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:
- 金额:$ 7.52万
- 依托单位:
- 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:
- 关键词:AcetylcholineAcuteAddressAdultAerosolsAffectAffinityAgricultureAnimalsBehaviorBindingBloodBrainCategoriesCellsChildChronicCognitionCompensationConsumptionCorpus striatum structureCountryDevelopmentDoseDustEnvironmentExposure toFemaleFiberFoodHairHippocampusHumanHuman MilkImmuneImpairmentInflammationInsectaInsecticidesInvertebratesLearningMammalsMeasuresMediatingMemoryMetabolicModelingMotorMusMutagenesisNervous SystemNeurophysiology - biologic functionNicotineNicotinic AgonistsNicotinic ReceptorsNorth AmericaOxidative StressPerformancePesticidesPhotometryPhysiological ProcessesPlantsPopulationPregnancyPrevention strategyProteinsPublic HealthReceptor Up-RegulationResearchRewardsRiskRodentSafetySalivaSamplingSex DifferencesShort-Term MemorySignal PathwaySoilStructureSynaptic plasticitySystemTestingTranscriptUrineVertebratesVirusWateralpha-bungarotoxin receptoranxiety-like behaviorbehavior testcognitive functiondesensitizationdrinking waterexposed human populationimidaclopridimprovedin uteromRNA Expressionmalemature animalnegative affectneuralneurogenesisneurophysiologyneurotransmitter releasenicotine exposurenovelpregnantprenatalprocedural memoryprotein expressionreceptorreceptor bindingreceptor expressionreceptor functionreceptor upregulationreproductiveresponsesensorspatial memorytrait
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,这一特征促进了它们的广泛使用并被认为是安全的
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,人们对这些系统知之甚少。
新烟碱类接触改变学习和记忆或扰乱的机制
神经生理信号通路是基本的认知。
功能很大程度上是由大脑的海马体和纹状体调节的。
部分,通过激活两种形式的 nAchR;α2ß4 和 α7。
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一假设,我们将治疗成年人。
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 毫克/公斤/天的吡虫啉是最常用的新烟碱类杀虫剂。
在儿童和成人的样本中检测到。
测试空间记忆和奖励学习记忆(目标 1)。
将分离这些动物的大脑,并检测 α2ß4 或 α7 的蛋白质和 mRNA 表达
最后,我们将在成年暴露动物中使用 nAchR 及其亚基进行量化(目标 2)。
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
我们还预测成人暴露会对 nAchR 产生更大的影响。
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。
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。
项目成果
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