• • Chang C-C, Kuo H-Y, Chen S-Y, Lin W-T, Lu K-M, Saito T, Liu F-C (2021). Developmental characterization of schizophrenia-associated gene Zswim6 in mouse forebrain. Front Neuroanat 2021 May 13;15:669631. doi: 10.3389/fnana.2021.669631.
  • Chen S-Y, Lu K-M, Ko H-A, Huang T-H, Hao JH, Yan Y-T, Chang SL, Evans SM, Liu F-C (2020) Parcellation of the striatal complex into dorsal and ventral districts. Proc Natl Acad Sci USA. 2020 Mar 31;117(13):7418-7429. doi: 10.1073/pnas.1921007117.
  • Kuo H-Y, Liu F-C (2020) Pathological alterations in striatal compartments in the human brain of autism spectrum disorder. Mol Brain 13, 83 (2020). https://doi.org/10.1186/s13041-020-00624-2
  • Chang C-C, Kuo H-Y, Chen S-Y, Lin W-T, Lu K-M, Saito T, Liu F-C (2020) Developmental characterization of Zswim5 expression in the progenitor domains and tangential migration pathways of cortical interneurons in the mouse forebrain. J Comp Neurol. 2020 Oct;528(14):2404-2419. doi: 10.1002/cne.24900.
  • Kuo H-Y, Liu F-C (2019) Synaptic Wiring of Corticostriatal Circuits in Basal Ganglia: Insights into the Pathogenesis of Neuropsychiatric Disorders. eNeuro 16 May 2019, ENEURO.0076-19.2019; DOI: https://doi.org/10.1523/ENEURO.0076-19.2019.
  • Kuo H-Y, Liu F-C (2018) Molecular pathology and pharmacological treatment of autism spectrum disorder-like phenotypes using rodent models. Front Cell Neurosci. 12:422. doi: 10.3389/fncel.2018.00422.
  • Chen S-Y, Kuo H-Y, Liu F-C (2018) Stereotaxic surgery for genetic manipulation in striatal cells of neonatal mouse brains. J Vis Exp (137) e57270, doi:10.3791/57270.
  • Fong L, Kuo H-Y, Wu H-L, Chen S-Y, Liu F-C (2018) Differential and overlapping expression pattern of Foxp1 and Foxp2 in the striatum of adult mouse brain. Neuroscience 388: 214-223.
  • Kuo H-Y, Liu F-C (2017) Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder. FASEB J 31: 4458-4471. doi: 10.1096/fj.201700054R.
  • Chen Y-C, Kuo H-Y, Bornschein U, Takahashi H, Chen S-Y, Lu K-M, Yang H-Y, Chen G-M, Lin J-R, Lee Y-H, Chou Y-C, Cheng S-J, Chen C-T, Enard W, Hevers W, Pääbo S, Graybiel AM, Liu F-C (2016) Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c. Nature Neuroscience 19:1513–1522. doi:10.1038/nn.4380.
  • Newman H, Liu F-C, Graybiel AM (2015) Dynamic ordering of early generated striatal cells destined to form the striosomal compartment of the striatum. J Comp Neurol 523(6):943-962. doi:10.1002/cne.23725.
  • Lu K-M, Evans, SM, Hirano S, Liu F-C (2014) Dual role for Islet-1 in promoting striatonigral and repressing striatopallidal genetic programs to specify striatonigral cell identity. Proc Natl Acad Sci USA 111(1):E168-177.
  • Chang SL-Y, Chen S-Y, Huang H-H, Ko H-A, Liu P-T, Liu Y-C, Chen P-H, Liu F-C (2013) Ectopic Expression of Nolz-1 in Neural Progenitors Promotes Cell Cycle Exit/Premature Neuronal Differentiation Accompanying with Abnormal Apoptosis in the Developing Mouse Telencephalon. PLoS ONE 8(9): e74975. doi:10.1371/journal.pone.0074975.
  • Chang SL-Y, Liu Y-C, Chen S-Y, Huang T-H, Liu P-T, Liu F-C (2013) Identification of two evolutionarily conserved 5′ cis-elements involved in regulating spatiotemporal expression of Nolz-1 during mouse embryogenesis. PLoS ONE 8(1): e54485. doi:10.1371/journal.pone.0054485.
  • Ko S-A, Chen S-Y, Chen H-Y, Liu F-C (2013) Cell type-selective expression of the zinc finger-containing gene Nolz-1/Zfp503 in the developing mouse striatum. Neurosci Lett 548:44-49.
  • Chang L-Y, Yan Y-T, Shi Y-L, Liu Y-C, Takahashi H, Liu F-C (2011) Region- and cell type-selective expression of Nolz-1/zfp503 mRNA in the developing mouse hindbrain. Gene Expression Patterns 11:525-532.
  • Chen C-M, Wang H-Y, You L-R, Shang R-L, Liu F-C (2010) Expression analysis of an evolutionary conserved metallophosphodiesterase gene, Mpped1, in the normal and β-catenin-deficient malformed dorsal telencephalon. Dev Dynamics 239:1797-1806.
