NRSA F31 APPLICATION ?Effect of Toluene on the Prefrontal-Amygdala Pathway and Risky Behavior? PI: Kevin M. Braunscheidel Sponsor: John J. Woodward ABSTRACT Volatile organic solvents like toluene cause intoxication and neurochemical alterations when inhaled at high concentrations. These include electrophysiological and morphological changes in cortical (e.g. medial prefrontal cortex, mPFC) and subcortical regions common among many addictive substances. As revealed by our lab, ex vivo application of toluene causes a persistent depression of excitatory signaling in the mPFC that is dependent on endocannabinoids. The behavioral consequences of this action are not currently known, but it is possibly responsible for the loss of executive control over complex behaviors such as decision making in the face of risky outcomes.
Aim 1 of this proposal will measure the effect of acute toluene intoxication on risky decision making in rodents using a semi-automated task termed probabilistic discounting. Appropriate responding in this task depends on functional connectivity between the mPFC and the basolateral amygdala (BLA). The BLA is traditionally viewed as mediating fear-related behaviors, but also clearly plays a role in addiction to abused substances including cocaine and alcohol. Virtually nothing is known about the role of the BLA in solvent-induced disruption of risky decision making and studies in this proposal will use in vivo fiber photometry combined with targeted viral delivery of calcium sensing GCaMP6 to determine which specific components of this task depend on mPFC-BLA connectivity. To provide the first characterization of the cellular actions of solvents on BLA neuron excitability, studies in Aim 2 will use whole-cell patch clamp brain slice electrophysiology to measure the effect of toluene on the intrinsic excitability of BLA neurons. The effects of toluene on mPFC-specific synaptic transmission will be assessed by optogenetically activating mPFC terminals and recording glutamatergic post- synaptic currents in voltage clamped BLA neurons. Follow up studies will use optical plasticity protocols to determine how toluene alters the ability of BLA neurons to modify synaptic strength. Completing these aims will provide outstanding training in behavioral pharmacology, fiber photometry, and slice electrophysiology and will address an important shortcoming in our understanding of the mechanisms underlying toluene?s effect on complex behaviors.
Completion of this proposal will provide new insights into how inhalant intoxication alters the neurocircuitry responsible for risky decision making. These studies will examine the contribution of a specific neurotransmitter system (endocannabinoids) in two distinct brain regions (prefrontal cortex, basolateral amygdala) that are implicated in drug addiction and relapse, topics highly relevant to public health. Addressing these unique mechanisms with the precision and control afforded by rodent models is key to furthering our understanding of addiction and developing novel relapse prevention therapies in humans.
