动物造模,精神分裂症模型 z-bio 2021-05-07 1045

　　Jīngshén fēnliè zhèng shì jīngshénbìng xué zhōng de yī zhǒng chángjiàn qiě yánzhòng de jīngshén jíbìng, cánjí lǜ hěn gāo, shì zuì fánzhòng de jīngshén jíbìng zhī yī, zhōngshēng huàn bìng lǜ yuē wèi zhěnggè rénkǒu de 1%. Yuányīn shàngwèi míngquè. Zài dāngqián de dà duōshù yánjiū zhōng, jīngshén fēnliè zhèng bèi rènwéi shì yóu shēngwù xué, xīnlǐ hé shèhuì huánjìng yǐjí tāmen zhī jiān de xiānghù zuòyòng yǐnqǐ de nǎo sǔnshāng de jiéguǒ. Jīngshén fēnliè zhèng dòngwù móxíng de jiànlì lì bù kāi duì jīngshén fēnliè zhèng de bìngyīn hé shēngwù xué jīzhì de gèng hǎo lǐjiě, kàng jīngshénbìng yào zuòyòng jīzhì de tànsuǒ yǐjí xīn liáofǎ de jiàndìng hé pínggū. Yóuyú jīngshén fēnliè zhèng de dútè rénxìng, dòngwù móxíng wúfǎ mónǐ jīngshén fēnliè zhèng huànzhě de xīnlǐ hé xīnlǐ yīnsù. Kāifā hé wánchéng dòngwù móxíng de tiǎozhàn miànlín tiǎozhàn. Yīncǐ, běnwén zǒngjiéle zhè fāngmiàn de yánjiū jìnzhǎn. 1 Dòngwù móxíng jiànlì de xiànzhuàng jīngshén fēnliè zhèng de dòngwù móxíng kě dàzhì fēn wéi sān lèi: Yàolǐ xué yòudǎo de dòngwù móxíng, fāyù xìng dòngwù móxíng hé zhuǎnjīyīn dòngwù móxíng [Cil.Am.Chem.Soc.,,,,,,,,,,]. Yàolǐ yòudǎo de dòngwù móxíng shǐyòng yàowù lái yòudǎo jīngshén fēnliè zhèng děng zhèngzhuàng. Duōbā'àn jiǎshuō shì jīngshén fēnliè zhèng bìngyīn de zuìzǎo jiǎshuō, jīngshén fēnliè zhèng de zhèngzhuàng bèi rènwéi shì yóuyú dànǎo zhōng guòliàng de duōbā'àn yǐnqǐ de. Tōngguò xīngfèn jì (lìrú běnbǐng'àn) zài dòngwù zhòng yòufā yìchángxíngwéi shì gāi móxíng de diǎnxíng tèzhēng. Gǔ ān suān shīhéng jiǎshuō jìnnián lái shòudào guǎngfàn guānzhù, yīnwèi duōbā'àn dì zhì shīhéng jiǎshuō bu néng wánquán jiěshì jīngshén fēnliè zhèng de bìngyīn. Yánjiū biǎomíng, xiàng réntǐ zhùshè NMDA shòu tǐ jiékàng jì kěyǐnqǐ huànjué, wàngxiǎng, qíguài xíngwéi yǐjí qítā yǔ jīngshén fēnliè zhèng xiāngsì de xíngwéi. Lèisì de, jiāng cǐ lèi yàowù zhùshè dào nièchǐ dòngwù zhòng huì yǐnqǐ xíngwéi gǎibiàn, lìrú jīngshén yùndòng mén kòng zhàng'ài, huódòng guòdù, shèjiāo tuìsuō yǐjí jīngshén zhàng'ài, lìrú xuéxí hé jìyì gōngnéng zhàng'ài. Jù bàodào, tōngguò zhùshè yīxiē línchuáng kàng jīngshénbìng yào kěyǐ shǐ zhèxiē yìcháng xíngwéi huīfù zhèngcháng. Yīncǐ, lǜ'āntóng,PCP,MIA yǐ chéngwéi chǎnmíng jīngshén fēnliè zhèng de bìnglǐ shēnglǐxué hé yànzhèng xīnxíng kàng jīngshénbìng yàowù yǒuxiào xìng de yǒulì gōngjù, bìngqiě shì guónèi wài yánjiū zhōng zuì chángyòng de móxíng jiànlì fāngfǎ. -801, Qízhōng,MIA-801 kě tóngshí mónǐ jīngshén fēnliè zhèng de yángxìng hé yīnxìng zhèngzhuàng, yīncǐ jìnnián lái yǐ guǎngfàn yòng yú móxíng jiànlì yánjiū. Wǒ jiàng zài zhèlǐ xiángxì jièshào tā. Cǐwài, yánjiū biǎomíng shénjīng jiàng yā sù yǔ jīngshén fēnliè zhèng de bìnglǐ jīzhì yǒuguān, bìng cānyù kàng jīngshénbìng yào de zuòyòng jīzhì. Gāi móxíng mùqián shàng bù chéngshú, hěn shǎo yòng yú yánjiū zhōng. Tōngguò pòhuài xīnshēng ér dànǎo (yóuqí shì hǎimǎ de fǎ yù), tāi'ér bìngdú gǎnrǎn huò pòhuài dòngwù shénjīng yuán de zhèngcháng fāyù lái shíxiàn shénjīng fāyù móxíng. Dòngwù duì chéngrén jīngshén fēnliè zhèng jìnxíngle yīxiē xíngwéi yánjiū. , Zhèxiē yǔ jīngshén fēnliè zhèng de shénjīng fāyù jiǎshuō shì yīzhì de. Chǎn