Alcohol and Developing Neuronal Circuits

酒精与发育中的神经元回路

• 批准号: 10684257
• 负责人: Carlos Fernando Valenzuela
• 金额: $ 52.16万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684257
• 关键词: Action Potentials; Adolescent; Affect; Alcohols; Animals; Anterior; Anterior Nuclear Group; Behavior; Behavioral; Biological; Brain; Brain region; Cells; Cognitive; Cognitive deficits; Data; Development; Electrodes; Electrophysiology (science); Emotional; Equilibrium; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Frequencies; Functional disorder; Generations; Glutamates; Goals; Head; Health; Hippocampal Formation; Hippocampus; Human; In Vitro; Individual; Interneurons; Intervention; Knowledge; Label; Learning; Life; Memory; Memory impairment; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Neurons; Pathology; Pathway interactions; Play; Pregnancy; Property; Public Health; Recovery; Research; Rodent; Role; Silicones; Slice; Strategic Planning; Structure; Synapses; Synaptic Transmission; System; Techniques; Testing; Thalamic Nuclei; Thalamic structure; Third Pregnancy Trimester; Time; United States; alcohol consequences; alcohol effect; alcohol exposure; cingulate cortex; cognitive function; density; distributed memory; effective therapy; hippocampal pyramidal neuron; in vivo; innovation; memory consolidation; memory retrieval; neurobiological mechanism; neuron apoptosis; neuronal circuitry; nonhuman primate; novel; optogenetics; postnatal; preclinical study; prevent; sex; showing emotion; signal processing; spatial memory; transmission process; way finding

Project Summary / Abstract Cognitive function deficits are among the most devastating consequences of fetal alcohol exposure. Currently available treatments against these deficits have limited efficacy. Our long-term goal is to identify specific functional mechanisms underlying the cognitive deficits associated with FASDs, so that circuit-specific treatments can be developed to prevent and correct them. Our objective is to leverage both in vitro and in vivo electrophysiological approaches to determine the long-term impact of third trimester-equivalent ethanol exposure (TTAE) on the limbic memory system. Our central hypothesis is that TTAE disrupts the balance of excitatory and inhibitory synaptic transmission at hippocampal formation→retrosplenial cortex (RSC) and RSC↔anterior thalamic nucleus (ATN) synapses, leading to deficits in information flow within and between these brain regions. Our rationale for the use of complementary in vitro and in vivo electrophysiological approaches is to provide a multi- scale view of the effects of TTAE on functional hippocampal CA1, subiculum (SUB), RSC and ATN connectivity. In Aim 1, we will determine the effects of TTAE on the function of CA1→RSC and SUB→RSC pathways. We will use slice electrophysiology, retrograde labeling, and optogenetics to test the hypothesis that TTAE persistently reduces glutamatergic transmission at SUB→RSC synapses, and increases direct monosynaptic long-range inhibition (CA1→RSC) and indirect feedforward di-synaptic inhibition (SUB→RSC interneurons→RSC pyramidal neurons). We will also use high-density silicone electrode recordings in freely behaving mice to test the hypothesis that ethanol exposure reduces the number, efficiency, and information content of high frequency oscillatory bursts in the RSC that are important for memory. In Aim 2, we will determine the effects of TTAE on the function of ATN↔RSC pathways. We will test the hypothesis that TTAE persistently reduces glutamatergic transmission at reciprocal monosynaptic connections between the ATN and RSC, without affecting di-synaptic feedforward inhibition at RSC→thalamic reticular nuclei→ATN synapses. We will also test the hypothesis that TTAE disrupts the activity of ATN and RSC neurons specifically modulated by an animal’s head direction that are essential in spatial learning and memory. The research proposed in this application is innovative because it will systematically characterize, for the first time, the developmental effects of ethanol on interactions among key components of the limbic memory network. The proposed research is significant because it will elucidate novel functional neurobiological mechanisms underlying developmental ethanol exposure- induced cognitive deficits, and identify specific biological targets for interventions to ameliorate them.

