Alcohol and Developing Neuronal Circuits

项目摘要/摘要 认知功能缺陷是胎儿酒精暴露最具破坏性的后果之一。 目前针对这些缺陷的现有治疗方法效果有限。我们的长期目标是 确定与FASD相关的认知缺陷潜在的特定功能机制，因此 可以开发专门针对电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 晚期妊娠相当酒精暴露(TTAE)对边缘记忆系统的影响。我们的中央 假说是TTAE破坏了兴奋性和抑制性突触传递的平衡 海马结构→脾后皮质和RSC↔丘脑前核 突触，导致这些大脑区域内部和之间的信息流不足。我们的理论基础 为使用体外和活体互补的电生理方法提供了一种多途径。 TTAE对功能性海马CA1、下丘脑(SUB)、RSC和ATN影响的比例尺观察 连通性。在目标1中，我们将确定TTAE对CA1→RSC功能的影响和 SubSet→RSC路径。我们将使用切片电生理学、逆行标记和光遗传学来 验证TTAE持续降低亚→RSC谷氨酸能传递的假设 突触，并增加直接单突触长距离抑制(CA1→RSC)和间接 前馈双突触抑制(亚→RSC中间神经元、→RSC锥体神经元)。我们还将 在行为自由的小鼠身上使用高密度硅胶电极记录来检验这一假设 酒精暴露降低了高频脑损伤的数量、效率和信息量 RSC中对记忆很重要的振荡脉冲。在目标2中，我们将确定 TTAE对ATN↔RSC通路功能的影响我们将检验TTAE持续存在的假设 减少ATN和ATN之间相互单突触连接的谷氨酸能传递 RSC，但不影响RSC→丘脑网状核→-ATN的双突触前馈抑制 突触。我们还将检验TTAE干扰ATN和RSC神经元活动的假设 特别是受动物头部方向的调节，这在空间学习和 记忆。本申请中提出的研究具有创新性，因为它将系统地 首次刻画了乙醇对关键基因之间相互作用的发育影响 边缘记忆网络的组成部分。这项拟议的研究意义重大，因为它将 阐明发育性酒精暴露的新的功能神经生物学机制 诱发的认知缺陷，并确定特定的生物靶点进行干预以改善这些缺陷。

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.