Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD

FASD 模型中的海马-丘脑-前额叶回路损伤和治疗干预

• 批准号: 10686884
• 负责人: ANNA Y KLINTSOVA
• 金额: $ 38.02万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686884
• 关键词: Address; Adult; Affect; Alcohol-Induced Disorders; Alcohols; Animal Model; Animals; Antibodies; Apoptosis; Attention; Behavior; Behavior Therapy; Behavioral; Brain; Brain Injuries; Brain region; Cells; Child; Cognitive; Cognitive deficits; Communication; Data; Development; Dorsal; Dose; Electrophysiology (science); Evaluation; Executive Dysfunction; Exercise; Failure; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Functional disorder; Gene Expression; Goals; Hippocampus; Human; Immediate-Early Genes; Immunoglobulin G; Impaired cognition; Impairment; Impulsivity; Incidence; Injections; Intervention; Label; Laboratories; Lesion; Maps; Measures; Medial; Memory; Memory impairment; Microspheres; Midline Thalamic Nuclei; Modeling; Neonatal; Neuroanatomy; Neurobiology; Neuroglia; Neuronal Plasticity; Pathology; Phase; Population; Prefrontal Cortex; Pregnancy; Primates; Public Health; Rattus; Research; Reuniens Thalamic Nucleus; Rodent; Role; Running; Short-Term Memory; Site; Structure; Symptoms; Synapses; Testing; Thalamic Nuclei; Therapeutic; Therapeutic Intervention; Third Pregnancy Trimester; United States; Viral; Virus; alcohol effect; alcohol exposure; behavior prediction; behavior test; behavioral impairment; behavioral outcome; biological sex; brain circuitry; care costs; cognitive function; connectome; executive function; experience; flexibility; in vivo; innovation; male; neural circuit; neuron loss; neurotrophic factor; object recognition; postnatal; response; rhomboid; spatial memory; stem; therapeutic target

ABSTRACT Fetal alcohol spectrum disorders (FASD) are estimated to affect 3-5% of the US population (1). Prenatal alcohol exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits (2, 3) that include abnormalities in executive functioning (EF) and working memory (4, 5). These abnormalities stem from orchestrated structural changes in several key brain regions including the prefrontal cortex (PFC) and hippocampus (HPC). While HPC and PFC have long been implicated in effective cognitive functioning, the role of the thalamic nucleus reuniens (Re), that controls information flow between these structures, has only recently been appreciated. The Re serves as a functional bridge between PFC and the HPC which are crucial for EF (6-9). Our preliminary data using a rat model of binge AE during the third trimester revealed persistent structural damage of Re, highly correlated to behavioral deficits consistent with fronto-hippocampal damage. The proposed research will test the hypothesis that binge AE during the third trimester produces neuronal loss as well as dendritic and synaptic reorganization in the Re and mPFC, which ultimately produces dysfunctional connectivity among mPFC-Re-HPC circuitry that is associated with EF deficits. In addition, we will evaluate if mPFC-Re-HPC dysfunction is mitigated via a therapeutic strategy, wheel-running (WR) followed by environmental complexity (EC), which has been successful in alleviating the deleterious AE effects on other behaviors disrupted in FASD(10-14) .Using our combined expertise in experience- dependent brain plasticity, developmental alcohol exposure and in vivo electrophysiology in freely moving rats during memory tasks, we aim to reveal AE vulnerability of the PFC-Re-HPC circuit and determine the cellular components and factors involved in plasticity of this circuit. integrity of the Re and PFC in a binge third trimester Aim 1 will establish the contributions of alcohol dose on structural AE rat model. Aim 2 working spatial memory deficits. Connectivity-behavior relationships will be will test the hypothesis that AE induces determined within the same animals via virus labeling to test the hypothesis that AE disrupts the structural connectivity between the Re, HPC and PFC. In addition, we will test the prediction that behavioral intervention (WR/EC) reduces AE-related deficits in behaviors that are dependent on the integrity of the PFC-Re-HPC circuit by enhancing neuroplasticity. We will assess whether neuroplasticity is critically dependent on increased expression of neurotrophic factors in the structural components of the circuitry. Finally, Aim 3 will determine whether AE-induced Re damage leads to reduced oscillatory synchrony between the dorsal HPC and PFC during a spatial working memory task and if WR/EC can reinstate mPFC-HPC synchrony. and in vivo Significance and Innovation : The proposed research is innovative. It will use viral neural circuit mapping multisite recording to fill a critical gap in our understanding of the mechanisms through which AE alters mPFC-Re-HPC circuitry and thus leads to cognitive impairment. Furthermore, because EF deficits are observed in children with FASD, these aims will elucidate the crucial role of mPFC-Re-HPC circuitry in the constellation of FASD deficits; thus this network may be a critical therapeutic target in FASD treatment.