qián, wéi chǎn qí hé chǎnhòu bùliáng shìjiàn kěnéng huì duì dànǎo fāyù chǎnshēng yīdìng yǐngxiǎng, dāng dànǎo zài 20 zhì 3 niánnèi chéngshú shí, zhèngzhuàng huì zài 10 nián hòu chūxiàn. Cǐ lèi móxíng kěyòng yú shāixuǎn xīnyào. Yóuyú yǐ jiāng jīngshén fēnliè zhèng quèdìng wèi gāodù yíchuán xìng jíbìng, yīncǐ chuàngjiànle zhuǎnjīyīn dòngwù móxíng. Zhuǎnjīyīn jìshù de shǐyòng kěyǐ xuǎnzé xìng huò quánmiàn yìzhì jīngshén fēnliè zhèng xiāngguān de shénjīng dì zhì, cóng'ér jiànlì xiāngguān yánjiū de móxíng. Gāi móxíng mùqián zhèngzài yánjiū zhōng, jiāng wèi jiānglái de jīyīn zhìliáo diàndìng jīchǔ. Guānyú 2MIA-801 de gěi yào fāngfǎ, xuǎn dìng jìliàng hé shíyàn dòngwù de xuǎnzé de xiàn yǒu yánjiū bìng bù tǒngyī. Zài guónèi yánjiū zhōng, dà jìliàng (0.Smg/kg) dān cì zhùshè [[A] huò xiǎo jìliàng (0.5Mg/kg) de C9,io7, zhǔyào zài wéi chǎn qí huò chéngnián Sprague} awley dà shǔ zhōng shǐyòng. Tā yěshì dān jì huò duō jì bùtóng pǐnxì de xiǎo shǔ [D'Yichuan yòng yú xiāngguān yánjiū. Guówài yánjiū zhǔyào shǐyòng SD dà shǔ huò Wistar dà shǔ. Yīxiē zuòzhě xuǎnzé jiànlì móxíng bìng zài chéngnián hòu jìnxíng xiāngguān yánjiū, huòzhě zài chūshēng hòu bùjiǔ (3-7 tiān) fúyòng gāi yàowù, yǒuxiē yánjiū zé yǐ gāo jìliàng (0.5-1 Mg) jìnxíng xuǎnzé./Kg) xuǎnzé dī jìliàng ((0.OS0.40 Mg/kg) měi rì huò měi rì jìliàng, huò 2 zhōu huò gèng cháng shíjiān de chóngfù jìliàng. Yīxiē yánjiū yǐ shǐyòng xiǎo shǔ jiànlì móxíng. Yǒu liǎng zhǒng fāngfǎ, dān jìliàng hé dān jìliàng. Chóngfù jìliàng mùqián shàng wúguānyú dòngwù zhǒnglèi, jìliàng hé gěi yào shíjiān de tǒngyī biāozhǔn, yīncǐ, yánjiū jiélùn yǒu suǒ bùtóng, zhè yī fāngmiàn shàngwèi chǎnmíng 3 shèhuì xíngwéi pínggū móshì qián chōngdòng yìzhì (PPI) xīnlǐ yùndòng mén kòng shì xìnxī chǔlǐ de zhòngyào lǐngyù, bāokuò duì chuán rù de gǎnjué xìnxī jìnxíngshìdàng guòlǜ, bìng zài zǔzhǐ wú guān huò fēi bìyào xìnxī fāngmiàn biǎoxiàn túchū. Gǎnjué yùndòng mén kòng de kě cāozuò xìng dùliàng, shì zhǐ zài rén hé nièchǐ dòngwù zhòng guānchá dào bìng cèliáng dào de, yóu túrán qiángliè de wàibù gǎnjué cìjī yǐnqǐ de fǎnshè fǎnyìng; yù màichōng yìzhì xiànxiàng bāokuò móhú; yù cìjī; zài màichōng qián 30/50 háomiǎo yǐnqǐ jīngxià, zhè kěnéng huì yǐnqǐ jīngxià, wúlùn tāmen shìfǒu shǔyú xiāngtóng de gǎnjué xíng shì, zhè shì zhǐ wúfǎ zhíxíng de yù màichōng de fǎ shēng, tū tiào fǎnshè qiángdù jiàngdī, yù màichōng yìzhì nénglì jiǎnruò, biǎoshì gǎnjué yùndòng mén kòng shòu sǔn, yóuqí shì huóyuè de xīnlǐ zhèngzhuàng, yánjiū biǎomíng shǐyòng kàng jīngshénbìng yào kěyǐ shǐ zhèxiē quēxiàn zhèngcháng huà, fēidiǎn xíng kàng jīngshénbìng yào de zuòyòng gèng wéi zhòngyào dào mùqián wéizhǐ, dòngwù chūshēng hòu bùjiǔ jiù chūxiànle MIA, yòng-801 jìnxíng zhìliáo shìfǒu duì PPI chǎnshēng chángqí yǐngxiǎng shàng cún zhēngyì. Xiānqián de yánjiū biǎomíng, chūshēng hòu 3 tiān xiàng dà shǔ dān cì zhùshè MIA-801 shì yī zhǒng jīběn de yù màichōng, duì yìzhì zuòyòng yǒuxiào, dàn zài nián zhǎng de dà shǔ zhōng, qí yù màichōng qiángdù de zuòyòng fànwéi kěyǐ jiǎn xiǎo. Zài Coleman JrLG hé qítā yánjiū zhōng yě bàodàole gǎibiàn de qián chōng yìzhì, yǔ cǐ xiāng yīzhì de shì,HarrisL děng rén Czal xiǎnshì, zài chéngnián xióngxìng dà shǔ zài