The impact of a neonicotinoid pesticide on neural functions underlying learning and memory

新烟碱类农药对学习和记忆神经功能的影响

• 批准号: 10646631
• 负责人: Megan M Mahoney
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646631
• 关键词: Acetylcholine; Acute; Address; Adult; Aerosols; Affect; Affinity; Agriculture; Animals; Behavior; Binding; Blood; Brain; Categories; Cells; Child; Chronic; Cognition; Compensation; Consumption; Corpus striatum structure; Country; Development; Dose; Dust; Environment; Exposure to; Female; Fiber; Food; Hair; Hippocampus; Human; Human Milk; Immune; Impairment; Inflammation; Insecta; Insecticides; Invertebrates; Learning; Mammals; Measures; Mediating; Memory; Metabolic; Modeling; Motor; Mus; Mutagenesis; Nervous System; Neurophysiology - biologic function; Nicotine; Nicotinic Agonists; Nicotinic Receptors; North America; Oxidative Stress; Performance; Pesticides; Photometry; Physiological Processes; Plants; Population; Pregnancy; Prevention strategy; Proteins; Public Health; Receptor Up-Regulation; Research; Rewards; Risk; Rodent; Safety; Saliva; Sampling; Sex Differences; Short-Term Memory; Signal Pathway; Soil; Structure; Synaptic plasticity; System; Testing; Transcript; Urine; Vertebrates; Virus; Water; alpha-bungarotoxin receptor; anxiety-like behavior; behavior test; cognitive function; desensitization; drinking water; exposed human population; imidacloprid; improved; in utero; mRNA Expression; male; mature animal; negative affect; neural; neurogenesis; neurophysiology; neurotransmitter release; nicotine exposure; novel; pregnant; prenatal; procedural memory; protein expression; receptor; receptor binding; receptor expression; receptor function; receptor upregulation; reproductive; response; sensor; spatial memory; trait

Neonicotinoids are pesticides used worldwide and humans are ubiquitously exposed to them. They are selective for invertebrate nicotinic acetylcholine receptors (nAchRs) with a low affinity for mammalian ones, a trait that has contributed to their widespread use and assumed safety in mammals. However, an increasing body of evidence in vertebrates indicates developmental and adult exposure to neonicotinoids negatively affects a broad range of physiological processes including immune, reproductive, and metabolic systems. However, relatively little is known about the mechanisms by which neonicotinoid exposure alters learning and memory or perturbs neurophysiological signaling pathways. Learning and memory are fundamental cognitive functions regulated in large part by the hippocampus and striatum of the brain. This is done, in part, through activation of two forms of nAchRs; α2ß4 and α7. The objective of this proposal is to test the global hypothesis that neonicotinoid exposure, gestationally or in adulthood, impairs performance on spatial and procedural memory tasks by perturbing expression of α2ß4 or α7 receptor expression and acetylcholine release. To address this hypothesis, we will treat adult mice, or pregnant dams, with vehicle, or the environmentally relevant doses of 5.7 mg/kg/day and 0.5 mg/kg/day of imidacloprid. Imidacloprid is the most commonly used neonicotinoid and it has been detected in samples from children and adults. Adult and gestationally exposed mice will be tested for spatial memory and reward learning memory (Aim 1). Following behavioral testing, brains from these animals will be isolated and the protein and mRNA expression of α2ß4 or α7 nAchRs and their subunits will be quantified (Aim 2). Lastly, in adult exposed animals, we will use a virus-mediated fluorescent acetylcholine sensor and fiber photometry to measure acetylcholine release targeting the hippocampus while a freely moving animal is engaged in a spatial working task (Aim 3). We predict males will be more sensitive to neonicotinoids than females and thus have a significantly disrupted performance on memory tasks and have a larger increase in nAchR expression in the brain. We also predict that adult exposure will have a larger effect on nAchR expression compared to gestational exposure. Finally, we predict that imidacloprid exposed animals will have a reduction in acetylcholine release in response to a memory task. The results of this novel and comprehensive study will provide a critical identification of possible mechanisms underlying the impact of neonicotinoids on learning and memory.

新烟碱类是世界范围内使用的杀虫剂，人类普遍暴露于它们。 它们对无脊椎动物烟碱乙酰胆碱受体（nAchR）具有选择性， 对于哺乳动物来说，这一特性有助于它们的广泛使用，并假定它们在 哺乳动物然而，越来越多的脊椎动物证据表明， 成人暴露于类烟碱会对多种生理过程产生负面影响 包括免疫、生殖和代谢系统。然而，相对而言， 类烟碱暴露改变学习和记忆或干扰 神经生理信号通路。学习和记忆是基本的认知 这些功能在很大程度上由大脑的海马体和纹状体调节。这一点，在 部分，通过激活两种形式的nAchR; α 2 β 4和α7。这项建议的目的是 测试全球假设，即妊娠期或成年期的类尼古丁暴露会损害 通过干扰α 2 β 4或α7的表达对空间和程序记忆任务的表现 受体表达和乙酰胆碱释放。为了解决这一假设，我们将治疗成人 小鼠或妊娠母鼠，给予溶剂或环境相关剂量5.7 mg/kg/天，以及 0.5 mg/kg/天。吡虫啉是最常用的类烟碱， 在儿童和成人的样本中检测到。成年和妊娠期暴露小鼠将 测试空间记忆和奖励学习记忆（目标1）。在行为测试之后， 将从这些动物的脑中分离出α 2 β 4或α7 β 8的蛋白质和mRNA表达， 将对nAchR及其亚基进行定量（目标2）。最后，在成年暴露动物中，我们将使用 一种病毒介导的荧光乙酰胆碱传感器和用于测定乙酰胆碱的光纤光度法 当自由移动的动物从事空间工作时， 任务（目标3）。我们预测男性对类尼古丁比女性更敏感， 在记忆任务上有显著中断的表现，并且nAchR有较大的增加， 在大脑中的表达。我们还预测，成人暴露将对nAchR产生更大的影响。 与妊娠期暴露相比。最后，我们预测， 动物响应记忆任务的乙酰胆碱释放减少。结果 这项新颖而全面的研究将提供一个关键的识别可能的机制 潜在的烟碱类物质对学习和记忆的影响。