癫痫（epilepsy）是最常见的慢性神经系统疾病之一，在世界范围影响广泛，造成沉重的全球疾病负担。当前主流观点认为癫痫发作是大脑神经环路兴奋-抑制失衡所致，然而现有癫痫药物与手术治疗效果却有很大局限。因此，我们需要进一步探索癫痫发病的新机制，从而发展癫痫治疗的新策略。一种特殊类型的癫痫综合征——反射性癫痫（reflex epilepsy）可以为我们带来新的启发。反射性癫痫发作是指由特定的运动、感觉或认知刺激触发的癫痫发作。在临床病例中，尽管反射性癫痫患者的触发因素与发作类型因人而异，特定触发因素与癫痫发作事件之间稳定的相关性是他们共同、核心的特征，与经典条件反射在表型上表现出高度相似性。由此，我们猜测反射性癫痫的发病机制可能也与条件记忆很大程度相似，即也形成了特异性的关联，存在着伴随蛋白质合成的再巩固过程，并随后进入了不稳定的可破坏状态。因此，本文系统性引入条件记忆的研究范式来探索反射性癫痫的潜在机制与干预策略。

在本研究中，为了模拟反射性癫痫触发发作的表型，我们在动物行为学水平对特定信号与化学诱导发作（chemical-induced seizures, CIS）进行配对训练，观察到癫痫发作能够与特定信号相关联并被特异性诱导，且这一现象在信号种类与物种类别上具有一定普遍性，从而建立起有效的信号诱导发作动物模型。为了研究这一关联是否持续存在，我们在更长时程中反复给予关联信号进行测试，观察到关联信号可以重复地诱导癫痫发作，说明信号诱导发作模型是长期稳定的。为了进一步研究其中机制，我们在信号诱导发作后数小时内，通过Western Blot检测小鼠海马记忆相关蛋白表达情况，发现BDNF、pERK和pmTOR表达水平呈时间依赖性动态变化，在诱导发作后1-2小时达峰，说明这些关键分子很可能参与信号诱导发作的再巩固过程。最后，为了确证以上分子的关键作用和治疗潜力，我们通过药理学手段进行干预：在特定信号与CIS关联后5分钟使用茴香霉素全面阻断蛋白合成或使用雷帕霉素阻断mTOR信号通路均可破坏其巩固过程，显著减少测试阶段信号诱导的癫痫发作；在信号诱导发作后5分钟使用茴香霉素全面阻断蛋白合成、使用雷帕霉素阻断mTOR信号通路、使用普萘洛尔抑制ERK信号通路或使用外源反义寡核苷酸干扰BDNF表达（提前90分钟），均可破坏其再巩固过程，显著减少后续测试中再次诱导的癫痫发作；而在关联或诱导后9小时（即关键时间窗外）进行以上干预，则对后续信号诱导癫痫发作无显著影响。

总而言之，为了系统性研究反射性癫痫，我们建立了新的信号诱导发作动物模型，提供了新的机制解释与干预策略，为理解和治疗癫痫提供了新的视角。

Epilepsy, one of the most common chronic neurological diseases, affects widely around the world and is responsible for a great proportion of the global burden of disease, leading it as a public health imperative. Epileptic seizures are currently considered to result from an imbalance between excitatory and inhibitory activity within a neuronal network. However, the medical and surgical therapeutic approaches show various limitations. Therefore, a large unmet need remains to explore a brand-new explanation of epileptic seizures that can be applied for the development of novel therapeutic strategies. A special epilepsy syndrome, reflex epilepsy, may provide us with new insights for the understanding of epilepsy. Reflex epileptic seizures are specific seizure types that can be triggered by certain sensory or cognitive stimuli. Regardless of the variation of triggering factors and seizure types among clinical cases, the consistent relationship between the occurrence of specific trigger events and subsequent occurrence of epileptic seizures is a common core characteristic, which phenotypically resembles classical conditioning. The phenotypical parallel between reflex epileptic seizures and conditioning memory suggests that in reflex epilepsy, there may also be an association that can be established specifically, reconsolidated with a protein synthesis-dependent process after each reactivation, and subsequently rendered labile and susceptible to impair. Therefore, we here systematically introduced the conditioning paradigms to explore the potential possible mechanism and intervention strategy of reflex epilepsy.

