Cell：可改变脑中高级网络连接强度的分子机制被阐明

佚名

    耶鲁大学医学院和克里特大学（University  of  Crete）医学院的研究者在《细胞》（Cell）杂志上公布了他们的最新研究成果，首次阐明可改变脑中高级网络连接强度的分子机制。此项发现将有助于治疗一些相关疾病，例如对正常老化的认知缺陷，精神分裂症（schizophrenia）、双极紊乱（bipolar  disorder）和多动症（attention  deficit  hyperactivity  disorder；ADHD）的认知改变，等等。

    “我们的数据揭示了大脑中觉醒系统（arousal  system）如何影响认知网络的过程。我们知道认知网络是会促进工作记忆（working  memory）的，而工作记忆在抽象思维、计划和组织，以及抑制注意力分散方面都有着关键性的作用和地位。”Amy  Arnsten介绍说，他是耶鲁大学神经生物学教授，也是这篇研究性文章的通讯作者。

    脑中前额叶皮质（prefrontal  cortex；PFC）对于执行功能（executive  function）的行使有着重要作用。在正常的衰老过程中，PFC在维持此类基于记忆的功能的能力上会不断减弱。在ADHD患者身上，这种能力则遭受一定程度的损伤，而在精神分裂症和双极紊乱患者身上，这种能力的损伤程度更大。

    最新的这篇文章表明，PFC中的脑细胞含有一种名为超极化活化环核苷酸门孔通道（hyperpolarization-activated  cyclic  nucleotide-gated  channel；HCN）的离子通道。这种离子通道一般分布在树突棘（dendritic  spine）上。当遇到cAMP时，这些通道就会打开。然而，在通道打开的状态下，信息就不会传入细胞，从而网络就会中断。Arnsten介绍说，如果抑制cAMP，就可以关闭通道，让网络重新得到连接。

    研究还表明在通道附近的α2A肾上腺素能受体可以抑制cAMP的表达，维持信号在细胞中传导过程的畅通。脑中的天然化合物去甲肾上腺素（norepinephrine）和类似胍法辛（guanfacine）的药物都可以刺激此类受体。

原始出处:

Cell, Vol 129, 397-410, 20 April 2007

Article

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Min Wang,1 Brian P. Ramos,1 Constantinos D. Paspalas,1,4 Yousheng Shu,1 Arthur Simen,2 Alvaro Duque,1 Susheel Vijayraghavan,1 Avis Brennan,1 Anne Dudley,1 Eric Nou,1 James A. Mazer,1 David A. McCormick,1,3 and Amy F.T. Arnsten1,3,

1 Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510 USA
2 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510 USA
3 The Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510 USA
4 Division of Neuroanatomy, University of Crete School of Medicine, Heraklion, Greece

Corresponding author
Amy F.T. Arnsten
amy.arnsten@yale.edu

Spatial working memory (WM; i.e., “scratchpad” memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic α2A adrenoceptors (α2A-ARs) is critical for WM. We report that α2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and α2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either α2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.