dì 7 tiān fúyào hòu, qí qián chōng yìzhì méiyǒu biànhuà, dàn zài tóngyī yánjiū zhōng, chéngnián cíxìng dà shǔ shǐyòng MIA-801 zhìliáo hòu,ZhaoYY děng rén zài 2013 nián yě bàogàole lèisì de fǎ xiàn; xiāngfǎn, lìng yī xiàng yánjiū shǐyòng cíxìng dà shǔ hé MIA-801 0.25 Mg/tiān. Chūshēng hòu 5 zhì 14 tiān, měitiān yǐ kg niánlíng zhùshè liǎng cì. Zài 2-9 zhōu nèi wèi fāxiàn yù màichōng yìzhì sǔnshāng} z}}. Yīncǐ, hěn nán quèdìng xìngbié shìfǒu duì shíyàn qǐ juédìngxìng zuòyòng. Qítā jǐ xiàng yánjiū yě bàogàole jījí de jiéguǒ. 7 Zhì 10 tiān de MIA-801 biǎoxiàn chūqián màichōng yìzhì de jìliàng hé niánlíng yīlài xìng. Yánjiū dà shǔ (lìrú LiM) liánxù 6 tiān jiēshòu NMDA shòu tǐ. Jiékàng jì hòu PPI sǔnshāng de chíxù shíjiān yǐ héngdìng jì liáng zǔhé héngdìng jì liáng zǔ zhújiàn zēngjiā de fāngshì gěi chū. Yánjiū biǎomíng, zhè liǎng zhǒng gěi yào fāngfǎ kěyǐ duì PPI zàochéng wěndìng hé yǒngjiǔ de sǔnhài, dàn hòu yī zhǒng fāngfǎ xiàoguǒ hěn hǎo. Kǎolǜ dào jìnxíng kěkào de qián màichōng yìzhì gǎibiàn de wèntí, zuìxīn de yánjiū jiāng MIA-801 yǔ gūlì qiújìn zhōng de xīnshēng ér zhìliáo xiāng jiéhé, yǐ mónǐ jīngshén fēnliè zhèng de liǎng cì qīng jí jiǎshè. Tōngguò sān gè yù màichōng yìzhì cèshì, fāxiàn zhǐyǒu MIA-801 chǔlǐ xīnshēng dà shǔ bùnéng chǎnshēng yù màichōng yìzhì quēxiàn, zhǐyǒu gélí hé sìyǎng huì chǎnshēng qīngwéi qiě bùyīzhì de yù màichōng yìzhì quēxiàn. Dànshì, liǎng gè móxíng de zǔhé yǔ zhè sān gè cèshì de jiéguǒ yīzhì, bìngqiě dǎozhìle yù màichōng yìzhì de jùdà biànhuà, yīncǐ, liǎng zhǒng fāngfǎ de zǔ hé kěnéng huì dǎozhì gèng kěkào de yù màichōng yìzhì biànhuà. Jìnnián lái, xǔduō xuézhě yīzhí zài duì yóu MIA-801 yǐnqǐ de gǎnjué mén kòng shītiáo de jīzhì jìnxíng xiāngguān yánjiū. BxaszczykJW děng. Xiāngxìn jīngguò bu tóng jìliàng de MIA-801 zhìliáo hòu, xiǎo shǔ zài tīngjué jīngxià fǎnshè zhòng jùyǒu bùtóng shuǐpíng de PPI, kěyòng lái jiěshì jīngxià fǎnshè de gǔ ān suān jīzhì. Zuìjìn de yánjiū, lìrú Valsamis B, jìnyībù zhīchíle zhè zhǒng guāndiǎn, jí zhōngyāng qián'é yè pícéng zhōnggǔ ān suān de guòdù huóhuà shì yóu quánshēn zhùshè MIA-801 yǐnqǐ de gǎnjué mén kòng zhàng'ài de zhǔyào jīzhì. Zhūlìyà·zàn gé lán (Julia Zangrand) děng. Yǒurén zhǐchū,PPI zài nièchǐ dòngwù zhòng de biǎodá shì yóu xià qiū de gǔ ān suān jiè dǎo de. FijaxK děng. [X330 yǐ fāxiàn 5-HT shòu tǐ yěshì gǎishàn PPI de kàng jīngshénbìng yàowù jīzhì zuòyòng de yībùfèn. 3.2 Zìfā huódòng MIA-801 duì xīnshēng dà shǔ de zhìliáo yǐnqǐ chángqí de xíngwéi gǎibiàn, zhè shì zìfā huódòng zuì pǔbiàn de tèzhēng. Jīngshén fēnliè zhèng de huódòng zēngjiā bèi rènwéi yǔ yángxìng zhèngzhuàng yǒuguān, kěnéng dàibiǎo zhōng nǎo biānyuán duōbā'àn xìtǒng huódòng zēngjiā. Dà duōshù yánjiū biǎomíng,MIA-801 kěyǐ yǐnqǐ dà shǔ zìfā xìng xíngwéi de zēngjiā. ParkSJ děng. Fāxiàn zài jíxìng jǐyǔ MIA-801 hòu xiǎo shǔ de zìfā xíngwéi zēngjiā. MissaultS hé qítā rén zài Wiltrat de gōngzuò zhōng yě xiǎnshì chū lèisì de fǎ xiàn. Zài wǒ de yánjiū xiǎozǔ zhōng, yǐ 0.3 Mg/kg de jìliàng shīyòng MIA-801 hòu, dà shǔ de zìfā huódòng dī yú duìzhào zǔ, bìngqiě MIA-801 duì zìfā huódòng de yǐngxiǎng kěnéng yǔ jìliàng yǒuguān. . XiuY děng. Fāxiàn zài yòng MIA-801 jìnxíng chángqí