In this study, to mimic the reflex epileptic seizures being triggered by certain stimuli at the animal behavioral level, we paired a specific cue and chemical-induced seizures (CIS) in the training session and observed that CIS could be associated with the specific cue and be induced specifically, also universally among stimuli types and species, indicating an animal model with cue-induced epileptic seizures was effectively established. To examine if the association was long-lasting, we tested with the CIS-paired cue repetitively over a longer period of time and found that epileptic seizures could be re-induced repetitively, which ensured the stability of the model. To further investigate the mechanism, using Western Blot to examine protein expression levels in the mouse hippocampus during the hours of critical time window after reactivation of cue-induced epileptic seizures, we found the expression levels of BDNF, pmTOR, and pERK appeared dynamic changes in a time-dependent manner with the peak at 1-2 h time points, indicating these key molecules were probably involved in the reconsolidation process. Finally, to verify their key roles and potential therapeutic effects, we applied pharmacological approaches to intervene in. We found disrupting these key molecules in the critical time window, in particular, interrupting the total protein synthesis process by anisomycin and targeting the key proteins by rapamycin, propranolol, and exogenous BDNF antisense oligodeoxynucleotide could pharmacologically impair the consolidation and reconsolidation processes of cue-induced epileptic seizures, and the subsequent induction of epileptic seizures was significantly controlled.

To sum up, our study designed a new animal model exhibiting cue-induced epileptic seizures for reflex epilepsy research, provided a new mechanism explanation and intervention strategy of reflex epilepsy, and raised a new aspect to understand epilepsy.

主要符号对照表 VI
第一章 文献综述 1
1.1 癫痫流行病学 1
1.2 癫痫定义及分类 2
1.3 癫痫主要发病机制 5
1.3.1 离子通道功能异常 5
1.3.2 神经递质失衡 8
1.4 癫痫主要治疗手段及疗效现状 11
1.4.1 抗癫痫药物治疗 11
1.4.2 神经外科手术治疗 13
1.5 总结与展望 14
第二章 引言 16
第三章 实验材料与方法 19
3.1 实验材料 19
3.1.1 实验动物 19
3.1.2 主要仪器 19
3.1.3 主要试剂及药品 20
3.1.4 主要溶液配制 22
3.2 实验方法 23
3.2.1 化学诱导发作 23
3.2.2 视频-脑电（Video-EEG）记录 24
3.2.3 蛋白质免疫印迹（Western Blot）检测 24
3.2.4 腹腔注射给药 26
3.2.5 背侧海马局部给药 27
3.2.6 统计分析 28
第四章 结果 29
4.1 癫痫发作可以被关联信号特异性诱导 29
4.1.1 小鼠癫痫发作可以被关联气味特异性诱导 29
4.1.2 关联信号对癫痫发作的特异性诱导现象具有一定普遍性 32
4.2 信号诱导癫痫发作现象持续存在且可以重复 36
4.3 信号诱导癫痫发作后海马记忆相关蛋白表达呈时间依赖性动态变化 38
4.4 全面阻断蛋白合成可减少信号诱导的癫痫发作 41
4.4.1 关联后阻断蛋白合成可破坏信号诱导发作的巩固过程 41
4.4.2 诱导后阻断蛋白合成可破坏信号诱导发作的再巩固过程 43
4.5 在巩固与再巩固时间窗内阻断mTOR通路均可减少信号诱导的癫痫发作 45
4.6 使用普萘洛尔破坏信号诱导发作后再巩固过程可减少再次诱导的癫痫发作 48
4.7 干预信号诱导发作后再巩固过程BDNF表达可减少再次诱导的癫痫发作 50
第五章 讨论 52
5.1 条件记忆范式为反射性癫痫研究建立新的动物模型 52
5.2 信号诱导发作模型为反射性癫痫机制提供新的解释 53
5.3 记忆再巩固原理为反射性癫痫治疗提示新的策略 54
第六章 结论及展望 56
6.1 结论 56
6.2 展望 57
参考文献 59
致谢 68
北京大学学位论文原创性声明和使用授权说明 70
个人简历、在学期间发表的学术论文与研究成果 71

[1]. Beghi E. The epidemiology of epilepsy[J]. Neuroepidemiology, 2020, 54(2):185-91.