  • Kaoru T, Liu F-C, Ishida M, Oishi T, Hayashi M, Kitagawa M, Shimoda K, Takahashi H (2010) Molecular characterization of the intercalated cell masses of the amygdala: implications for the relationship with the striatum. Neuroscience 166:220-230.
  • Takahashi H, Takahashi K, Liu F-C (2009) FOXP genes, neural development, speech and language disorders. In: Forkhead Transcription Factors: Vital Elements in Biology and Medicine, Section II, Chapter 9, pp1-13, Maiese K, editor, Landes Bioscience, Austin, Texas. (Invited book chapter) (Advances in Experimental Medicine and Biology, Vol. 665, 2009, pp. 117-129. doi:10.1007/978-1-4419-1599-3_9.)
  • Chen Y-F, Kao C-H, Chen Y-T, Wang C-H, Wu C-Y, Tsai C-Y, Liu F-C, Yang C-W, Wei Y-H, Hsu M-T, Tsai S-F, Tsai T-F (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes & Development 23:1183-1194.
  • Tsuchiya R, Takahashi K, Liu F-C, Takahashi H (2009) Aberrant axonal projections from mammillary bodies in Pax6 mutant mice: possible roles of Netrin-1 and Slit 2 in mammillary projections. J Neurosci Res 87:1620-1633.
  • Sato T, Miura M, Yamada M, Yoshida T, Wood JD, Yazawa I, Masuda M, Suzuki T, Shin R-M, Yau H-J, Liu F-C, Shimohata T, Onodera O, Ross C A, Katsuki M, Takahashi H, Kano M, Aosaki T, Tsuji S (2009) Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice. Human Mol Genetics 18:723-736.
  • Liao W-L, Tsai H-C, Wang H-F, Chang J, Lu K-M, Wu H-L, Lee Y-C, Tsai T-F, Takahashi T, Wagner M, Ghyselinck NB, Chambon P, Liu F-C (2008) Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci USA 105: 6765-6770.
  • Takahashi K, Liu F-C, Oishi T, Mori T, Higo N, Hayashi M, Takahashi H (2008) Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3 and MEIS2. J Comp Neurol 509:180-189.
  • Takahashi K, Liu F-C, Hirokawa K, Takahashi H (2008) Expression of Foxp4 in the developing and adult rat forebrain. J Neuosci Res 86:3106-3116.
  • Takahashi H, Liu F-C (2006) Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors. Birth Defects Res C Embryo Today: Reviews 78:256-266. (Invited review)
  • Liao W-L, Wang H-F, Tsai H-C, Chambon P, Wagner M, Kakizuka A, Liu F-C (2005) Retinoid signaling competence and RARb-mediated gene regulation in the developing mammalian telencephalon. Dev Dynamics 232:887-900.
  • Liao W-L, Tsai H-C, Wu C-Y, Liu F-C (2005) Differential expression of RARb isoforms in the mouse striatum during development: a gradient of RARb2 expression along the rostrocaudal axis. Dev Dynamics 233:584–594.
  • Liao W-L, Liu F-C (2005) RARb isoform-specific regulation of DARPP-32 gene expression: an ectopic expression study in the developing rat telencephalon. Eur J Neurosci 21: 3262-3268.
  • Wang H-F, Liu F-C (2005) Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum. Neuroscience 134:97-105.
  • Chang C-W, Tsai C-W, Wang H-F, Tsai H-C, Chen H-Y, Tsai T-F, Takahashi H, Li H-Y, Fann M-J, Yang C-W, Hayashizaki Y, Saito T, Liu F-C (2004) Identification of a developmentally regulated striatum-enriched zinc-finger gene Nolz-1 in the mammalian brain. Proc Natl Acad Sci USA 101:2613-2618.
  • Takahashi K, Liu F-C, Hirokawa K, Takahashi H (2003) Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. J Neuosci Res 73:61-72.
  • Liu F-C (2003) Organotypic culture of developing striatum: Pharmacological induction of gene expression. In: Methods in Molecular Medicine, vol. 79: Drugs of Abuse: Neurological Reviews and Protocols, pp.405-412, Humana Press, Totowa, New Jersey. (Invited book chapter)
  • Yau H-J, Wang H-F, Lai C, Liu F-C (2003) Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cerebral Cortex 13:252-264.
  • Lee YC, Chien CL, Sun CN, Huang CL, Huang NK, Chiang MC, Lai HL, Lin YS, Chou SY, Wang CK, Tai MH, Liao WL, Lin TN, Liu FC, Chern Y (2003) Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur J Neurosci 7:1786-96.
  • Wang H-F, Liu F-C (2001) Developmental restriction of the LIM homeodomain transcription factor Isl-1 expression to cholinergic neurons in the striatum. Neuroscience 103:999-1016.
  • Liu F-C, Graybiel AM (1999) Neural development of the striatal dopamine system. In: The Development of Dopaminergic Neurons, (U. di Porzio, R. Pernas-Alonso, C. Perrone-Capano, eds). Landes Biosciences, Texas, pp.87-100.
