耶魯大學醫(yī)學院和克里特大學（University of Crete）醫(yī)學院的研究者在《細胞》（Cell）雜志上公布了他們的最新研究成果，首次闡明可改變腦中高級網(wǎng)絡(luò)連接強度的分子機制,。此項發(fā)現(xiàn)將有助于治療一些相關(guān)疾病,，例如對正常老化的認知缺陷,，精神分裂癥（schizophrenia）、雙極紊亂（bipolar disorder）和多動癥（attention deficit hyperactivity disorder,；ADHD）的認知改變,，等等。
“我們的數(shù)據(jù)揭示了大腦中覺醒系統(tǒng)（arousal system）如何影響認知網(wǎng)絡(luò)的過程,。我們知道認知網(wǎng)絡(luò)是會促進工作記憶（working memory）的,，而工作記憶在抽象思維、計劃和組織,，以及抑制注意力分散方面都有著關(guān)鍵性的作用和地位,。”Amy Arnsten介紹說，他是耶魯大學神經(jīng)生物學教授,，也是這篇研究性文章的通訊作者,。
腦中前額葉皮質(zhì)（prefrontal cortex；PFC）對于執(zhí)行功能（executive function）的行使有著重要作用,。在正常的衰老過程中,，PFC在維持此類基于記憶的功能的能力上會不斷減弱。在ADHD患者身上,，這種能力則遭受一定程度的損傷,，而在精神分裂癥和雙極紊亂患者身上，這種能力的損傷程度更大,。
最新的這篇文章表明,，PFC中的腦細胞含有一種名為超極化活化環(huán)核苷酸門孔通道（hyperpolarization-activated cyclic nucleotide-gated channel；HCN）的離子通道,。這種離子通道一般分布在樹突棘（dendritic spine）上,。當遇到cAMP時，這些通道就會打開,。然而,，在通道打開的狀態(tài)下，信息就不會傳入細胞,，從而網(wǎng)絡(luò)就會中斷,。Arnsten介紹說，如果抑制cAMP,，就可以關(guān)閉通道,，讓網(wǎng)絡(luò)重新得到連接。
研究還表明在通道附近的α2A腎上腺素能受體可以抑制cAMP的表達,，維持信號在細胞中傳導過程的暢通,。腦中的天然化合物去甲腎上腺素（norepinephrine）和類似胍法辛（guanfacine）的藥物都可以刺激此類受體。
原始出處:
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
[email protected]
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.
