Date of Award

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

John J. Woodward

Second Advisor

Howard C. Becker

Third Advisor

Patrick J. Mulholland

Fourth Advisor

Justin T. Gass

Fifth Advisor

Thomas C. Jhou

Abstract

Volatile organic solvents like toluene induce euphoria and intoxication when inhaled at high concentrations. Inhalant misuse is linked to behavioral, cognitive, and anatomical deficits in humans leading to a reduced productivity and quality of life. Yet, preclinical studies on the effect of inhalants on executive control in animal models are limited. We address this gap in knowledge using rodent models in two ways: first, by examining the long-lasting effects of repeated toluene inhalation during adolescence on several measures of executive function in adulthood and second, by studying the effects of acute toluene inhalation on risk/reward decision making and related neurocircuitry. Repeated inhalation of toluene during adolescence blunted acquisition of operant and Pavlovian learning in adulthood without affecting probabilistic discounting, progressive ratio breakpoint, latent inhibition or reversal learning. Acute toluene vapor inhalation, however, caused a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting, a pattern that implicates dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients during during task performance using in vivo fiber photometry. Peaks in GCaMP6f activity shifted from pre-risky to pre-safe choice during contingency updating, an effect that was eliminated by acute toluene exposure. mPFC activity in toluene-treated animals also did not distinguish between risky/large wins and safe/small wins. Interestingly, previous studies from our lab demonstrated a toluene-induced long-term depression of AMPA-mediated synaptic activity in deep-layer mPFC neurons. This effect was dependent on endocannabinoids (EC) synthesis and presynaptic cannabinoid receptor (CB1R) function. Here, we found that pharmacological inhibition of CB1Rs in the mPFC or systemically did not mitigate toluene’s effect on probabilistic discounting. Behavioral flexibility in this task also depends on functional mPFC-basolateral amygdala (BLA) neurocircuitry. Electrophysiological interrogation of BLA neurons innervated by the mPFC using ex vivo slice electrophysiology and optogenetics revealed a CB1R-dependent decrease in excitatory synaptic transmission following toluene application. These data elucidate learning and behavioral flexibility deficits caused by toluene, including insights on potential mPFC-BLA- and CB1R-dependent mechanisms.

Rights

All rights reserved. Copyright is held by the author.

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