  • Liu F-C, Graybiel AM (1998) Phosphorylation of CREB in organotypic cultures of developing striatum: Kinetics of dopamine and calcium signal interactions. In: Advances in Pharmacology, vol. 42, Catecholamines: Bridging Basic Science with Clinical Medicine, (D.S. Goldstein, G. Eisenhofer, R. McCarty, eds), Academic Press, San Diego, California, pp.682-686.
  • Liu F-C, Wu G-C, Hsieh S-T, Lai H-L, Wang H-F, Wang T-W, Chern Y (1998) Expression of adenylyl cyclase type VI in the central nervous system: Implication for a general coincidence detector in neurons, FEBS letters 436:92-98.
  • Liu F-C, Graybiel AM (1998) Region-dependent dynamics of cAMP response element-binding protein phosphorylation in the basal ganglia, Proc. Natl. Acad. Sci. USA 95:4708-4713.
  • Liu F-C, Graybiel AM (1998) Activity-regulated phosphorylation of CREB in the developing striatum: Implications for patterning the neurochemical phenotypes of striatal compartments. Dev. Neurosci. 20:229-236.
  • Liu F-C, Graybiel AM (1996) Protein phosphatases regulate CREB phosphorylation and Fos expression in the developing striatum: Evidence and a hypothesis. In: Advances in Behavioral Biology, vol. 47, The Basal Ganglia V, (C.Ohye, M. Kimura and J.S. McKenzie, eds), Plenum Press, New York, pp.97-103.
  • Liu F-C, Graybiel AM (1996) Spatiotemporal dynamics of CREB phosphorylation: Transient versus sustained phosphorylation in the developing striatum. Neuron 17:1133-1144.
  • Liu F-C, Graybiel AM (1995) Dopamine-mediated signaling in organotypic striatal slice cultures. In: Molecular and Cellular Mechanisms of the Neostriatal Function, (M. A. Ariano and J. Surmeier, eds), R.G. Landes, Georgetown, Texas, pp.311-319.
    Graybiel AM, Berretta B, Moratalla R, Liu F-C, Elibol B (1995) Effects of cocaine on signal transduction in striatal neurons. In: Neurobiology of Cocaine, (R. Hammer, ed), CRC Press, Boca Raton, Florida, pp.215-223.
  • Liu F-C, Dunnett SB, Graybiel AM (1995) Embryonic striatal grafting: Progress and future directions for therapeutic approaches to neurodegenerative diseases of the basal ganglia. In: Age-related dopamine-dependent disorders, (N. Segawa and Y. Nomura, eds), Karger, Basel, Monogr. Neural Sci. 14:225-234.
  • Liu F-C, Takahashi H, McKay RDG, Graybiel AM (1995) Dopaminergic regulation of transcription factor expression in organotypic cultures of developing striatum. J. Neurosci. 15:2367-2384.
  • Liu F-C, Dunnett SB, Graybiel AM (1993) Intrastriatal grafts derived from fetal striatal primordia. IV. Host and donor neurons are not intermixed. Neuroscience 55:363-372.
  • Liu F-C, Dunnett SB, Graybiel AM (1992) Influence of mesostriatal afferents on the development and transmitter regulation of intrastriatal grafts derived from embryonic striatal primordia. J. Neurosci. 12:4281-4297.
  • Liu F-C, Graybiel AM (1992) Transient calbindin-D28K-positive systems in the telencephalon: Ganglionic eminence, developing striatum and cerebral cortex. J. Neurosci. 12:674-690.
  • Liu F-C, Graybiel AM (1992) Heterogeneous development of calbindin-D28K expression in the developing striatum. J. Comp. Neurol. 320:304-322.
  • Liu F-C, Dunnett SB, Robertson HA, Graybiel AM (1991) Intrastriatal grafts derived from fetal striatal primordia. III. Induction of modular patterns of Fos-like immunoreactivity by cocaine. Exp. Brain. Res. 85:501-506.
  • Liu F-C, Graybiel AM, Dunnett SB, Baughman RW (1990) Intrastriatal grafts derived from fetal striatal primordia: II. Reconstitution of cholinergic and dopaminergic systems. J. Comp. Neurol. 295:1-14.
  • Graybiel AM, Liu F-C, Dunnett SB (1990) Cellular reaggregation in vivo: Modular patterns in intrastriatal grafts derived from fetal striatal primordia. Prog. Brain Res. 82:401-405.
  • Graybiel, AM, Liu F-C, Dunnett SB (1989) Intrastriatal grafts derived from fetal striatal primordia. I. Phenotypy and modular organization. J. Neurosci. 9:3250-3271.

