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

NRSA F31应用程序 “甲苯对前额叶-杏仁核通路和危险行为的影响” 少年派：凯文·M·布朗谢德尔 赞助商：约翰伍德沃德 摘要 甲苯等挥发性有机溶剂在高浓度吸入时会引起中毒和神经化学改变 浓度。这些变化包括皮质的电生理和形态变化(例如，前额内侧 在许多成瘾物质中常见的皮层和皮质下区域。正如我们的实验室所揭示的那样，例如 甲苯体内应用可持续抑制依赖的mPFC兴奋性信号 关于内源性大麻素。这一行为的行为后果目前尚不清楚，但有可能 对在面临风险时做出决策等复杂行为失去执行控制负有责任 结果。该提案的目标1将衡量急性甲苯中毒对风险决策的影响。 在啮齿动物中使用一种名为概率贴现的半自动任务。在此任务中做出适当的响应 取决于mPFC和杏仁基底外侧核(BLA)之间的功能连接。《血盟公约》是 传统上被认为是与恐惧相关的行为的中介，但显然也在对虐待上瘾方面发挥了作用 可卡因和酒精等物质。关于BLA在溶剂诱导中的作用，人们几乎一无所知。 这项提案中的风险决策和研究的中断将使用体内纤维光度法结合 靶向病毒递送钙感应GCaMP6以确定该任务的哪些特定成分依赖于 关于mPFC-BLA的连接。首次描述了溶剂对BLA神经元的细胞作用 兴奋性，目标2的研究将使用全细胞膜片钳脑片电生理学来测量效应 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 将通过光遗传激活mPFC终末并记录谷氨酸能后反应来评估传递。 电压钳制BLA神经元中的突触电流。后续研究将使用光学可塑性协议来 确定甲苯如何改变BLA神经元修改突触强度的能力。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卓越的培训，并将 解决我们对甲苯影响的潜在机制的理解中的一个重大缺陷 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.