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

基本信息

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
项目类别：
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

项目摘要

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.

新烟碱是全世界使用的农药，人类无处不在。他们对低亲和力的无脊椎动物烟碱乙酰胆碱受体（NACHR）有选择性对于哺乳动物的特征，有助于其宽度使用并假定安全性哺乳动物。但是，脊椎动物中越来越多的证据表明发育和成人接触新烟素会对广泛的物理过程产生负面影响包括免疫，生殖和代谢系统。但是，对新烟碱暴露会改变学习和记忆或遗传的机制神经生理信号通路。学习和记忆是基本的认知大脑的海马和纹状体在很大程度上调节功能。这是完成的部分，通过激活两种形式的NACHR； α2ß4和α7。该提议的目的是测试全球假设，即新烟碱样暴露在妊娠或成年期间损害通过扰动α2ß4或α7的表达来实现空间和程序记忆任务的性能受体表达和乙酰胆碱释放。为了解决这一假设，我们将对待成人小鼠或怀孕的大坝，有车辆或与环境相关的剂量为5.7 mg/kg/day， 0.5 mg/kg/day imidacloprid。咪二藻虫是最常用的新烟素，它具有在儿童和成人的样本中检测到。成人和妊娠暴露的小鼠将是测试了空间记忆和奖励学习记忆（AIM 1）。进行行为测试，这些动物的大脑将分离出来，α2ß4或α7的蛋白质和mRNA表达 NACHR及其亚基将被量化（AIM 2）。最后，在成年暴露的动物中，我们将使用病毒介导的荧光乙酰胆碱传感器和纤维光度法，以测量乙酰胆碱释放针对海马的，而自由移动的动物进行空间工作任务（目标3）。我们预测，男性对新烟素会比女性更敏感，因此在内存任务上具有显着残疾的性能，并且NACHR的增加更大在大脑中的表达。我们还预测，成年人接触将对NACHR产生更大的影响与妊娠暴露相比表达。最后，我们预测咪二藻普及暴露响应记忆任务，动物将减少乙酰胆碱释放。结果这项新颖而全面的研究将为可能的机制提供重要的识别新烟碱对学习和记忆的影响是基本的。