zhìliáo hòu, xiǎo shǔ zài yěwài shíyàn zhōng biǎoxiàn chū zìfā xíngwéi zēngjiā, zài kǒng bǎn shi yàn zhōng duì xīn huánjìng de tànsuǒ jiǎnshǎo, zài mígōng shíyàn zhōng de jiāolǜ zēngjiā. LatyshevaV děng. Dà shǔ zài zhìliáo jiēduàn (zhùshè hòu 23 xiǎoshí) xiǎnshì chū zìyuàn de huódòng jiǎnshǎo, dàn zhè zhǒng biànhuà zài 6 tiān huò 4 gè yuè dà shí bù míngxiǎn, yīncǐ bùnéng chángqí cúnzài. Zài xiǎo shǔ zhōng, fāxiàn suīrán jiēchù xíngwéi zēngjiā, dàn zìfāyùndòng wúfǎ wéichí chángqí biànhuà. Zài xìngbié yánjiū zhōng,GuoC děng rén. [09] Fāxiàn cíxìng lǎoshǔ zài fúyào hòu kěnéng huì chūxiàn zìfā xìng xíngwéi, dàn yóuyú gāi yánjiū jǐn shǐyòng cíxìng shòu shì zhě, yīncǐ wúfǎ dé chūqítā xìngbié de jiélùn. SchiffelholzT děng. [Zài chūshēng hòu dì 21 tiān lěng zhùshè 0.25 Mg/kg MIA-801, dà shǔ zài chéngnián ((60d) shí biǎoxiàn chū jiào dī de zìfā huódòng, dàn zài dì 30 tiān biǎoxiàn chū zēngjiā de huódòng. Jù cǐ tuīcè. Értóng zhōng de gāo huódòng kěnéng biǎomíng yǒu zhèngzhuàng. Xiāngfǎn, chéngnián hòu huódòng jiǎnshǎo fǎnyìngle jīngshén yùndòng zǔ zhì, shì yī zhǒng fāzuò hòu de zhuàngkuàng,BaierPC děng rén shǐyòng xiāngtóng de zhìliáo fāngfǎ yě bàogàole fēicháng xiāngsì de fǎ xiàn,MIA-801 zhìliáole dà shǔ de zìfā huódòng bìng zài shēng gāo de zhuàngtài xià jìnxíngle zhìliáo. Chuānyuè mígōng de jùlí hé shàngshēng shíjiān de cèliáng jiéguǒ xiǎnshì, zài 60 tiān hé 90 tiānhòu, qí háng jùlí hé shàngshēng shíjiān xiǎnzhe jiǎnshǎo, zài yěwài hé shēng gāo de mígōng zhōng cèliáng dào de zìfā huódòng yóuyú shèjì hé shèbèi yòngtú de bùtóng yìyì, kěnéng huì dà bù xiāngtóng, yīncǐ, jiéguǒ kěnéng wúfǎ zhǔnquè fǎnyìng zìyuàn huódòng, zài biāozhǔn shèbèi (huódòng shì huò kuàngyě) zhōng guānchá dào,MIA-801 dà shǔ de zìfā huódòng jiào dī, qí jiāolǜ zhǐshù hěn kěnéng shì yóu lǎoshǔ yǐnqǐ de fǎnyìng kěnéng fǎnyìng chū gāo shuǐpíng de jiāolǜ hé chōngdòng 3.3 Rèn zhī gōngnéng 3.3.1 Xīn wùtǐ shìbié xīn wùtǐ shìbié cèshì tōngcháng yòng yú pínggū nièchǐ dòngwù de rèn zhī jìyì jīyú xiāngduì shúxī de shìwù, dòngwù jùyǒu dútè de qū yú mòshēng de qīngxiàng yě jiùshì shuō, yǔ yǐwǎng xiāng bǐ, dòngwù jiàng zài xīn shìwù shàng huāfèi gèng duō de shíjiān, xǔduō yánjiū dōu duì MIA-801 jìnxíngle jíxìng zhìliáo, fāxiàn dòngwù huì yǐnqǐ xīn de wùtǐ shìbié zhàng'ài, ér kàng jīngshénbìng yàowù kěnéng huì jiǎnqīng zhè zhǒng sǔnhài. Jíxìng lǜ dàn píng zhùshè yè kě míngxiǎn gǎishàn zhè zhǒng jíbìng, dàn tōngguò jíxìng lǜ dàn píng zhùshè kě míngxiǎn gǎishàn zhè zhǒng jíbìng, dàn duì er tóng zǎoqí shīyòng MIA-801 de cháng qī xiàoguǒ sìhū bù quèdìng, zài 7 zhì 10 tiān zhī nèi wèi 0.1 Mg zài chéngnián dà shǔ cèshì qíjiān, měi gōngjīn MIA-801,StefaniMR hé qítā Caal de gěi yào liàng wèi fāxiàn duì xīn wùtǐ shìbié de rènhé sǔnhài; MK-801 huò sì bèi de zhùshè shíjiān,BaierPC děng rén pī fà xiàn shòu sǔn. Shēnghuó zhōng rènhé jiēduàn de rèn zhī jìyì LimALetal.