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卫生问题，新出现的证据表明，青春期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继续成熟到成年早期。在过去的几年里，NADIA联盟和其他实验室发表的研究表明，青少年间歇性酒精（AIE）暴露会产生严重的行为，认知，电生理和神经解剖学损伤，这些损伤在成年啮齿动物中持续存在。潜在的神经适应，有助于高风险的青少年饮酒的持续后果仍然在很大程度上未知。NADIA联盟的三个组成部分发现，AIE暴露改变了成年杏仁核（Pandey组成部分）、前额叶皮层（钱德勒组成部分）和海马体（Swartzwelder组成部分）的树突棘密度和形态。脊柱的形态特征的分析表明，AIE暴露选择性地增加了成人前额叶皮层和海马中“不成熟”的长而薄的树突棘的患病率。以前的研究结果表明，在发育修剪的自然过程中，不对称突触的成熟包括用与蘑菇形树突棘相关的成熟突触替换与长而细的棘相关的不成熟突触。因此，AIE暴露似乎损害了成年大脑中突触修剪的正常成熟。由于树突棘形态影响突触生理学和行为，因此成人脑中神经元的异常结构可塑性可能是与AIE暴露相关的认知和行为缺陷的潜在神经机制。这些发现的融合促使了NADIA树突棘核心的形成，该核心将整合AIE暴露诱导的多个脑区域中的树突棘变化。这个NADIA树突棘核心的首要假设是，AIE暴露锁定了成人大脑中与正常修剪过程不同的青少年形态表型。本核心的目的是提供与NADIA联盟的行为、电生理和表观遗传学研究相关的大脑区域中树突棘密度和棘形态的详细分析。树突棘核心将提供每个NADIA组件的主要和次要脑区树突棘变化分析。该核心还将表征与NADIA联盟组件相关的大脑区域中树突棘密度和形态的发育变化。该核心向NADIA联盟提供的关于AIE暴露对树突棘适应性和棘形态发育轨迹的影响的数据将影响神经科学领域并为公共卫生提供信息。

 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.