1/2 NADIA U24 Dendritic Spine Core

 描述(由申请人提供)：酒精使用障碍是一个主要的公共健康问题，新出现的证据表明，青春期的高风险饮酒对行为和大脑发育有长期影响。大脑在整个青春期经历了深刻的结构和功能适应，一些关键的大脑区域甚至在成年早期继续成熟。在过去的几年里，Nadia联合会和其他实验室发表的研究表明，青少年间歇性酒精(AIE)暴露会导致严重的行为、认知、电生理和神经解剖学损害，这些损害在成年啮齿动物中持续存在。导致高危青少年饮酒持续后果的潜在神经适应在很大程度上仍不清楚。Nadia Consortium的三个组成部分发现，AIE暴露改变了成人杏仁核(Pandey组成部分)、前额叶皮质(Chandler组成部分)和海马区(SwartzWelder组成部分)的树突棘密度和形态。对棘突形态特征的分析表明，AIE暴露选择性地增加了成年前额叶皮质和海马区“未成熟”细长树突棘的发生率。先前的发现表明，在发育修剪的自然过程中，不对称突触的成熟涉及用与蘑菇状树突棘相关的成熟突触取代与细长刺相关的未成熟突触。因此，AIE暴露似乎损害了成人大脑中突触修剪的正常成熟。由于树突棘形态影响突触的生理和行为，成人脑内神经元结构的异常可塑性可能是AIE暴露导致认知和行为缺陷的神经机制。这些发现的汇聚促使了Nadia树突脊椎核心的形成，该核心将整合AIE暴露引起的多个脑区的树突变化。这个Nadia树枝状脊柱核心的首要假设是，AIE暴露锁定了成人大脑中与正常修剪过程背道而驰的青春期形态表型。本核心的目的是提供与Nadia Consortium的行为、电生理和表观遗传学研究相关的脑区树突棘突密度和棘突形态的详细分析。树突脊椎核心将为每个Nadia成分提供主要和次要脑区树突棘突变化的分析。这一核心还将描述与Nadia Consortium成分相关的脑区树突密度和形态的发育变化。该中心向NADIA联合会提供的有关AIE暴露对树突棘适应的影响以及脊椎形态发育轨迹的数据将影响神经科学领域并告知公众健康。

 DESCRIPTION (provided by applicant): Alcohol use disorders are a major public health issue and emerging evidence suggests that high-risk drinking during adolescence has long-term consequences on behavior and brain development. The brain undergoes profound structural and functional adaptations throughout adolescence, and some critical brain regions even continue to mature into early adulthood. Over the last few years, studies published from the NADIA Consortium and other laboratories showed that adolescent intermittent alcohol (AIE) exposure produces profound behavioral, cognitive, electrophysiological, and neuroanatomical impairments that persist in adult rodents. The underlying neuroadaptations that contribute to the persistent consequences of high-risk adolescent drinking remain largely unknown. Three components of the NADIA Consortium found that AIE exposure alters dendritic spine density and morphology in the adult amygdala (Pandey component), prefrontal cortex (Chandler component), and hippocampus (Swartzwelder component). An analysis of the morphological characteristics of spines revealed that AIE exposure selectively increased the prevalence of `immature' long, thin dendritic spines in the adult prefrontal cortex and hippocampus. Previous findings suggest that maturation of asymmetric synapses during the natural process of developmental pruning involves replacing immature synapses associated with long, thin spines with mature synapses associated with mushroom-shaped dendritic spines. Thus, AIE exposure appears to impair the normal maturation of synaptic pruning in the adult brain. Because dendritic spine morphology influences synaptic physiology and behavior, aberrant structural plasticity of neurons in the adult brain is a likely neural mechanism underlying deficits in cognition and behavior associated with AIE exposure. The convergence of these findings prompted the formation of a NADIA Dendritic Spine Core that will integrate dendritic spines changes in multiple brain regions induced by AIE exposure. The overarching hypothesis of this NADIA Dendritic Spine Core is that AIE exposure locks-in an adolescent morphological phenotype in the adult brain that diverges from the normal pruning process. The purpose of this Core is to provide a detailed analysis of dendritic spine density and spine morphology in brain regions relevant to the behavioral, electrophysiological, and epigenetic studies of the NADIA Consortium. The Dendritic Spine Core will provide analysis of dendritic spine changes in a primary and secondary brain region for each NADIA component. This Core will also characterize developmental changes in dendritic spine density and morphology in brain regions related to the NADIA Consortium components. The data provided to the NADIA Consortium by this Core on the impact of AIE exposure on dendritic spine adaptations and the developmental trajectory of spine morphology will influence the neuroscience field and inform public health.