我的實驗室致力於研究哺乳類動物大腦基底核神經迴路的神經發育與可塑性。大腦基底核神經迴路負責處理執行動作、認知、情緒、動機和學習記憶可塑性等多方面的關鍵性神經功能。基底核神經迴路的重要性也反應在許多疾病的病理機制上如帕金森氏症、亨丁頓舞蹈症、思覺失調症與焦慮、憂鬰情緒異常疾病。此外，伏隔核所在的腹側紋狀體更是古柯鹼與安非他命等濫用藥物的主要目標核區。有鑑於此，研究基底核迴路的發育與功能不但可以暸解大腦整合性功能，更可以幫助神經與精神疾病治療策略的發展。

我們的研究長期目標為暸解大腦基底核神經迴路中，各個次級核區如何建構其功能。我們研究的基本信念是，如果我們能暸解大腦神經迴路正常建構其功能的分子基因藍圖(molecular genetic blue print)，我們將能運用此基因藍圖修復治療相關的神經疾病。在此前提下，我們聚焦專研基因轉錄因子如何調控大腦基底核神經迴路建構與功能的分子基礎。我們過去二十多年的研究主要突破發現包括大腦基因如何建構原始說話語言功能的神經迴路與心理動作控制神經迴路，基底核紋狀體如何分化建構截然不同神經功能的次級核區的分子機制。我們的持續深入研究提供大腦基底核神經迴路如何建構其功能的重要分子基因與神經元编碼訊息(genetic and neural codes)。

