Data><Delta-9-Tetrahydrocannabinol><Development><Developmental Process><Disinhibition><Electrophysiology><Electrophysiology (science)><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Equilibrium><Exposure to><GABA><Glutamates><Goals><Hippocampus><Human><Impairment><Infusion><Infusion procedures><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><L-Glutamate><Life><Link><Mediating><Mission><Modern Man><NIDA><NIH><National Institute of Drug Abuse><National Institute on Drug Abuse><National Institutes of Health><Neurobiology><Neurophysiology / Electrophysiology><Predisposition><Prefrontal Cortex><Process><Public Health><Rat><Rats Mammals><Rattus><Research><Risk><Saccharose><Signal Transduction><Signal Transduction Systems><Signaling><Smoking><Substance Use Disorder><Sucrose><Susceptibility><Synapses><Synaptic><THC exposure><Testing><Tetrahydrocannabinol><Transmission><United States National Institutes of Health><adolescence (12-20)><adulthood><adulthood transition><age associated><age correlated><age dependent><age linked><age related><age specific><ages><attenuate><attenuates><balance><balance function><behavior response><behavioral control><behavioral response><biological signal transduction><cannabinoid receptor 1><cannabinoid receptor type 1><cannabinoid type 1><cognitive defects><cognitive reappraisal><cognitive regulation><critical period><delta(1)-THC><delta(1)-Tetrahydrocannabinol><delta(9)-THC><delta(9)-Tetrahydrocannabinol><designer receptors exclusively activated by designer drugs><developmental><driving><electrophysiological><emotion dysregulation><emotion regulation><emotional dysregulation><emotional regulation><epidemiologic investigation><epidemiology study><fear memory><gamma-Aminobutyric Acid><glutamatergic><hippocampal><in vivo><infusions><interest><interventional strategy><juvenile><juvenile human><neural circuit><neural circuitry><neurobiological><neurocircuitry><neuronal circuit><neuronal circuitry><postnatal><preference><prevent><preventing><substance use><substance use and disorder><substance using><synapse><synaptic circuit><synaptic circuitry><tetrahydrocannabinol exposure><transition from adolescence to adulthood><transition into adulthood><transition to adulthood><transmission process><vulnerable adolescent><Δ(1)-THC><Δ(1)-tetrahydrocannabinol><Δ(9)-THC><Δ(9)-tetrahydrocannabinol><Δ-9-tetrahydrocannabinol><Δ9-tetrahydrocannabinol><γ-Aminobutyric Acid>