Effects of the Abused Inhalant Toluene on mPFC-Dependent Cognitive Behaviors and Associated Neural Activity

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

Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area

International audienceBrain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VIA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VIA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations

Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area

International audienceBrain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VIA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VIA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations