Mills Brian D, Pearce Hadley L, Khan Omar, Jarrett Ben R, Fair Damien A, Lahvis Garet P
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States; Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, United States; Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR 97239, United States.
Behav Brain Res. 2016 Jul 15;308:14-23. doi: 10.1016/j.bbr.2016.03.039. Epub 2016 Apr 2.
Domoic acid (DA) is a toxin produced by marine algae and known primarily for its role in isolated outbreaks of Amnestic Shellfish Poisoning and for the damage it inflicts on marine mammals, particularly California sea lions. Lethal effects of DA are often preceded by seizures and coma. Exposure to DA during development can result in subtle and highly persistent effects on brain development and include behavioral changes that resemble diagnostic features of schizophrenia and anomalies in social behavior we believe are relevant to autism spectrum disorder (ASD). To more fully examine this hypothesis, we chose to examine adolescent mice exposed in utero to DA for endpoints relevant to ASD, specifically changes in social behavior and network structure, the latter measured by resting state functional connectivity (rs-fcMRI). We found that male offspring exposed in utero to DA expressed reproducible declines in social interaction and atypical patterns of functional connectivity in the anterior cingulate, a region of the default mode network that is critical for social functioning. We also found disruptions in global topology in regions involved in the processing of reward, social, and sensory experiences. Finally, we found that DA exposed males expressed a pattern of local over-connectivity. These anomalies in brain connectivity bear resemblance to connectivity patterns in ASD and help validate DA-exposed mice as a model of this mental disability.
软骨藻酸（DA）是一种由海藻产生的毒素，主要因其在失忆性贝类中毒的个别暴发事件中所起的作用以及对海洋哺乳动物，尤其是加利福尼亚海狮造成的损害而闻名。DA的致死效应通常先于癫痫发作和昏迷出现。在发育过程中接触DA会对大脑发育产生微妙且高度持久的影响，包括类似精神分裂症诊断特征的行为变化以及我们认为与自闭症谱系障碍（ASD）相关的社会行为异常。为了更全面地检验这一假设，我们选择检查在子宫内接触DA的青春期小鼠，以观察与ASD相关的终点指标，特别是社会行为和网络结构的变化，后者通过静息态功能连接性（rs-fcMRI）来测量。我们发现，在子宫内接触DA的雄性后代在社会互动方面表现出可重复的下降，以及前扣带回中功能连接的非典型模式，前扣带回是默认模式网络中对社会功能至关重要的一个区域。我们还发现，参与奖励、社会和感官体验处理的区域的全局拓扑结构受到破坏。最后，我们发现接触DA的雄性小鼠表现出局部过度连接的模式。这些大脑连接异常与ASD中的连接模式相似，有助于验证接触DA的小鼠作为这种精神残疾模型的有效性。