[2 9] Méiyǒu fāxiàn yóu MIA yǐnqǐ de xīn de duìxiàng shìbié quēxiàn. Jǐnguǎn pínggū chéngnián dà shǔ de yánjiū bùzú, dàn qìjīn wéizhǐ de fǎ xiàn biǎomíng,MIA-801 yòudǎo de NMDA shòu tǐ jiékàng zuòyòng zài cǎijí hòu 1.5 Xiǎoshí hé 2 xiǎoshí nèi chūxiàn, huòzhě biǎomíng zài Sh zǎoqí de shēngmìng zǎoqí chóngfù shǐyòng. Bǎoliú jiēduàn bù huì duì xīn shìwù de gǎnzhī hé jìyì chǎnshēng chángqí bùlì yǐngxiǎng, dànshì kōngjiān bùzú de jiéguǒ shàng bùkě xíng. 3.3.2 Kōngjiān jìyì kōngjiān jìyì zài yǐ zhìliáo dà shǔ de rèn zhī yánjiū zhōng zuì jù yǐngxiǎng lì shuǐ mígōng fànshì tōngcháng yòng yú yánjiū dà shǔ/xiǎo shǔ de kōngjiān jìyì. Tōngcháng, cǐ cèshì huì fàngzhì dòngwù. Shūrù bùtòumíng shuǐ de yuán xíng shuǐchí, ràng nín jièzhù mígōng wài de xiànsuǒ zhǎodào bìng pá shàng yǐncáng de píngtái, cóng'ér xiāo chú liǎo bùduàn zài shuǐ xià de wèntí. Tōngguò diédài cèshì, kōngjiān xuéxí yǒu zhù yú jiǎnshǎo táoshēng děngdài shíjiān. Bǎoliú kōngjiān jìyì, jíshǐ píngtái cóng shuǐchí zhōng yíchū, dòngwù yě kěyǐ yánchángqí zài píngtái qūyù de háng xíng shíjiān. Zài értóng zǎoqí duì MIA-801 jìnxíng zhìliáo huì dǎozhì shuǐ mígōng dì xìngnéng xiàjiàng. Zhè zhǔyào chūxiàn zài chéngshú zhīhòu. McLambRL děng. Wèi chéngshú cíxìng dà shǔ de shuǐ mígōng xíngwéi méiyǒu biànhuà, dànshì SuYA děng rén. Fāxiàn cíxìng dà shǔ yǒu qīngwéi de gōngnéng zhàng'ài. Gēnjù wǒ de tuánduì de yī xiàng yánjiū, gěi 6 rì líng de yòu quǎn měitiān liǎng cì fùmó nèi zhùshè 0.3 Mg/kg de MIA-801, liánxù 2 zhōu. Gěi yào jiéshù hòu yīzhōu jìnxíng xiǎo shǔ shuǐ mígōng cèshì. Fāxiàn le MIA-801 zǔ, dà shǔ de xuéxí nénglì xiàjiàng, xuéxí sùdù jiǎn màn, chángqí jìyì shòu sǔn, dàn réng jùyǒu xuéxí nénglì. Li Jitao děng rén fà xiàn, fùqiāng nèi zhùshè MIA-801 kěnéng huì pòhuài dà shǔ cānkǎo jìyì, kōngjiān gōngzuò jìyì hé huígù xìng xuéxí, zài duō gè rèn zhī wéidù shàng mónǐ jīngshén fēnliè zhèng huànzhě de rèn zhī zhàng'ài, zhè biǎomíng nín kěyǐ zuò dào. Wángyīnglì děng rén liánxù zhùshè MIA-801 hòu, dà shǔ de xíngwéi hé xuéxí biǎoxiàn chū yǔ rénlèi jīngshén fēnliè zhèng lèisì de jìyì zhàng'ài, zhè shì yóuyú xuéxí hé jìyì quēxiàn bìngfēi bùkě nìzhuǎn, liǎng zhě zhī jiān de guānxì jìnyībù jiāshēnle yánjiū. Gēnjù guónèi hé guójì yánjiū xīnwén de bàodào, yòng MIA-801 zhìliáo de dà shǔ yǐnqǐle jíxìng jīngshénbìng fāzuò, dàn yánzhòng pòhuàile tú chù kěsùxìng, bìng yǒngjiǔ pòhuàile kōngjiān jìyì de xíngchéng. SuYA hé qítā yánjiū fāxiàn, zài chūshēng chū qí yòng MIA-801 zhìliáo de dà shǔ zài qīngchūnqí yǒu zhòng dù gōngzuò jìyì zhàng'ài, dàn zhè zhǒng zhàng'ài zài chéngnián hòu yìcháng xiǎnzhe. Dànshì, zài zhè liǎng gè jiēduàn zhōng yùndòng nénglì hé PPI jūn wèi shòudào sǔnhài. Xiǎo shǔ yánjiū yě bàogàole kōngjiān gōngzuò jìyì de xiǎnzhe bùzú. Kōngjiān jìyì zài xuéxí jiēduàn méiyǒu tài dà biànhuà, dànshì jiāng píngtái yídòng dào mígōng de qítā xiàngxiàn zé xiǎnshì chū míngxiǎn de quēxiàn. Lèisì de, kě yǐ zài dà shǔ zhōng guānchá dào guāngxué mígōng de xuéxí quēxiàn, qí zuòyòng shì jìliàng yīlài xìng de. Yǔ duìzhào zǔ xiāng bǐ, yǐ 0.2 Mg/kg chǔlǐ de dà shǔ de xuéxí shíjiān jīhū shì duìzhào zǔ de liǎng bèi, ér yǐ 0.4 Mg/k chǔlǐ de dà shǔ zài zhǐdìng de shíjiān jiàngé nèi dádào xuéxí biāozhǔn, gēnběn wúfǎ dádào biāozhǔn jìng hánliàng. Lìng yī xiàng yǐnshí jiǎngshǎng mígōng yán jiù bàogào shuō, yǔ duìzhào zǔ xiāng bǐ, zhìliáo zǔ de kōngjiān xuéxí nénglì yǒu suǒ yánchí, bìngqiě zài chíxù xùnliàn guòchéng zhōng zhújiàn fāzhǎn, dàn MIA. Yōu yú-801 zhìliáo zǔ de duìzhào zǔ

