The impact of hallucinogens on active sampling and the olfactory bulb

项目总结 嗅觉幻觉出现在许多疾病中，包括帕金森氏症、癫痫、精神分裂症和 偏头痛，但这些幻觉背后的神经机制尚不清楚。老鼠有一种强大的 嗅觉系统在分子、系统和行为水平上都得到了很好的研究。重要的是 迷幻剂，如LSD、裸盖菇素和DOI，主要作用于5-羟色胺途径，这些途径大量地向 老鼠的嗅觉系统。这项拟议的研究将确定嗅觉驱动的行为变化 并确定其对嗅球神经活动的影响。 对动物模型中幻觉的机械学研究基本上是有限的，因为其他动物不会 用言语表达他们所感知到的。但是，代替口头报告，可以从 动物外部可观察到的行为。使用机器学习工具，我们的实验室已经证明了老鼠的 行为状态可以从对嗅探和运动的仔细分析中推断出来。在这个项目中，我们将 用高分辨率行为分析和神经元集成研究小鼠的致幻剂反应 嗅球里的录音。我们假设致幻剂会影响嗅觉知觉 报告和战略嗅探行为。此外，我们假设嗅觉中的神经活动 在注射迷幻剂后，在没有气味的情况下，灯泡将类似于气味诱发的活动。 为了解决我们关于知觉报告的假设，在目标1中，我们将训练自由移动的小鼠两个- 另一项选择任务是在记录移动和嗅探的同时定位气味的来源。在老鼠之后 受过训练，我们会给他注射DOI或生理盐水。我们的假设预测DOI会引发错误警报， 当存在气味刺激时，准确性会降低，信心也会降低。来解释我们的假设 关于神经活动，在目标2中，我们将记录下嗅球运动、嗅觉和神经活动 自发的、未经指导的、自由移动的行为。我们将测试迷幻剂给药的预测 在没有气味的情况下，改变嗅球的神经动力学，使其类似于气味诱发的活动 刺激。这项建议的完成将提供对嗅觉和神经回路的行为和神经回路的洞察 帮助为使用迷幻剂治疗各种疾病的治疗和政策提供信息。

PROJECT SUMMARY Olfactory hallucinations occur in many disorders, including Parkinson’s disease, epilepsy, schizophrenia, and migraines, but the neural mechanisms underlying these hallucinations are unknown. Mice have a powerful olfactory system that is well-studied at the molecular, systems, and behavioral levels. Importantly, hallucinogens such as LSD, psilocybin, and DOI primarily act on serotonin pathways, which feed heavily into the mouse olfactory system. The proposed research will determine the behavioral changes in olfactory-driven behaviors and identify the impact on neural activity in the olfactory bulb. Mechanistic studies of hallucination in animal models are fundamentally limited, since other animals do not verbalize what they perceive. However, in lieu of a verbal report, internal states can be inferred from an animal’s externally observable behavior. Using machine-learning tools, our lab has shown that a mouse’s behavioral states can be inferred from close analysis of sniffing and movement. In this project, we will investigate the mouse hallucinogen response using high resolution behavioral analysis and neuronal ensemble recordings in the olfactory bulb. We hypothesize that hallucinogens will impact olfactory perceptual reports and strategic sniffing behavior. Further, we hypothesize that the neural activity in the olfactory bulb will resemble odor-evoked activity in the absence of odor after hallucinogen administration. To address our hypothesis about perceptual reports, in aim 1 we will train freely-moving mice on a two- alternative choice task to locate the source of an odor while recording movement and sniffing. After the mice are trained, we will administer DOI or saline. Our hypothesis predicts that DOI will induce false alarms, decrease accuracy, and decrease confidence in the presence of an odor stimulus. To address our hypothesis about neural activity, in aim 2 we will record movement, sniffing, and neural activity in the olfactory bulb during spontaneous, uninstructed, freely-moving behavior. We will test the prediction that hallucinogen administration alters the neural dynamics of the olfactory bulb to resemble odor-evoked activity in the absence of an odor stimulus. Completion of this proposal will provide insight into the behavior and neural circuitry of olfaction and help inform treatment and policy on the use of hallucinogens to treat various disorders.