[2]. Epilepsy: a public health imperative. Summary. Geneva: World Health Organization; 2019 (WHO/MSD/MER/19.2). Licence: CC BY-NC-SA 3.0 IGO.

[3]. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies[J]. Neurology, 2017, 88(3):296-303.

[4]. Song P, Liu Y, Yu X, et al. Prevalence of epilepsy in China between 1990 and 2015: A systematic review and meta-analysis[J]. J Glob Health, 2017, 7(2):020706.

[5]. 王素萍. 流行病学 2版[M]. 中国协和医科大学出版社, 2009.

[6]. Collaborators GN. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. The Lancet Neurology, 2019, 18(5):459-80.

[7]. Keezer MR, Sisodiya SM, Sander JW. Comorbidities of epilepsy: current concepts and future perspectives[J]. The Lancet Neurology, 2016, 15(1):106-15.

[8]. Gross RA. A brief history of epilepsy and its therapy in the Western Hemisphere[J]. Epilepsy research, 1992, 12(2):65-74.

[9]. Smith MC, Buelow JM. Epilepsy[J]. Disease-a-month: DM, 1996, 42(11):729-827.

[10]. Jackson JH. On the anatomical investigation of epilepsy and epileptiform convulsions[J]. British medical journal, 1873, 1(645):531.

[11]. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)[J]. Epilepsia, 2005, 46(4):470-72.

[12]. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy[J]. Epilepsia, 2014, 55(4):475-82.

[13]. Gastaut H, Caveness WF, Landolt W, et al. A proposed classification of epileptic seizures[J]. Epilepsia, 1964, 5:297-306.

[14]. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures[J]. Epilepsia, 1981, 22(4):489-501.

[15]. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology[J]. Epilepsia, 2017, 58(4):522-30.

[16]. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology[J]. Epilepsia, 2017, 58(4):512-21.

[17]. 梁锦平. 国际抗癫痫联盟2017年版癫痫分类特点及其解读[J]. 中国实用儿科杂志, 2020, 35(1):47-54.

[18]. Scheffer IE, Berkovic S, Capovilla G, et al. 癫痫的ILAE分类:ILAE委员会关于分类和术语的意见书[J]. 癫痫杂志, 2018, 004(006):517-25.

[19]. Lüders H, Akamatsu N, Amina S, et al. Critique of the 2017 epileptic seizure and epilepsy classifications[J]. Epilepsia, 2019, 60(6):1032-39.

[20]. Shorvon SD. The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years[J]. Epilepsia, 2011, 52(6):1033-44.

[21]. Staley K. Molecular mechanisms of epilepsy[J]. Nat Neurosci, 2015, 18(3):367-72.

[22]. Reid CA, Berkovic SF, Petrou S. Mechanisms of human inherited epilepsies[J]. Progress in neurobiology, 2009, 87(1):41-57.

[23]. Wang J, Lin Z-J, Liu L, et al. Epilepsy-associated genes[J]. Seizure, 2017, 44:11-20.

[24]. Wei F, Yan LM, Su T, et al. Ion channel genes and epilepsy: Functional alteration, pathogenic potential, and mechanism of epilepsy[J]. Neurosci Bull, 2017, 33(4):455-77.

[25]. Oyrer J, Maljevic S, Scheffer IE, et al. Ion channels in genetic epilepsy: From genes and mechanisms to disease-targeted therapies[J]. Pharmacol Rev, 2018, 70(1):142-73.