基底核實驗室重要突破研究發現
大腦基因如何建構原始說話語言功能的神經迴路

探討解開Foxp2語言基因在大腦神經元分子、神經迴路、行為控制的作用機制

https://web.ym.edu.tw/files/14-1133-28801,r1-1.php

語言溝通是人類社會互動的獨特基本能力。目前對於人類大腦神經系統如何建構控制語言說話能力仍然不甚清楚。反觀其他物種雖不具有複雜豐富說話語言能力，但仍有其它類似簡單能力，例如小鼠有超音波發聲能力，藉以達成溝通目的。

國立陽明大學神經科學研究所劉福清教授研究團隊以小鼠超音波發聲溝通能力為行為模式，研究大腦神經系統如何建構原始語言說話能力。劉福清教授研究團隊發現Foxp2語言基因能夠開啟Mef2c自閉症基因對於「大腦皮質—基底核神經迴路」突觸接點建立的抑制。這項研究除了深入瞭解基本原始說話語言神經迴路的建立外，亦對自閉症語言能力缺陷的病理基礎有所探討。這篇研究論文發表於國際知名頂尖期刊「自然神經科學」(Nature Neuroscience)。

Foxp2基因控制神經元突觸接點的建立

Foxp2基因在分子層次如何控制神經元突觸接點的建立? 研究團隊發現Foxp2基因抑制下游標的Mef2c基因，間接開啟神經迴路突觸接點的建立。Mef2c突變基因己知是個自閉症基因。正常的Mef2c基因會抑制大腦皮質訊息傳送至基底核神經元突觸接點的發育形成。比喻來說，Mef2c基因正常作用就如同一道安全鎖(Safety Lock)，在胚胎發育早期先行鎖住神經突觸接點形成，避免在發育早期尚無大腦皮質訊息輸入下，神經突觸接點不成熟提早建立，因而形成錯誤的神經迴路。那麼正常下何者是一支鑰匙(Key)可以打開這道安全鎖？研究團隊發現Foxp2基因正是可以打開(Unlock) Mef2c基因這道安全鎖的鑰匙。Foxp2基因可以直接解開Mef2c基因對於神經接點的抑制，進而開啟「大腦皮質—基底核神經迴路」正確的神經突觸接點發育形成。倘若Foxp2基因或Mef2c基因突變喪失其正常功能，Mef2c基因這道安全鎖將會壞掉，導致異常錯誤的神經突觸接點形成，因而建構出錯誤的神經迴路。Mef2c基因突變所導致錯誤的「大腦皮質—基底核神經迴路」有可能是自閉症說話語言功能缺失的病理機制。

Foxp2-Mef2c基因交互作用調控神經迴路功能的重要性

本篇論文第一作者郭曉縈博士說，研究團隊接下來探討的問題是，「大腦皮質—基底核神經迴路」的正常功能為何? 郭曉縈博士解釋研究團隊進一步的研究發現，Foxp2-Mef2c基因交互作用所控制的「大腦皮質—基底核神經迴路」突觸接點建立，對於調控初生小鼠超音波發聲溝通行為(Ultrasonic vocal communication) 扮演著關鍵重要角色。當Foxp2基因或Mef2c基因突變喪失功能，會導致「大腦皮質—基底核神經迴路」突觸接點無法正確建立，進而導致初生小鼠超音波發聲溝通行為異常。

基因分子－神經迴路－行為控制的整合性神經科學研究

劉福清教授實驗室這項與德國、日本、美國、中研院研究團隊合作的研究結果：Foxp2與Mef2c兩個基因的交互作用調控「大腦皮質－基底核神經迴路」的建立與初生小鼠超音波發聲溝通能力，在基礎科學與神經疾病研究有重要引申意義：

基礎科學研究方面

Foxp2已知是個與人類語言說話能力相關的基因，如果我們將小鼠超音波發聲溝通能力比喻為人類的原始說話語言功能，Foxp2-Mef2c基因交互作用所控制的「大腦皮質—基底核神經迴路」突觸接點形成，有可能是人類嬰兒出生後學習建立說話語言溝通能力的一個重要大腦神經元分子發育機制。

