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

基本信息

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
项目类别：
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

项目摘要

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) 影响着 3-5% 的美国人口 (1)。产前饮酒暴露 (AE) 会导致大脑回路显着扰动和持续的认知缺陷 (2, 3)，包括执行功能 (EF) 和工作记忆异常 (4, 5)。这些异常现象源于精心策划几个关键大脑区域的结构变化，包括前额皮质（PFC）和海马体（HPC）。尽管 HPC 和 PFC 长期以来一直与有效的认知功能、丘脑团聚核的作用有关（Re）控制这些结构之间的信息流，直到最近才得到重视。 Re 充当 PFC 和 HPC 之间的功能桥梁，这对于 EF 至关重要 (6-9)。我们使用大鼠模型的初步数据妊娠晚期的暴食 AE 揭示了 Re 的持续结构损伤，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：在妊娠晚期会导致 Re 和 mPFC 中的神经元损失以及树突和突触重组，最终在 mPFC-Re-HPC 电路之间产生功能失调的连接，该电路与 EF 赤字。此外，我们将评估 mPFC-Re-HPC 功能障碍是否可以通过治疗策略得到缓解，车轮运行（WR），其次是环境复杂性（EC），成功地缓解了不良事件对 FASD 中其他行为的破坏产生有害影响 (10-14) .利用我们的综合专业知识和经验- 自由活动大鼠的依赖性大脑可塑性、发育性酒精暴露和体内电生理学记忆任务，我们的目标是揭示 PFC-Re-HPC 电路的 AE 漏洞并确定细胞组件以及影响该电路可塑性的因素。妊娠晚期狂饮时 Re 和 PFC 的完整性目标1 将确定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。连接行为关系将是将检验 AE 引发的假设通过在同一动物内确定病毒标记来测试 AE 破坏 Re、HPC 和 PFC 之间的结构连接的假设。在此外，我们将测试以下预测：行为干预 (WR/EC) 可减少与 AE 相关的行为缺陷：通过增强神经可塑性来依赖 PFC-Re-HPC 回路的完整性。我们将评估是否神经可塑性关键取决于结构成分中神经营养因子表达的增加电路。最后，目标 3 将确定 AE 引起的 Re 损伤是否会导致振荡同步性降低空间工作记忆任务期间背侧 HPC 和 PFC 之间的关系以及 WR/EC 是否可以恢复 mPFC-HPC 同步。和体内意义与创新：所提出的研究具有创新性。它将使用病毒神经回路映射多站点记录填补了我们对 AE 改变机制理解的关键空白 mPFC-Re-HPC 电路，从而导致认知障碍。此外，由于观察到 EF 缺陷对于患有 FASD 的儿童，这些目标将阐明 mPFC-Re-HPC 电路在 FASD 群中的关键作用赤字；因此，该网络可能是 FASD 治疗的关键治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

妊娠晚期酗酒大鼠模型中前额叶-丘脑-海马回路中丘脑投射神经元表征的变化。

DOI：
发表时间：
2021-03-04
期刊：
影响因子：
3.3
作者：
Gursky, Zachary H;Klintsova, Anna Y
通讯作者：
Klintsova, Anna Y

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

在胎儿酒精谱系障碍大鼠模型中，青春期锻炼可增强女性大脑胼胝体白质的细化。

DOI：
发表时间：
2023-03-23
期刊：
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

Rat Model of Late Gestational Alcohol Exposure Produces Similar Life-Long Changes in Thalamic Nucleus Reuniens Following Moderate- Versus High-Dose Insult.

妊娠晚期酒精暴露的大鼠模型在中度与高剂量的侮辱后丘脑 Reuniens 核产生类似的终生变化。

DOI：
发表时间：
2022-07-09
期刊：
影响因子：
0
作者：
Gursky, Zachary H;Klintsova, Anna Y
通讯作者：
Klintsova, Anna Y

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

神经胶质细胞驱动的大脑回路细化因早年逆境而改变：行为结果。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Milbocker, Katrina A;Campbell, Taylor S;Collins, Nicholas;Kim, SuHyeong;Smith, Ian F;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.

在妊娠晚期胎儿酒精暴露的啮齿动物模型中，丘脑团聚核中前额叶轴突传出的表示。