[26]. Jiang S-H, Hu L-P, Wang X, et al. Neurotransmitters: emerging targets in cancer[J]. Oncogene, 2020, 39(3):503-15.

[27]. Kandimalla R, Reddy PH. Therapeutics of neurotransmitters in Alzheimer's disease[J]. Journal of Alzheimer's disease : JAD, 2017, 57(4):1049-69.

[28]. Lascano AM, Korff CM, Picard F. Seizures and epilepsies due to channelopathies and neurotransmitter receptor dysfunction: A parallel between genetic and immune aspects[J]. Molecular syndromology, 2016, 7(4):197-209.

[29]. Sánchez Fernández I, Loddenkemper T. Subunit composition of neurotransmitter receptors in the immature and in the epileptic brain[J]. BioMed research international, 2014, 2014:301950.

[30]. Akyuz E, Polat AK, Eroglu E, et al. Revisiting the role of neurotransmitters in epilepsy: An updated review[J]. Life Sci, 2021, 265:118826.

[31]. Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, et al. Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy[J]. Oxidative medicine and cellular longevity, 2014, 2014:293689.

[32]. Treiman DM. GABAergic mechanisms in epilepsy[J]. Epilepsia, 2001, 42 Suppl 3:8-12.

[33]. Gallagher MJ, Ding L, Maheshwari A, et al. The GABAA receptor alpha1 subunit epilepsy mutation A322D inhibits transmembrane helix formation and causes proteasomal degradation[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(32):12999-3004.

[34]. Neuray C, Maroofian R, Scala M, et al. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants[J]. Brain: a journal of neurology, 2020, 143(8):2388-97.

[35]. Gigout S, Wierschke S, Lehmann TN, et al. Muscarinic acetylcholine receptor-mediated effects in slices from human epileptogenic cortex[J]. Neuroscience, 2012, 223:399-411.

[36]. Hillert MH, Imran I, Zimmermann M, et al. Dynamics of hippocampal acetylcholine release during lithium-pilocarpine-induced status epilepticus in rats[J]. Journal of neurochemistry, 2014, 131(1):42-52.

[37]. Sayg? Bacanak M, Ayd?n B, Cabadak H, et al. Contribution of M1 and M2 muscarinic receptor subtypes to convulsions in fasted mice treated with scopolamine and given food[J]. Behavioural brain research, 2019, 364:423-30.

[38]. Cruickshank JW, Brudzynski SM, McLachlan RS. Involvement of M1 muscarinic receptors in the initiation of cholinergically induced epileptic seizures in the rat brain[J]. Brain research, 1994, 643(1-2):125-29.

[39]. Akyüz E, Do?anyi?it Z, Paudel YN, et al. Increased ACh-associated immunoreactivity in autonomic centers in PTZ kindling model of epilepsy[J]. Biomedicines, 2020, 8(5):113.

[40]. Dineley KT, Pandya AA, Yakel JL. Nicotinic ACh receptors as therapeutic targets in CNS disorders[J]. Trends in pharmacological sciences, 2015, 36(2):96-108.

[41]. Baranowska U, Wi?niewska RJ. The α7-nACh nicotinic receptor and its role in memory and selected diseases of the central nervous system[J]. Postepy Hig Med Dosw (Online), 2017, 71(0):633-48.

[42]. Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: Implications in the pathology of the gastrointestinal tract[J]. Frontiers in immunology, 2017, 8:1452.

[43]. Paul S, Elsinga PH, Ishiwata K, et al. Adenosine A(1) receptors in the central nervous system: their functions in health and disease, and possible elucidation by PET imaging[J]. Current medicinal chemistry, 2011, 18(31):4820-35.

[44]. Boison D. Adenosine dysfunction in epilepsy[J]. Glia, 2012, 60(8):1234-43.

[45]. Masino SA, Kawamura M, Ruskin DN. Adenosine receptors and epilepsy: Current evidence and future potential // Mori A. International review of neurobiology. Academic Press, 2014(119): 233-55.