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　　Schizophrenia is a common and serious mental illness in psychiatry, with a high disability rate. It is one of the most severe mental illnesses. The lifetime prevalence is about 1% of the entire population. The reason is not clear. In most current studies, schizophrenia is considered to be the result of brain damage caused by the biological, psychological, and social environment and the interaction between them. The establishment of animal models of schizophrenia is inseparable from a better understanding of the etiology and biological mechanisms of schizophrenia, the exploration of the mechanism of action of antipsychotics, and the identification and evaluation of new therapies. Due to the unique human nature of schizophrenia, animal models cannot simulate the psychological and psychological factors of patients with schizophrenia. The challenge of developing and completing animal models faces challenges. Therefore, this article summarizes the research progress in this area.

　　1 Current status of animal model establishment

　　Animal models of schizophrenia can be roughly divided into three categories: pharmacologically induced animal models, developmental animal models and transgenic animal models [Cil.Am.Chem.Soc. ,,,,,,,,,,]. Pharmacologically induced animal models use drugs to induce symptoms such as schizophrenia. The dopamine hypothesis is the earliest hypothesis of the etiology of schizophrenia. The symptoms of schizophrenia are thought to be caused by excessive dopamine in the brain. The induction of abnormal behaviors in animals by stimulants (such as amphetamine) is a typical feature of this model. The glutamate imbalance hypothesis has received widespread attention in recent years, because the dopamine transmitter imbalance hypothesis cannot fully explain the cause of schizophrenia. Studies have shown that injection of NMDA receptor antagonists into the human body can cause hallucinations, delusions, strange behaviors and other behaviors similar to schizophrenia. Similarly, injection of such drugs into rodents can cause behavioral changes such as psychomotor gating disorders, hyperactivity, social withdrawal, and mental disorders such as learning and memory dysfunction. According to reports, these abnormal behaviors can be restored to normal by injecting some clinical antipsychotics. Therefore, ketamine, PCP, and MIA have become powerful tools to clarify the pathophysiology of schizophrenia and verify the effectiveness of new antipsychotic drugs, and are the most commonly used model building methods in domestic and foreign research. -801. Among them, MIA-801 can simulate the positive and negative symptoms of schizophrenia at the same time, so it has been widely used in model establishment research in recent years. I will introduce it in detail here. In addition, studies have shown that neurotensin is related to the pathological mechanism of schizophrenia and participates in the mechanism of action of antipsychotics. This model is not yet mature and is rarely used in research. The neural development model is achieved by destroying the neonatal brain (especially the development of the hippocampus), fetal virus infection or destroying the normal development of animal neurons. Animals have conducted some behavioral studies on adult schizophrenia. These are consistent with the neurodevelopmental hypothesis of schizophrenia. Prenatal, perinatal and postpartum adverse events may have a certain impact on brain development. When the brain matures within 20 to 3 years, symptoms will appear after 10 years. Such models can be used to screen new drugs. Since schizophrenia has been identified as a highly hereditary disease, a genetically modified animal model has been created. The use of transgenic technology can selectively or comprehensively inhibit neurotransmitters related to schizophrenia, thereby establishing a model for related research. This model is currently under study and will lay the foundation for future gene therapy. Regarding the administration method of 2MIA-801, the existing research on the selected dose and the selection of experimental animals is not uniform. In domestic studies, a single injection of high-dose (0.Smg/kg) [[A] or low-dose (0.5mg/kg) of C9,io7 is mainly used in perinatal or adult Sprague} awley rats. It is also a single dose or multiple doses of different strains of mice [D'Yichuan is used in related research. Foreign research mainly uses SD rats or Wistar rats. Some authors choose to establish a model and conduct related studies in adulthood, or take the drug shortly after birth (3-7 days), and some studies choose to use high doses (0.5-1 mg). /kg) Choose a low dose ((0.OS0.40 mg/kg) daily or daily dose, or repeated doses for 2 weeks or longer. Some studies have used mice to establish models. There are two methods, single Dose and single dose. There is no uniform standard for animal species, dose and time of administration for repeated doses. Therefore, the research conclusions are different. This aspect has not been clarified.

　　3 Social Behavior Evaluation Model

　　Pre-impulse inhibition (PPI) psychomotor gating is an important area of information processing, including proper filtering of incoming sensory information and outstanding performance in preventing irrelevant or unnecessary information. The operability measure of sensorimotor gating refers to the reflex response caused by sudden and strong external sensory stimulation observed and measured in humans and rodents; pre-pulse suppression phenomena include blur; pre-stimulation; before pulse 30/50 milliseconds cause startle, which may cause startle, regardless of whether they belong to the same sensory form. This refers to the occurrence of pre-pulses that cannot be executed, the intensity of kick reflexes is reduced, and the ability of pre-pulse suppression is weakened, indicating sensorimotor gating Damage, especially active psychological symptoms, research shows that the use of antipsychotics can normalize these defects, and the effect of atypical antipsychotics is more important

　　So far, MIA has appeared soon after animals are born. Whether treatment with -801 has a long-term effect on PPI is still controversial. Previous studies have shown that a single injection of MIA-801 into rats 3 days after birth is a basic pre-pulse, which is effective for inhibition, but in older rats, the range of pre-pulse intensity can be reduced . Coleman JrLG and other studies have also reported altered antejection inhibition. Consistent with this, HarrisL et al. Czal showed that after taking the drug on day 7 in adult male rats, there was no change in the antejection inhibition, but In the same study, after adult female rats were treated with MIA-801, ZhaoYY et al. also reported similar findings in 2013; on the contrary, another study used female rats and MIA-801 0.25 mg/day. From 5 to 14 days after birth, they are injected twice a day at the age of kg. No pre-pulse suppression damage was found in 2-9 weeks} z}}. Therefore, it is difficult to determine whether gender played a decisive role in the experiment. Several other studies also reported positive results. 7 to 10 days of MIA-801 showed a dose- and age-dependent prepulse inhibition. Study rats (eg LiM) receive NMDA receptors for 6 consecutive days. The duration of PPI injury after the antagonist is given in the constant dose group and the constant dose group gradually increasing. Studies have shown that these two methods of administration can cause stable and permanent damage to PPI, but the latter method is effective.

　　Considering the problem of making reliable prepulse suppression changes, the latest research combines MIA-801 with neonatal treatment in isolated captivity to simulate the two-tap hypothesis of schizophrenia. Through three prepulse suppression tests, it was found that only MIA-801 treatment of neonatal rats could not produce prepulse suppression defects, and only isolation and rearing would produce slight and inconsistent prepulse suppression defects. However, the combination of the two models is consistent with the results of these three tests and has caused a huge change in prepulse suppression. Therefore, the combination of the two methods may lead to more reliable prepulse suppression changes. In recent years, many scholars have been conducting related research on the mechanism of sensory gating disorder caused by MIA-801. BxaszczykJW etc. It is believed that after different doses of MIA-801 treatment, mice have different levels of PPI in the auditory startle reflex, which can be used to explain the glutamate mechanism of the startle reflex. Recent studies, such as Valsamis B, further support the idea that the overactivation of glutamate in the central prefrontal cortex is the main mechanism of sensory gating disorder caused by systemic injection of MIA-801. Julia Zangrand (Julia Zangrand) and so on. It has been pointed out that the expression of PPI in rodents is mediated by glutamate in the lower colliculus. FijaxK etc. [X330 has found that 5-HT receptors are also part of the mechanism of antipsychotic drugs that improve PPI. 3.2 Spontaneous activity MIA-801 treatment of newborn rats caused long-term behavioral changes, which is the most common feature of spontaneous activity. Increased activity in schizophrenia is considered to be related to positive symptoms, which may represent increased activity of the midbrain limbic dopamine system. Most studies have shown that MIA-801 can cause an increase in spontaneous behavior in rats. ParkSJ et al. It was found that the spontaneous behavior of mice increased after acute administration of MIA-801.