项目总结/摘要 认知功能缺陷是胎儿酒精暴露的最具破坏性的后果之一。 目前针对这些缺陷的可用治疗具有有限的功效。我们的长期目标是 确定与FASD相关的认知缺陷的具体功能机制， 可以开发特定于回路的治疗方法来预防和纠正它们。我们的目标是 利用体外和体内电生理方法来确定长期影响 的第三个孕期当量乙醇暴露（TTAE）的边缘记忆系统。我们的中央 一种假说认为TTAE在一定程度上破坏了兴奋性和抑制性突触传递的平衡， 海马结构→压后皮质（RSC）和RSC参与丘脑前核（ATN） 突触，导致这些大脑区域内部和之间的信息流不足。我们的理据 使用互补的体外和体内电生理学方法的目的是提供一种多功能的 TTAE对功能性海马CA 1、下托（CA 1）、RSC和ATN影响的量表视图 连通性。在目标1中，我们将确定TTAE对CA 1 →RSC功能的影响， SUB→RSC途径。我们将使用切片电生理学、逆行标记和光遗传学， 检验TTAE持续降低在RSC-RSC时的多巴胺能传递的假设 突触，并增加直接单突触长程抑制（CA 1 →RSC）和间接 前馈双突触抑制（突触前体→RSC中间神经元→RSC锥体神经元）。我们还将 在自由活动的小鼠中使用高密度硅胶电极记录，以检验以下假设： 乙醇暴露降低了高频的数量、效率和信息含量， 对记忆很重要的振荡爆发。在目标2中，我们将确定 TTAE对ATN ParticipRSC通路功能的影响。我们将检验TTAE持续存在的假设， 减少ATN之间的相互单突触连接处的突触能传递， RSC，不影响RSC→丘脑网状核→ATN处的双突触前馈抑制 突触我们还将测试TTAE干扰ATN和RSC神经元活动的假设 特别是由动物的头部方向调制，这在空间学习中是必不可少的， 记忆本申请中提出的研究是创新的，因为它将系统地 首次描述了乙醇对关键因素之间相互作用的发展影响， 边缘记忆网络的组成部分。这项研究意义重大，因为它将 阐明乙醇暴露在发育过程中的新的功能性神经生物学机制 诱发的认知缺陷，并确定具体的生物干预目标，以改善他们。

项目成果

Ethanol untangles the amygdala-anxiety circuit through tonic GABA inhibition.

• DOI: 10.1111/acer.12298
• 发表时间: 2014-03
• 期刊: Alcoholism, clinical and experimental research
• 作者: Diaz MR;Morton RA
• 通讯作者: Morton RA

Modulation of glutamatergic transmission by sulfated steroids: role in fetal alcohol spectrum disorder.

硫酸类固醇对谷氨酸能传递的调节：在胎儿酒精谱系障碍中的作用。

• DOI: 10.1016/j.brainresrev.2007.04.009
• 发表时间: 2008
• 期刊: Brain research reviews
• 作者: Valenzuela,CFernando;Partridge,LDonald;Mameli,Manuel;Meyer,DouglasA
• 通讯作者: Meyer,DouglasA

Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum.

• DOI: 10.1371/journal.pone.0019351
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Guo W;Crossey EL;Zhang L;Zucca S;George OL;Valenzuela CF;Zhao X
• 通讯作者: Zhao X

The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in developing retrosplenial cortex neurons from mice.

• DOI: 10.1002/npr2.12306
• 发表时间: 2023-03
• 期刊: Neuropsychopharmacology reports
• 影响因子: 2.5

Experimental data on developmental elimination of retrosplenial cortex GABAergic interneurons in a mouse model of ethanol exposure during the last trimester of human pregnancy.

• DOI: 10.1016/j.dib.2022.108355
• 发表时间: 2022-08
• 期刊: DATA IN BRIEF
• 影响因子: 1.2
• 作者: Barber, Megan J.;McDonald, Casey D.;Chavez, Glenna J.;Bird, Clark W.;Valenzuela, C. Fernando
• 通讯作者: Valenzuela, C. Fernando