[46]. Boison D. Adenosinergic signaling in epilepsy[J]. Neuropharmacology, 2016, 104:131-39.

[47]. Kommajosyula SP, Randall ME, Faingold CL. Inhibition of adenosine metabolism induces changes in post-ictal depression, respiration, and mortality in genetically epilepsy prone rats[J]. Epilepsy research, 2016, 119:13-19.

[48]. Roseti C, Martinello K, Fucile S, et al. Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors[J]. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(39):15118-23.

[49]. Ilie A, Raimondo JV, Akerman CJ. Adenosine release during seizures attenuates GABAA receptor-mediated depolarization[J]. The Journal of neuroscience, 2012, 32(15):5321-32.

[50]. Dede F, Karadenizli S, Ozsoy OD, et al. Antagonism of adenosinergic system decrease SWD occurrence via an increment in thalamic NFkB and IL-6 in absence epilepsy[J]. Journal of neuroimmunology, 2019, 326:1-8.

[51]. Dede F, Karadenizli S, ?zsoy ?D, et al. The effects of adenosinergic modulation on cytokine levels in a pentylenetetrazole-induced generalized tonic-clonic seizure model[J]. Neuroimmunomodulation, 2017, 24(1):54-59.

[52]. Wang Y, Chen Z. An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy[J]. Pharmacol Ther, 2019, 201:77-93.

[53]. 肖波, 龙泓羽. 浅谈抗癫痫药物应用现状与前景展望[J]. 中华神经科杂志, 2021, 54(1):4.

[54]. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies[J]. Epilepsia, 2010, 51(6):1069-77.

[55]. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs[J]. The Lancet Neurology, 2012, 11(9):792-802.

[56]. Schmidt D. Drug treatment of epilepsy: options and limitations[J]. Epilepsy & behavior : E&B, 2009, 15(1):56-65.

[57]. Kobow K, Auvin S, Jensen F, et al. Finding a better drug for epilepsy: antiepileptogenesis targets[J]. Epilepsia, 2012, 53(11):1868-76.

[58]. Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs[J]. Neuropharmacology, 2020, 168:107966.

[59]. Chen JW, Borgelt LM, Blackmer AB. Cannabidiol: A new hope for patients with Dravet or Lennox-Gastaut syndromes[J]. The Annals of pharmacotherapy, 2019, 53(6):603-11.

[60]. Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex[J]. Annals of neurology, 2013, 74(5):679-87.

[61]. Brodie MJ, Sills GJ. Combining antiepileptic drugs--rational polytherapy?[J]. Seizure, 2011, 20(5):369-75.

[62]. Reddy AS, Zhang S. Polypharmacology: drug discovery for the future[J]. Expert review of clinical pharmacology, 2013, 6(1):41-47.

[63]. Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial[J]. The Lancet Neurology, 2020, 19(1):38-48.

[64]. Krook-Magnuson E, Soltesz I. Beyond the hammer and the scalpel: selective circuit control for the epilepsies[J]. Nature neuroscience, 2015, 18(3):331-38.

[65]. Thijs RD, Surges R, O'Brien TJ, et al. Epilepsy in adults[J]. The Lancet, 2019, 393(10172):689-701.

[66]. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy[J]. The New England journal of medicine, 2001, 345(5):311-18.

[67]. Engel J. The current place of epilepsy surgery[J]. Current opinion in neurology, 2018, 31(2):192-97.

[68]. Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults[J]. The Lancet Neurology, 2014, 13(11):1114-26.

[69]. Picot M-C, Jaussent A, Neveu D, et al. Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study[J]. Epilepsia, 2016, 57(10):1669-79.

[70]. Engel J, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons[J]. Neurology, 2003, 60(4):538-47.

[71]. Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery[J]. Epilepsia, 2006, 47(6):952-59.

[72]. Duncan JS, Winston GP, Koepp MJ, et al. Brain imaging in the assessment for epilepsy surgery[J]. The Lancet Neurology, 2016, 15(4):420-33.

