海马-前额叶相干性在不同频段介导工作记忆和选择性注意，并提供精神分裂症与其风险基因 GRIA1 之间的因果关系。,Translational Psychiatry

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海马-前额叶相干性在不同频段介导工作记忆和选择性注意，并提供精神分裂症与其风险基因 GRIA1 之间的因果关系。
Translational Psychiatry ( IF 5.8 ) Pub Date : 2019-04-18 , DOI: 10.1038/s41398-019-0471-0
Alexei M Bygrave _{1,

2,

3} , Thomas Jahans-Price ₁ , Amy R Wolff _{1,

2} , Rolf Sprengel _{4,

5} , Dimitri M Kullmann ₂ , David M Bannerman ₁ , Dennis Kätzel _{1,

2,

6}

Affiliation

在精神分裂症中已经报道了额颞θ相干性增加和其刺激特异性调节的失败，但心理相关性和潜在的神经机制仍然难以捉摸。缺乏编码 GLUA1 的假定精神分裂症风险基因 GRIA1 (Gria1-/-) 的小鼠，由于缺乏刺激特异性短期习惯，表现出空间工作记忆严重受损和选择性注意力升高。有人提出短期习惯的失败会导致显着性的异常分配，从而导致精神分裂症中的精神病。我们在评估这些动物、野生型 (WT) 对照和 Gria1-/- 小鼠的空间工作记忆和短期习惯时记录了海马前额叶的连贯性，其中 GLUA1 表达在海马亚区 CA2 和 CA3 中恢复。我们发现 beta (20-30 Hz) 和低 gamma (30-48 Hz) 频率相干性可以预测工作记忆性能，而令人惊讶的是，theta (6-12 Hz) 相干性与性能无关，并且在很大程度上不受基因型的影响这个任务。相比之下，在新环境中，theta 相干性专门跟踪 WT 小鼠中与探索相关的注意力，但在 Gria1 基因敲除中强烈升高和未调节，从而与短期习惯受损相关。引人注目的是，将 GLUA1 选择性地重新引入 CA2/CA3 可以恢复异常的短期习惯、θ 连贯性以及海马和前额叶θ 振荡。尽管其他频带（β、γ）中的局部振荡和相干性以及 θ-γ 交叉频率耦合也显示出对 GLUA1 的依赖性，但它们都与短期习惯无关。

"点击查看英文标题和摘要"

Hippocampal-prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1.

Increased fronto-temporal theta coherence and failure of its stimulus-specific modulation have been reported in schizophrenia, but the psychological correlates and underlying neural mechanisms remain elusive. Mice lacking the putative schizophrenia risk gene GRIA1 (Gria1-/-), which encodes GLUA1, show strongly impaired spatial working memory and elevated selective attention owing to a deficit in stimulus-specific short-term habituation. A failure of short-term habituation has been suggested to cause an aberrant assignment of salience and thereby psychosis in schizophrenia. We recorded hippocampal-prefrontal coherence while assessing spatial working memory and short-term habituation in these animals, wildtype (WT) controls, and Gria1-/- mice in which GLUA1 expression was restored in hippocampal subfields CA2 and CA3. We found that beta (20-30 Hz) and low-gamma (30-48 Hz) frequency coherence could predict working memory performance, whereas-surprisingly-theta (6-12 Hz) coherence was unrelated to performance and largely unaffected by genotype in this task. In contrast, in novel environments, theta coherence specifically tracked exploration-related attention in WT mice, but was strongly elevated and unmodulated in Gria1-knockouts, thereby correlating with impaired short-term habituation. Strikingly, reintroduction of GLUA1 selectively into CA2/CA3 restored abnormal short-term habituation, theta coherence, and hippocampal and prefrontal theta oscillations. Although local oscillations and coherence in other frequency bands (beta, gamma), and theta-gamma cross-frequency coupling also showed dependence on GLUA1, none of them correlated with short-term habituation. Therefore, sustained elevation of hippocampal-prefrontal theta coherence may underlie a failure in regulating novelty-related selective attention leading to aberrant salience, and thereby represents a mechanistic link between GRIA1 and schizophrenia.

更新日期：2019-05-16

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