　　MissaultS and others showed similar findings in Wiltrat's work. In my research group, after administering MIA-801 at a dose of 0.3 mg/kg, the spontaneous activity of rats was lower than that of the control group, and the effect of MIA-801 on spontaneous activity may be related to the dose. . XiuY et al. It was found that after long-term treatment with MIA-801, mice showed increased spontaneous behavior in field experiments, decreased exploration of new environments in orifice experiments, and increased anxiety in maze experiments. LatyshevaV et al. The rats showed a reduction in voluntary activity during the treatment phase (23 hours after injection), but this change was not obvious at 6 days or 4 months of age, so it could not exist for a long time. In mice,

　　found that despite the increase in contact behavior, spontaneous exercise cannot maintain long-term changes. In gender research, GuoC et al. [09] It was found that female rats may have spontaneous sexual behavior after taking the drug, but because the study only used female subjects, it was impossible to draw conclusions about other sexes.

　　SchiffelholzT et al. [Cold injection of 0.25 mg/kg MIA-801 on the 21st day after birth, the rats showed low spontaneous activity in adulthood ((60d), but showed increased activity on the 30th day. It is speculated that children. Moderately high activity may indicate symptoms. On the contrary, decreased activity in adulthood reflects psychomotor block, which is a post-onset condition. BaierPC et al. also reported very similar findings using the same treatment method, MIA-801 treatment The spontaneous activities of the rats were treated and the rats were treated in an elevated state. The measurement results of the distance through the maze and the ascent time showed that after 60 days and 90 days, the riding distance and ascent time were significantly reduced. The spontaneous activities measured in the high maze may be very different due to the different meanings of the design and equipment usage. Therefore, the results may not accurately reflect voluntary activities. Observed in standard equipment (activity room or wilderness), MIA-801 The spontaneous activity of rats is low, and its anxiety index is likely to be caused by the reaction caused by rats, which may reflect high levels of anxiety and impulse. 3.3 Cognitive function 3.3.1 New object recognition New object recognition test is usually used to assess the recognition of rodents. Knowing and memory are based on relatively familiar things. Animals have a unique tendency to become unfamiliar. That is to say, compared with the past, animals will spend more time on new things. Many studies have conducted acute treatment on MIA-801. It has been found that animals can cause new object recognition disorders, and antipsychotic drugs may reduce this damage. Acute clozapine injection can significantly improve this disease, but acute clozapine injection can significantly improve this disease, but it is not The long-term effects of MIA-801 in early childhood seem to be uncertain, 0.1 mg within 7 to 10 days. During the test in adult rats, no new object recognition was found per kilogram of MIA-801, StefaniMR and other Caal doses. Any damage to MK-801 or four times the injection time, BaierPC et al. were found to be impaired. Cognitive memory LimALetal at any stage of life. [29] No new object recognition defects caused by MIA were found. Despite evaluation Research on adult rats is insufficient, but the findings so far indicate that MIA-801-induced NMDA receptor antagonism appears within 1.5 hours and 2 hours after collection, or indicates repeated use in the early stages of Sh in life. The retention phase will not It has long-term adverse effects on the perception and memory of new things, but the results of insufficient space are not yet feasible. 3.3.2 Spatial memory Spatial memory is the most influential in the cognitive research of treated rats. The water maze paradigm is usually used for research. Spatial memory of mice/mice. Normally, this test will place animals. Enter a circular pool of opaque water, allowing you to find and climb the hidden platform with clues outside the maze, thus eliminating the problem of constantly being underwater. Passed Iterative testing and spatial learning can help reduce the waiting time for escape.

　　Spatial memory, even if the platform is removed from the pool, the animal can extend its navigation time in the platform area. Treatment of MIA-801 in early childhood can cause the performance of the water maze to decrease. This mainly occurs after maturity. McLambRL et al. The water maze behavior of immature female rats did not change, but SuYA et al. It was found that the female rats had slight dysfunction. According to a study by my team, 6-day-old puppies were injected intraperitoneally with 0.3 mg/kg of MIA-801 twice a day for 2 weeks. A mouse water maze test was performed one week after the end of the administration. It was found that in the MIA-801 group, the rats' learning ability decreased, the learning speed slowed down, and the long-term memory was impaired, but they still had the learning ability. Li Jitao et al. found that intraperitoneal injection of MIA-801 may destroy reference memory, spatial working memory and retrospective learning in rats, and simulate the cognitive impairment of patients with schizophrenia in multiple cognitive dimensions, which shows that you can do To. After continuous injection of MIA-801 by Wang Yingli and others, the behavior and learning of rats showed memory impairment similar to that of human schizophrenia. This is because learning and memory deficits are not irreversible, and the relationship between the two has been further studied. According to reports from domestic and international research news, rats treated with MIA-801 caused acute psychotic episodes, but severely destroyed synaptic plasticity and permanently destroyed the formation of spatial memory. SuYA and other studies have found that rats treated with MIA-801 at the beginning of life have moderate working memory impairment in adolescence, but this impairment is abnormally significant in adulthood. However, athletic ability and PPI were not impaired in these two stages. Mouse studies have also reported significant deficiencies in spatial working memory. Spatial memory did not change much in the learning phase, but moving the platform to the other quadrants of the maze showed obvious defects. Similarly, the learning deficit of the optical maze can be observed in rats, and its effect is dose-dependent. Compared with the control group, the learning time of the rats treated with 0.2 mg/kg was almost twice that of the control group, while the rats treated with 0.4 mg/k reached the learning standard within the specified time interval, which was not up to the standard at all net weight. Another diet reward maze study reported that compared with the control group, the spatial learning ability of the treatment group was delayed and gradually developed during continuous training, but MIA. Better than the control group of -801 treatment group behaves like vanderStagyFJ, whether it is subcutaneously or intramuscularly, as long as the rodent dose of MIA-801 does not exceed 0.1 mg/kg, it is still considered to be very low. It can meet the criteria of the cognitive impairment model without causing gating damage or toxic effects.