[73]. Engel J, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial[J]. JAMA, 2012, 307(9):922-30.

[74]. Kaiboriboon K, Malkhachroum AM, Zrik A, et al. Epilepsy surgery in the United States: Analysis of data from the National Association of Epilepsy Centers[J]. Epilepsy research, 2015, 116:105-09.

[75]. Rolston JD, Englot DJ, Knowlton RC, et al. Rate and complications of adult epilepsy surgery in North America: Analysis of multiple databases[J]. Epilepsy research, 2016, 124:55-62.

[76]. Sperling MR, Barshow S, Nei M, et al. A reappraisal of mortality after epilepsy surgery[J]. Neurology, 2016, 86(21):1938-44.

[77]. Alonso Vanegas MA, Lew SM, Morino M, et al. Microsurgical techniques in temporal lobe epilepsy[J]. Epilepsia, 2017, 58 Suppl 1:10-18.

[78]. Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy[J]. Nat Rev Dis Primers, 2018, 4:18024.

[79]. Kwan P, Brodie MJ. Early identification of refractory epilepsy[J]. The New England journal of medicine, 2000, 342(5):314-19.

[80]. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules[J]. European journal of neurology, 2006, 13(3):277-82.

[81]. Loscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs[J]. Seizure, 2011, 20(5):359-68.

[82]. L?scher W. Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs[J]. Neurochemical research, 2017, 42(7):1873-88.

[83]. Becker AJ. Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis[J]. Neuropathology and applied neurobiology, 2018, 44(1):112-29.

[84]. Italiano D, Ferlazzo E, Gasparini S, et al. Generalized versus partial reflex seizures: a review[J]. Seizure, 2014, 23(7):512-20.

[85]. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes[J]. Epilepsia, 1989, 30(4):389-99.

[86]. 金丽日. 反射性发作及癫痫的新认识//上海: 第六届CAAE国际癫痫论坛, 2015:23-4.

[87]. Okudan ZV, Ozkara C. Reflex epilepsy: triggers and management strategies[J]. Neuropsychiatr Dis Treat, 2018, 14:327-37.

[88]. Baumer FM, Porter BE. Clinical and electrographic features of sunflower syndrome[J]. Epilepsy Res, 2018, 142:58-63.

[89]. Sanchez-Carpintero R, Patino-Garcia A, Urrestarazu E. Musicogenic seizures in Dravet syndrome[J]. Dev Med Child Neurol, 2013, 55(7):668-70.

[90]. Ilik F, Pazarli AC. Reflex epilepsy triggered by smell[J]. Clin EEG Neurosci, 2015, 46(3):263-5.

[91]. Weaver DF. Font specific reading-induced seizures[J]. Clin Neurol Neurosurg, 2014, 125:210-1.

[92]. Gilboa T. Emotional stress-induced seizures: another reflex epilepsy?[J]. Epilepsia, 2012, 53(2):e29-32.

[93]. Nevler N, Gandelman-Marton R. Acute provoked reflex seizures induced by thinking[J]. Neurologist, 2012, 18(6):415-7.

[94]. Asok A, Leroy F, Rayman JB, et al. Molecular mechanisms of the memory trace[J]. Trends in neurosciences, 2019, 42(1):14-22.

[95]. Frankland PW, Bontempi B. The organization of recent and remote memories[J]. Nature reviews Neuroscience, 2005, 6(2):119-30.

[96]. Tronson NC, Taylor JR. Molecular mechanisms of memory reconsolidation[J]. Nat Rev Neurosci, 2007, 8(4):262-75.

[97]. Debiec J, LeDoux JE, Nader K. Cellular and systems reconsolidation in the hippocampus[J]. Neuron, 2002, 36(3):527-38.

[98]. Dudai Y. The neurobiology of consolidations, or, how stable is the engram?[J]. Annu Rev Psychol, 2004, 55:51-86.

[99]. Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval[J]. Nature, 2000, 406(6797):722-26.

