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.

新烟碱是世界各地使用的杀虫剂，人类无处不在地接触到它们。 它们对低亲和力的无脊椎动物烟碱型乙酰胆碱受体(NAChRs)具有选择性 对于哺乳动物来说，这一特征有助于它们的广泛使用，并在 哺乳动物。然而，越来越多的脊椎动物证据表明，发育和 成人接触新烟碱会对广泛的生理过程产生负面影响 包括免疫、生殖和新陈代谢系统。然而，人们对此知之甚少。 新烟碱暴露改变学习和记忆或扰乱的机制 神经生理信号通路。学习和记忆是基本的认知 功能很大程度上由大脑的海马体和纹状体调节。此操作已完成，在 部分，通过激活两种形式的nAChR：α2？4和α7。这项提议的目的是 检验全球假设，即孕期或成年期接触新烟碱会损害 干扰α-2？4或α-7基因表达对空间和程序记忆任务的影响 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 小鼠或怀孕的母鼠携带车辆，或与环境有关的剂量为5.7毫克/公斤/天，以及 吡虫啉0.5 mg/kg/d。吡虫啉是最常用的新烟碱类化合物，它有 在儿童和成人的样本中检测到。成年和妊娠期暴露的小鼠将 测试空间记忆和奖赏学习记忆(目标1)。在行为测试之后， 这些动物的大脑将被分离出来，α2？4或α7的蛋白和mR NA表达 将量化nAChRs及其亚单位(目标2)。最后，在成年暴露的动物中，我们将使用 病毒介导型乙酰胆碱荧光传感器及光纤光度法测定乙酰胆碱 当自由活动的动物进行空间工作时，针对海马体的释放 任务(目标3)。我们预测男性将比女性对新烟碱更敏感，因此 内存任务的性能显著中断，nAchR的增幅更大 在大脑中的表达。我们还预测，成人接触将对nAchR产生更大的影响 与妊娠期暴露进行比较。最后，我们预测了吡虫啉的暴露 动物对记忆任务的反应会减少乙酰胆碱的释放。结果是 这项新颖而全面的研究将为可能的机制提供关键的识别 新烟碱对学习和记忆的影响。