Hippocampal-thalamo-prefrontal circuitry damage in an animal model of FASD

FASD 动物模型中的海马-丘脑-前额叶回路损伤

• 批准号: 9794635
• 负责人: ANNA Y KLINTSOVA
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-27 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794635
• 关键词: Address; Adult; Affect; Alcohol consumption; Alcohols; Animal Model; Animals; Attention; Behavior; Behavioral; Behavioral Assay; Brain Injuries; Brain region; Cell Count; Cell Nucleus; Cells; Child; Cognitive; Cognitive deficits; Communication; Data; Development; Discrimination Learning; Dose; Elements; Ethanol; Executive Dysfunction; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal alcohol effects; Functional disorder; Goals; Golgi Apparatus; Hippocampus (Brain); Human; Hyperactive behavior; Impaired cognition; Impairment; Impulsivity; Incidence; Injections; Knowledge; Label; Life; Longevity; Medial; Midline Thalamic Nuclei; Modeling; Neurodevelopmental Disorder; Neuroglia; Neurons; Outcome; Pathology; Phenotype; Population; Prefrontal Cortex; Pregnancy; Primates; Public Health; Rattus; Research; Reuniens Thalamic Nucleus; Reversal Learning; Rodent; Role; Short-Term Memory; Specificity; Structure; Symptoms; Synapses; Testing; Thalamic Nuclei; Thalamic structure; Third Pregnancy Trimester; United States; Viral; Virus; alcohol effect; alcohol exposure; behavioral impairment; behavioral outcome; binge drinking; biological sex; brain circuitry; care costs; cell type; cognitive function; executive function; experimental study; flexibility; fluorophore; innovation; male; mind control; neural circuit; neuron loss; novel; postnatal; relating to nervous system; response; rhomboid; spatial memory; stem; therapeutic target

ABSTRACT Fetal alcohol spectrum disorder (FASD) is estimated to affect 3-5% of the population in the United States [1]. Prenatal alcohol exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits [2, 3]. The cognitive impairments associated with FASD include abnormalities in executive functioning (EF) and working memory[4, 5]. These abnormalities stem from orchestrated structural changes in several key brain regions including medial prefrontal cortex (mPFC) and hippocampus (HPC). While HPC and mPFC have long been implicated in effective cognitive functioning, the critical role of the thalamic nucleus reuniens (RE), that controls infromation flow between these structures has only recently been appreciated. Our preliminary data have revealed that prenatal AE affects the structure of RE and leads to behavioral deficits in fronto-hippocampal functitoning. The proposed research will test an innovative and novel hypothesis that developmental AE disrupts the HPC-RE-mPFC circuitry by altering the integrity of the midline thalamic RE . In healthy animals RE is reciprocally connected with the HPC and the mPFC and has been shown to be critical for a variety of working memory tasks. It is noted that while mPFC does not send direct projections to HPC, it connects with HPC via RE. Our preliminary data using animal model of binge drinking during third trimester indicate that postnatal day (PD) 4-9 AE produces persistent structural damage and loss of cells in RE in adult rat that is expected to produce a disruption in the functional connections between the three regions: mPFC, HPC and RE. The proposed research will test the hypothesis thatbinge AE during third trimester produces neuronal loss in the RE and this leads to dendritic and synaptic reorganization in thalamic RE, which ultimately produces dysfunctional connectivity with prefrontal cortex and hippocampus. Further, we will determine whether binge AE targets this nucleus exclusively and specifically among the midline thalamic nuclei and whether it affects behavior that depends on integrity of HPC-RE-PFC circuitry.In Aim 1, we will use classic and state of the art viral tracing and phenotypic analysis to reveal the effect of postnatal binge AE on neuronal organization and connectivity of RE with mPFC and HPC. Furthermore, in Aim 2 we use a specific set of behavioral assays that will reveal whether loss of HPC-RE-mPFC connectivity is critical to behavioral maladaption observed in AE. Significance and Innovation: The proposed research is innovative because it will use current viral neural circuit mapping and will fill a critical gap in our understanding of the mechanisms through which fetal alcohol exposure influence HPC-RE-mPFC circuitry damage and cognitive impairment. Further, because executive functioning deficits are observed in children with FASD, these aims will elucidate the crucial role of HPC-RE-mPFC circuitry in constellation of behavioral deficits in FASD; thus this region may be a critical therapeutic target in the treatment of FASD.

抽象的 据估计，美国 3-5% 的人口患有胎儿酒精谱系障碍 (FASD) [1]。产前 酒精暴露 (AE) 会导致大脑回路显着扰动和持续的认知缺陷 [2, 3]。这 与 FASD 相关的认知障碍包括执行功能 (EF) 和工作记忆异常[4， 5]。这些异常源于几个关键大脑区域（包括内侧区域）精心策划的结构变化 前额皮质 (mPFC) 和海马体 (HPC)。虽然 HPC 和 mPFC 长期以来一直与有效 认知功能，丘脑团聚核 (RE) 的关键作用，控制着人与人之间的信息流动 这些结构直到最近才受到重视。我们的初步数据显示，产前 AE 会影响 RE 的结构并导致额海马功能的行为缺陷。 拟议的研究将测试 创新和新颖的假设，即发育性 AE 通过改变 HPC-RE-mPFC 电路的完整性来破坏 中线丘脑 RE 。在健康动物中，RE 与 HPC 和 mPFC 相互关联，并且已被证实 研究表明，它对于各种工作记忆任务至关重要。值得注意的是，虽然 mPFC 不发送直接投影 对于HPC，它通过RE与HPC连接。我们使用妊娠晚期酗酒动物模型得到的初步数据 表明出生后 (PD) 4-9 AE 在成年大鼠的 RE 中产生持续的结构损伤和细胞损失，即 预计会破坏 mPFC、HPC 和 RE 三个区域之间的功能连接。这 拟议的研究将检验以下假设：妊娠晚期的暴食 AE 会导致大脑中的神经元损失。 RE 导致丘脑 RE 中的树突和突触重组，最终产生 与前额皮质和海马体的连接功能失调。此外，我们将确定是否暴饮暴食 AE 专门针对中线丘脑核中的该核，以及它是否影响 行为取决于 HPC-RE-PFC 电路的完整性。在目标 1 中，我们将使用经典和最先进的病毒 追踪和表型分析揭示产后暴饮暴食对神经元组织和连接的影响 RE 具有 mPFC 和 HPC。此外，在目标 2 中，我们使用一组特定的行为分析来揭示是否 HPC-RE-mPFC 连接的丧失对于 AE 中观察到的行为适应不良至关重要。意义及 创新：拟议的研究具有创新性，因为它将使用当前的病毒神经回路图谱，并将填补 我们对胎儿酒精暴露影响 HPC-RE-mPFC 机制的理解存在重大差距 电路损伤和认知障碍。此外，由于在儿童中观察到执行功能缺陷 与 FASD 一起，这些目标将阐明 HPC-RE-mPFC 电路在一系列行为缺陷中的关键作用 胎儿酒精谱系障碍；因此该区域可能是治疗 FASD 的关键治疗靶点。