[100]. Lee JLC, Nader K, Schiller D. An update on memory reconsolidation updating[J]. Trends Cogn Sci, 2017, 21(7):531-45.

[101]. Agren T, Engman J, Frick A, et al. Disruption of reconsolidation erases a fear memory trace in the human amygdala[J]. Science, 2012, 337(6101):1550-52.

[102]. Schiller D, Monfils M-H, Raio CM, et al. Preventing the return of fear in humans using reconsolidation update mechanisms[J]. Nature, 2010, 463(7277):49-53.

[103]. Brunet A, Orr SP, Tremblay J, et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder[J]. Journal of psychiatric research, 2008, 42(6):503-06.

[104]. Xue YX, Deng JH, Chen YY, et al. Effect of selective inhibition of reactivated nicotine-associated memories with propranolol on nicotine craving[J]. JAMA Psychiatry, 2017, 74(3):224-32.

[105]. Barak S, Liu F, Ben Hamida S, et al. Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse[J]. Nat Neurosci, 2013, 16(8):1111-7.

[106]. Shah MM, Anderson AE, Leung V, et al. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons[J]. Neuron, 2004, 44(3):495-508.

[107]. Huang Z, Walker MC, Shah MM. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis[J]. The Journal of neuroscience, 2009, 29(35):10979-88.

[108]. Lévesque M, Avoli M. The kainic acid model of temporal lobe epilepsy[J]. Neuroscience and biobehavioral reviews, 2013, 37(10 Pt 2):2887-99.

[109]. Paxinos G, Franklin KB. The mouse brain in stereotaxic coordinates: second edition[M]. Elsevier, 2001.

[110]. Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition[M]. Elsevier, 2006.

[111]. Liu Y, Lai S, Ma W, et al. CDYL suppresses epileptogenesis in mice through repression of axonal NaV1.6 sodium channel expression[J]. Nature communications, 2017, 8(1):355.

[112]. Flood JF, Rosenzweig MR, Bennett EL, et al. The influence of duration of protein synthesis inhibition on memory[J]. Physiology & behavior, 1973, 10(3):555-62.

[113]. Ben-Ari Y, Cossart R. Kainate, a double agent that generates seizures: two decades of progress[J]. Trends in Neurosciences, 2000, 23(11):580-87.

[114]. Williams PA, White AM, Clark S, et al. Development of spontaneous recurrent seizures after kainate-induced status epilepticus[J]. The Journal of neuroscience, 2009, 29(7):2103-12.

[115]. Dudek FE, Hellier JL, Williams PA, et al. The course of cellular alterations associated with the development of spontaneous seizures after status epilepticus[J]. Progress in brain research, 2002, 135:53-65.

[116]. Gonzalez MC, Radiske A, Cammarota M. On the involvement of BDNF signaling in memory reconsolidation[J]. Frontiers in cellular neuroscience, 2019, 13:383.

[117]. Gonzalez MC, Rossato JI, Radiske A, et al. Recognition memory reconsolidation requires hippocampal Zif268[J]. Scientific reports, 2019, 9(1):16620.

[118]. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease[J]. Trends in neurosciences, 2010, 33(2):67-75.

[119]. Gafford GM, Parsons RG, Helmstetter FJ. Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus[J]. Neuroscience, 2011, 182:98-104.

[120]. Atkins CM, Selcher JC, Petraitis JJ, et al. The MAPK cascade is required for mammalian associative learning[J]. Nature neuroscience, 1998, 1(7):602-09.

[121]. Kelly á, Laroche S, Davis S. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory[J]. The Journal of Neuroscience, 2003, 23(12):5354.

[122]. Liu X, Ma L, Li HH, et al. β-Arrestin-biased signaling mediates memory reconsolidation[J]. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(14):4483-88.

[123]. Wolf P. Introduction: contributions to the understanding of the reflex epilepsies, and the reflex epilepsies' contributions to the understanding of epilepsy[J]. Reflex Epilepsies: Progress in Understanding, 2004:1-5.