　　4 Long-term effects of MIA-801 on brain morphology and neurochemistry

　　4.1 Brain morphology It has been reported that rats treated with MIA-801 have lost weight after birth. FacchinettF et al. measured brain weight immediately after MK-801 treatment (1-12 days after birth) and recorded a significant decrease in brain weight, and this effect can continue into adulthood. More detailed research shows that the effects on different brain regions are inconsistent. The most obvious areas for weight loss are the cerebellum and striatum, which have the least impact on the hippocampus. KawaheK et al. [[52] also reported that killing rats in adulthood would reduce brain weight, but they did not attempt to further understand the characteristics of the effects of MIA-801 on different brain regions. In addition, brain weight loss may be the result of a decrease in brain size and the number of neurons. In the study of the hippocampus, Hari et al. It was found that when the animal was two months old, especially when it was sacrificed in the lower corner of the brain, the hippocampus volume tended to decrease, and therefore the number of hippocampus decreased. Neurons in the CA1 area. Similarly, studies have shown that the prefrontal cortex V pyramidal neurons in the adult rat brain are reduced. 4.2 Neurochemical Nerve structure and functional imaging studies have shown that the prefrontal cortex is one of the main cortical causes of schizophrenia. When studying the relationship between cognitive impairment and cortical function in rats, BlotK et al. found that a single injection of 0.1 mg/kg MIA-801 may cause a gradual and long-term response in the hippocampal prefrontal cortex. This is the same as the long-term strengthening mechanism. After administration of MIA-801, rats developed cortical-independent cognitive flexibility deficits and hippocampal frontal lobe-related spatial memory deficits. These effects were gradually reduced within 24 hours. Jia Jiao and so on. It is found that blocking NMDA receptors in the neonatal stage can compensate the hippocampus NR1 and NR2A of adult rats, and reduce frontal lobe NGF in adolescence. Therefore, it is believed that the NMDA receptor is blocked. It causes the regulation of NGF in the neonatal period. Changes, long-term compensation for glutamate. A study by Tang Yamei et al., in a schizophrenia model caused by repeated treatment with MIA-801 during the perinatal period, reduced the mPFC area, hippocampal SHIT transmitter system and hippocampal NE transmitter system in rats. Nerve growth factor is an important neurotrophic factor, and research [54] shows that the change in its level may be related to the onset of schizophrenia. A study in my country confirmed that brain-derived neurotrophic factor has different expression patterns in the frontal lobe and hippocampus. The increase observed in the former during the postpartum period cannot be sustained into adulthood or adolescence, while the latter shows high levels of expression in adulthood and adolescence, but not before. Some studies believe that the adult changes in rats treated with MIA-801 early are mainly due to their effects on the main neurotransmitter system. HarrisL et al. Czal detailed that the NR1 subtype of the NMDA receptor is under-expressed in the dorsal thalamus and dorsal hippocampus, while over-expressed in the ventral and ventral CA3 regions. In addition, an increase in NR1 expression was also found in the cortex. Monoamine metabolism studies have shown that dopamine metabolism increases in the frontal lobe and striatum, while 5-phototryptamine and norepinephrine only increase in the frontal lobe and striatum, affecting neurotransmitters. .. Studies have shown that compared with the control group, the treatment group lost nearly half of the microalbumin-mediated neurons in the prefrontal cortex. Studies have also shown that MIA-801 has a protective effect on the brain. Yuan Fenggang et al. In a 2014 study, MIA-801 inhibited ASIA S-nitrosylation caused by global cerebral ischemia/reperfusion in SD rats, affected the apoptotic signal transduction pathway of ASIA and caused neuronal damage. I found that I can protect it. Zhou Hongxia and others have similar findings. Therefore, the mechanism of MK-801 needs to be further studied.

　　5 level of efficacy

　　Schizophrenia is a complex group of diseases, and it is difficult to reproduce all symptoms in animal models. Guidelines need to be established because they are almost impossible to achieve with current science and technology. Evaluate these models. Therefore, we investigated whether it is reasonable to use MIA-801 to establish an animal model of schizophrenia. First, it is a pathogenesis model mainly based on the NMDA receptor hypothesis, which is based on the conduction disorders of dopaminergic neurotransmitters in schizophrenia. Secondly, the changes in adulthood are caused by the interference of unfavorable factors in early childhood. This model is consistent with the neurodevelopmental model of schizophrenia. In addition, increased apoptosis is related to the pathogenesis of schizophrenia. This is because, despite the evidence, it can explain the subtle neuropathological changes observed in postmortem tissues, such as decreased nerve fibers and cell structure defects without the appearance of glial cells. Early animals treated with MIA-801 can mimic some of the symptoms of schizophrenia, but there is still evidence that there are differences between them, especially in terms of prepulse inhibition and spontaneous activity. insufficient. In addition, the reported changes are mainly limited to positive and cognitive impairment, and current findings related to negative symptoms are not sufficient to draw clear conclusions. Negative symptoms such as social dysfunction and social withdrawal are one of the early symptoms of the first mental illness before the onset, and one of the symptoms of poor response to treatment. Therefore, treatment should be adhered to after alleviating the symptoms of psychosis. Therefore, the establishment of animal models plays an important role in the discovery of therapeutic agents, and we believe that models that can cause behaviors related to adverse symptoms have greater value.

　　6 summary

　　The treatment of MIA-801 neonatal rats causes abnormal NMDA receptor function, accelerates the induction of diffuse apoptosis in the immature brain, and subsequently rearranges cell structure and synapses. These abnormalities may cause later psychotic symptoms. MIA-801 can establish a stable animal model of schizophrenia, which has positive symptoms and cognitive impairment, and has reasonable structural validity. Due to the poor reproducibility of some observations, whether their long-term effects on behavior are consistent has been controversial, especially in the behavioral research of schizophrenia models, the most extensive pre-pulse inhibition and spontaneous activity. In addition, the detection of behaviors related to adverse symptoms is insufficient, and further research is needed in this regard. In addition, due to differences in administration methods, dosages, and animal species, research results usually vary greatly. Therefore, the establishment of an animal model of schizophrenia under the management of MIA-801 is still one of the controversial topics. In order to ensure the consistency of the research results, the method of further establishing the model still needs to be unified. How to establish a negative symptom model of schizophrenia.