抽象的 据估计，胎儿酒精谱系障碍（FASD）会影响3-5％的美国人群（1）。产前酒精 暴露（AE）导致脑电路的明显扰动和持续的认知缺陷（2，3）包括 执行功能（EF）和工作记忆的异常（4，5）。这些异常来自精心策划 包括前额叶皮层（PFC）和海马（HPC）在内的几个关键大脑区域的结构变化。尽管 HPC和PFC长期以来一直与有效的认知功能有关，这是丘脑核团聚的作用 （re）控制这些结构之间的信息流，直到最近才得到理解。 Re用作 PFC和HPC之间的功能桥，对于EF至关重要（6-9）。我们使用大鼠模型的初步数据 三个月中的暴饮暴食揭示了RE的持续结构损害，与行为缺陷高度相关 与额 - 海马损伤一致。拟议的研究将检验以下假设 三个月在RE和MPFC中产生神经元丧失以及树突状和突触重组， 最终会在MPFC-RE-HPC电路之间产生功能失调的连接性 EF缺陷。此外， 我们将通过治疗策略来评估MPFC-RE-HPC功能障碍是否得到减轻 车轮运行（WR），然后是环境复杂性（EC），这在减轻了 有害的AE对FASD中断的其他行为的影响（10-14） 。 依赖的大脑可塑性，发育性酒精暴露和在自由移动大鼠的体内电生理学期间 内存任务，我们旨在揭示PFC-RE-HPC电路的AE漏洞并确定细胞组件 以及该电路可塑性涉及的因素。 RE和PFC的完整性在三个月的狂欢中 目标1 将建立酒精剂量对结构的贡献 AE大鼠模型。 目标2 工作空间记忆缺陷。连通性 - 行为关系将是 将检验AE诱导的假设 通过同一动物在同一动物中确定 病毒标记以检验AE的假设，即AE破坏了RE，HPC和PFC之间的结构连通性。在 此外，我们还将测试行为干预（WR/EC）的预测可减少与AE相关的行为缺陷 通过增强神经可塑性，取决于PFC-RE-HPC电路的完整性。我们将评估是否 神经塑性严重取决于神经营养因子在结构成分中的表达增加 电路。最后， 目标3 将确定AE诱导的RE损伤是否导致振荡同步降低 在空间工作记忆任务中，在背侧HPC和PFC之间，如果WR/EC可以恢复MPFC-HPC 同步。 和体内 意义和创新 ：拟议的研究是创新的。它将使用病毒神经电路映射 多站点记录以填补我们对AE改变机制的理解的关键空白 MPFC-RE-HPC电路，因此导致认知障碍。此外，由于在 FASD儿童，这些目标将阐明MPFC-RE-HPC电路在FASD星座中的关键作用 缺陷；因此，该网络可能是FASD治疗中的关键治疗靶标。

项目成果

Changes in Representation of Thalamic Projection Neurons within Prefrontal-Thalamic-Hippocampal Circuitry in a Rat Model of Third Trimester Binge Drinking.

• DOI: 10.3390/brainsci11030323
• 发表时间: 2021-03-04
• 期刊: Brain sciences
• 影响因子: 3.3
• 作者: Gursky ZH;Klintsova AY
• 通讯作者: Klintsova AY

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes.

• DOI: 10.3389/fnbeh.2021.786234
• 发表时间: 2021
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Milbocker KA;Campbell TS;Collins N;Kim S;Smith IF;Roth TL;Klintsova AY
• 通讯作者: Klintsova AY

Exercise in Adolescence Enhances Callosal White Matter Refinement in the Female Brain in a Rat Model of Fetal Alcohol Spectrum Disorders.

• DOI: 10.3390/cells12070975
• 发表时间: 2023-03-23
• 期刊: CELLS
• 影响因子: 6
• 作者: Milbocker, Katrina A.;Smith, Ian F.;Brengel, Eric K.;LeBlanc, Gillian L.;Roth, Tania L.;Klintsova, Anna Y.
• 通讯作者: Klintsova, Anna Y.

Representation of prefrontal axonal efferents in the thalamic nucleus reuniens in a rodent model of fetal alcohol exposure during third trimester.

• DOI: 10.3389/fnbeh.2022.993601
• 发表时间: 2022
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3