Effect of Toluene on the Prefrontal-Amygdala Pathway and Risky Behavior

NRSA F31应用 “甲苯对前额叶-杏仁核通路和危险行为的影响” PI：Kevin M.布劳恩沙伊德尔 赞助商：约翰·J·伍德沃德 摘要 挥发性有机溶剂，如甲苯，在高温下吸入会导致中毒和神经化学变化。 浓度的这些包括皮层（例如内侧前额叶）的电生理和形态学变化 皮质（mPFC）和皮质下区域在许多成瘾物质中很常见。根据我们的实验室， 甲苯的体内应用导致mPFC中兴奋性信号的持续抑制， 内源性大麻素这种行为的后果目前尚不清楚，但可能是 负责失去对复杂行为的执行控制，例如面对风险时的决策 结果。本提案的目标1将衡量急性甲苯中毒对风险决策的影响 在啮齿类动物中使用称为概率折扣的半自动任务。在此任务中适当响应 这取决于mPFC和基底外侧杏仁核（BLA）之间的功能连接。BLA是 传统上被认为是调解恐惧相关的行为，但也显然在成瘾滥用中发挥作用。 包括可卡因和酒精。事实上，关于BLA在溶剂诱导的聚合中的作用， 本提案中的风险决策和研究中断将使用体内纤维光度法， 钙敏感GCaMP 6的靶向病毒递送，以确定该任务的哪些特定组分依赖于 mPFC-BLA连通性。提供溶剂对BLA神经元的细胞作用的第一个表征 兴奋性，目标2中的研究将使用全细胞膜片钳脑切片电生理学来测量效果 甲苯对BLA神经元内在兴奋性的影响。甲苯对mPFC特异性突触的影响 将通过光遗传学激活mPFC末端并记录mPFC后的突触后能来评估传递。 电压钳位BLA神经元的突触电流。后续研究将使用光学可塑性协议， 确定甲苯如何改变BLA神经元的能力，以修改突触强度。实现这些目标将 在行为药理学、纤维光度学和切片电生理学方面提供出色的培训，并将 解决了一个重要的缺陷，我们的理解的机制，甲苯的影响， 复杂的行为

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.