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.

新烟碱类杀虫剂是全世界使用的杀虫剂，人类无处不在地接触它们。 它们对无脊椎动物烟碱乙酰胆碱受体 (nAchR) 具有低亲和力选择性 对于哺乳动物来说，这一特性促进了它们的广泛使用并被认为是安全的 哺乳动物。然而，越来越多的脊椎动物证据表明，发育和 成人接触新烟碱类杀虫剂会对广泛的生理过程产生负面影响 包括免疫、生殖和代谢系统。然而，人们对此知之甚少 新烟碱类接触改变学习和记忆或扰乱的机制 神经生理信号传导途径。学习和记忆是基本认知 功能很大程度上由大脑的海马体和纹状体调节。这是完成的，在 部分是通过激活两种形式的 nAchR； α2ß4 和 α7。该提案的目的是 检验新烟碱类药物暴露（妊娠期或成年期）会损害这一总体假设 通过干扰 α2ß4 或 α7 的表达来提高空间和程序记忆任务的表现 受体表达和乙酰胆碱释放。为了解决这个假设，我们将治疗成人 小鼠或怀孕母鼠，使用媒介物，或环境相关剂量 5.7 毫克/公斤/天，并且 0.5 mg/kg/天吡虫啉。吡虫啉是最常用的新烟碱类杀虫剂，它具有 在儿童和成人的样本中均检测到。成年和妊娠期暴露的小鼠将 测试空间记忆和奖励学习记忆（目标 1）。经过行为测试后， 将分离这些动物的大脑，并检测 α2ß4 或 α7 的蛋白质和 mRNA 表达 nAchR 及其亚基将被量化（目标 2）。最后，对于成年暴露动物，我们将使用 病毒介导的荧光乙酰胆碱传感器和光纤光度法来测量乙酰胆碱 当自由移动的动物进行空间工作时，针对海马体进行释放 任务（目标 3）。我们预测男性对新烟碱类杀虫剂比女性更敏感，因此 记忆任务的表现明显受损，nAchR 增加幅度更大 大脑中的表达。我们还预测成人暴露会对 nAchR 产生更大的影响 与妊娠暴露相比的表达。最后，我们预测吡虫啉暴露 动物在执行记忆任务时乙酰胆碱的释放会减少。结果 这项新颖而全面的研究将提供对可能机制的关键识别 新烟碱类杀虫剂对学习和记忆的影响。