Investigating cortex-brainstem interactions in conditioned taste aversion

研究条件性味觉厌恶中的皮层-脑干相互作用

• 批准号: 10600472
• 负责人: Rachel Essner
• 金额: $ 3.46万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600472
• 关键词: Affect; Animals; Attenuated; Automobile Driving; Axon; Behavioral; Bilateral; Brain; Brain Stem; Brain region; Calcitonin Gene-Related Peptide; Calcium; Caliber; Cells; Chronic; Clinical; Conditioned Stimulus; Consumption; Data; Desire for food; Ensure; Exposure to; Feeling; Food; Goals; Image; Impairment; Implant; Ingestion; Injections; Ipsilateral; Isotonic Exercise; Knowledge; Lateral; Learning; Liquid substance; Lithium Chloride; Malaise; Methods; Modality; Mus; Nausea; Neurons; Outcome; Patients; Pattern; Perception; Pharmaceutical Preparations; Population; Regulation; Resolution; Retrieval; Rodent; Role; Saline; Sensory; Shapes; Signal Transduction; Stimulus; Surface; Taste Perception; Taste aversion; Testing; Visceral; Work; avoidance behavior; behavioral response; cellular imaging; chemotherapy; clinical application; experience; food avoidance; food consumption; gastrointestinal; in vivo calcium imaging; indexing; individual response; insight; lens; multimodality; neural circuit; neuromechanism; neuronal cell body; novel; optogenetics; parabrachial nucleus; preference; prevent; relating to nervous system; response; sensory input; sweet taste perception; taste stimuli; transmission process; two-photon

Project Summary/Abstract The main goal of this proposal is to elucidate how cortex-brainstem interactions shape the neural representations of taste to drive avoidance behavior during conditioned taste aversion (CTA) in mice. Taste perception guides appropriate food choices. While animals display innate preferences for sweet tastes associated with calorically dense foods, new learned associations can reverse these preferences to protect against consumption of potentially toxic or harmful foods. For example, CTA occurs when visceral illness (unconditioned stimulus, US) follows consumption of a novel taste (conditioned stimulus, CS), which leads to a robust and long-lasting avoidance of the CS, even after only a single taste-illness (CS-US) pairing. However, the neural circuit mechanisms underlying CTA remain poorly understood. Prior work has implicated the insular cortex (InsCtx), which encompasses primary gustatory and visceral cortex, and the brainstem lateral parabrachial nucleus (LPBN), which integrates multimodal sensory input from the body, as key brain regions for the learning and retrieval of CTA in rodents. It was long known that LPBN neurons respond to and are necessary for the transmission of visceral malaise signals during acquisition of CTA. In addition, recent work has demonstrated that a specific population of LPBN neurons, those expressing calcitonin gene-related peptide (CGRP), develop learned responses to the CS after CTA and are necessary for CTA retrieval. Likewise, InsCtx contains representations of both taste and malaise, and its CS-evoked population activity shifts after CTA, leading to the question of whether a functional interaction between InsCtx and LPBN may drive the neural and behavioral response to CTA. Indeed, InsCtx sends a dense excitatory projection to LPBN (InsCtxLPBN), the function of which is entirely unknown. I will test the hypothesis that upon re-exposure to the CS during CTA expression, InsCtxLPBN neurons drive activity patterns in LPBN that simulate and reinstate feelings of malaise, leading to avoidance of the CS. In Aim 1, I will use two-photon calcium imaging to determine how LPBN neurons and InsCtxLPBN axons represent the CS and US, and how representations of the CS shift after CTA learning. Preliminary studies show that CTA dramatically shifts the CS-evoked pattern of activity in LPBN, and that this new pattern may resemble that of LiCl-induced malaise. In Aim 2, I will investigate the influence of InsCtxLPBN axons on LPBN activity and on avoidance behavior during the expression of CTA. These studies will elucidate the neural circuit mechanisms underlying CTA with important clinical applications for understanding maladaptive taste learning, which can occur during treatment with nausea-inducing medications or chronic gastrointestinal illnesses. Furthermore, these studies will advance our broader understanding of how cortex-brainstem interactions can shape taste perception, with implications for sensory modalities and learning mechanisms beyond CTA.

项目摘要/摘要 这项提议的主要目的是阐明皮质-脑干相互作用如何塑造神经。 在小鼠的条件性味觉厌恶(CTA)过程中，味觉表征驱动回避行为。 味觉指导适当的食物选择。虽然动物表现出对甜味的天生偏好 与高热量食物相关的新学会的联想可以逆转这些偏好以保护 反对食用可能有毒或有害的食物。例如，CTA发生在内脏疾病时 (无条件刺激，美国)随着一种新口味的消费(条件刺激，CS)，这会导致 强劲而持久的CS避免，即使只有一次味觉-疾病(CS-US)配对也是如此。然而， CTA背后的神经回路机制仍然知之甚少。先前的研究表明岛叶皮质 (InsCtx)，它包括初级味觉和内脏皮质，以及脑干外侧臂旁 核团(LPBN)整合了来自身体的多模式感觉输入，作为学习的关键大脑区域 以及在啮齿类动物体内CTA的提取。人们很早就知道LPBN神经元对 CTA采集过程中内脏不适信号的传递。此外，最近的研究表明， 表达降钙素基因相关肽(CGRP)的LPBN神经元的特定群体 CTA后对CS的学习反应是CTA检索所必需的。同样，InsCtx包含 味觉和不适的表现，以及其CS诱发的群体活动在CTA之后发生变化，导致 InsCtx和LPBN之间的功能相互作用是否可能驱动神经和行为 对CTA的回应。实际上，InsCtx向LPBN(InsCtxLPBN)发送密集的兴奋性投影，其功能是 是完全未知的。我将测试这一假设，即在CTA表达期间再次暴露于CS时， InsCtxLPBN神经元驱动LPBN中模拟和恢复不适感觉的活动模式，导致 为避免政务司司长。在目标1中，我将使用双光子钙成像来确定LPBN神经元和 InsCtxLPBN轴突代表CS和US，以及学习CTA后CS的表示如何变化。 初步研究表明，CTA显著改变了LPBN中CS诱发的活动模式，这 新的模式可能类似于氯化锂引起的不适。在目标2中，我将调查InsCtxLPBN对 CTA表达过程中轴突对LPBN活性和回避行为的影响。这些研究将阐明 CTA的神经回路机制及其在理解适应不良中的重要临床应用 味觉学习，这可能发生在用引起恶心的药物或慢性胃肠道治疗期间 疾病。此外，这些研究将促进我们更广泛地理解皮质-脑干如何 交互作用可以塑造味觉，并对感觉形式和学习机制产生影响 超越CTA。