瞭解自閉症語言功能缺失的病理基礎方面

本篇論文研究除了瞭解語言神經元迴路建立與其相關疾病外，對自閉症的神經迴路與分子機轉的病理基礎亦可能有所助益。根據臨床醫學文獻報導MEF2C是個自閉症基因，因為帶有MEF2C基因突變缺失患者有智力遲緩與自閉徵症，包括說話語言功能的缺陷。文獻報導自閉症小孩患者的說話語言功能病理異常相當複雜— 從說話語言功能嚴重受損、語言能力發展遲緩、乃至高功能說話異常流利皆有。但是自閉症為何會影響到說話語言溝通能力？目前仍然不清楚。劉福清教授團隊的研究結果顯示自閉症基因病變，可能影響到大腦控制說話語言神經迴路的發育建置。後續研究可以提供線索，幫助我們瞭解說話語言相關神經疾病和自閉症的神經迴路與分子機轉的病理基礎，並進而發展治療疾病策略。

掌管動作習慣與動機情緒的腦神經如何形成？

習慣養成與行為成癮也和基因有關。陽明大學找到調控大腦基底核紋狀體神經元分化與遷移的關鍵基因，不僅解答掌管動作習慣與動機情緒的神經元是如何形成，也破解其建構神經迴路的基因分子機制。

位於大腦深部一群神經核組成的基底核，是掌管動作學習、獎勵、動機、情感以及自主運動的中樞，發揮這些神經功能的關鍵，仰賴於基底核中的紋狀體背側與腹側核區的神經迴路。背側核區調控動作與認知功能，是養成習慣行為的關鍵區域；腹側核區則參與獎賞與成癮機制，是影響動機情緒的關鍵區域。但紋狀體核區如何建構，並劃分成這兩個區域的神經迴路仍然未知。

16年前，陽明大學神經科學研究所教授劉福清，以及他的指導學生張瓈云(現中國醫藥大學副教授)，在哺乳類類動物的大腦中發現一種名為Nolz-1的基因，可能參與控制紋狀體發育的遺傳程序，但當時並不瞭解其背後的機轉。16年後，在經歷指導張瓈云、柯信安、盧冠名、陳仕昀四名博士之後，研究團隊終於發現經過有絲分裂後，Nolz-1藉由抑制Dlx1與Dlx2基因，促進神經元細胞分化並決定細胞遷移方向，從而建構成背側或腹側紋狀體，證實了Nolz-1與Dlx1與Dlx2基因的交互作用，調控不同種類神經元命運與分化過程。

研究團隊在動物模型中觀察到，Nolz-1在胚胎神經發育階段，透過抑制Dlx1與Dlx2基因所表達的功能蛋白，讓神經元可以順利分化並遷移成紋狀體的兩個區域，形成背側紋狀體與腹側紋狀體。一旦動物剔除Nolz-1基因後，Dlx1與Dlx2大量表現，會造成神經元細胞分化遷移錯誤，導致背側核區萎縮，腹側核區擴大，確立了Nolz-1是直接調控Dlx1與Dlx2的基因。這項研究解開大腦的基底核區域，如何劃分為不同的次級區域，從而建構出不同的次級神經迴路，讓大腦能執行精確與複雜的神經功能。

劉福清表示，無論是背側還是腹側紋狀體，神經發育皆源自同一區神經幹細胞分化而來，這項研究想解答的是為什麼來自同一區的神經細胞，最後會分化遷移到不同的區域，建構成不同的神經功能迴路。由於基底核除了控管不同的神經功能外，神經迴路的正常與否也與許多神經疾病的病理機制有關，例如巴金森氏症、亨廷頓舞蹈症、思覺失調症等，瞭解不同神經迴路的建構與功能，有助於發展治療神經與精神疾病的策略。

劉福清研究團隊長期致力於研究大腦基底核神經迴路的神經發育與功能，過去曾揭開原始說話語言能力的神經迴路，如今再發現劃分紋狀體核區的神經迴路建構機制。這項研究已刊登在《美國國家科學院院刊》。