[124]. Striano S, Coppola A, del Gaudio L, et al. Reflex seizures and reflex epilepsies: old models for understanding mechanisms of epileptogenesis[J]. Epilepsy Res, 2012, 100(1-2):1-11.

[125]. Italiano D, Striano P, Russo E, et al. Genetics of reflex seizures and epilepsies in humans and animals[J]. Epilepsy Res, 2016, 121:47-54.

[126]. Kandratavicius L, Balista PA, Lopes-Aguiar C, et al. Animal models of epilepsy: use and limitations[J]. Neuropsychiatric disease and treatment, 2014, 10:1693-705.

[127]. Killam EK. Photomyoclonic seizures in the baboon, Papio papio[J]. Federation proceedings, 1979, 38(10):2429-33.

[128]. Poletaeva, II, Surina NM, Kostina ZA, et al. The Krushinsky-Molodkina rat strain: The study of audiogenic epilepsy for 65 years[J]. Epilepsy Behav, 2017, 71(Pt B):130-41.

[129]. De Sarro G, Russo E, Citraro R, et al. Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs[J]. Epilepsy Behav, 2017, 71(Pt B):165-73.

[130]. Koepp MJ, Caciagli L, Pressler RM, et al. Reflex seizures, traits, and epilepsies: from physiology to pathology[J]. The Lancet Neurology, 2016, 15(1):92-105.

[131]. Hanif S, Musick ST. Reflex Epilepsy[J]. Aging Dis, 2021, 12(4):1010-20.

[132]. Isnard J, Guénot M, Fischer C, et al. A stereoelectroencephalographic (SEEG) study of light-induced mesiotemporal epileptic seizures[J]. Epilepsia, 1998, 39(10):1098-103.

[133]. Varotto G, Visani E, Canafoglia L, et al. Enhanced frontocentral EEG connectivity in photosensitive generalized epilepsies: a partial directed coherence study[J]. Epilepsia, 2012, 53(2):359-67.

[134]. Vollmar C, O'Muircheartaigh J, Barker GJ, et al. Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study[J]. Brain, 2011, 134(Pt 6):1710-9.

[135]. Semon RW. The Mneme[M]. G. Allen & Unwin Limited, 1921.

[136]. Hebb DO. The organization of behavior: A neuropsychological theory[M]. John Wiley and Sons, Inc., 1949.

[137]. Josselyn SA, Kohler S, Frankland PW. Finding the engram[J]. Nat Rev Neurosci, 2015, 16(9):521-34.

[138]. Zhou JL, Shatskikh TN, Liu X, et al. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures[J]. Eur J Neurosci, 2007, 25(12):3667-77.

[139]. Tramoni-Negre E, Lambert I, Bartolomei F, et al. Long-term memory deficits in temporal lobe epilepsy[J]. Revue neurologique, 2017, 173(7-8):490-97.

[140]. Beenhakker MP, Huguenard JR. Neurons that fire together also conspire together: is normal sleep circuitry hijacked to generate epilepsy?[J]. Neuron, 2009, 62(5):612-32.

[141]. Goddard GV, Douglas RM. Does the engram of kindling model the engram of normal long term memory?[J]. Can J Neurol Sci, 1975, 2(4):385-94.

[142]. Epilepsy and the functional anatomy of the human brain[J]. AMA Archives of Neurology & Psychiatry, 1954, 72(5):663-64.

[143]. Kandel ER, Schwartz JH, Jessell TM, et al. Principles of neural science[M]. McGraw-hill New York, 2000.

[144]. Geinisman Y, Morrell F, deToledo-Morrell L. Remodeling of synaptic architecture during hippocampal "kindling"[J]. Proceedings of the National Academy of Sciences of the United States of America, 1988, 85(9):3260-64.

[145]. Cavazos JE, Zhang P, Qazi R, et al. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats[J]. J Comp Neurol, 2003, 458(3):272-92.

[146]. Zhang N, Houser CR. Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses[J]. The Journal of comparative neurology, 1999, 405(4):472-90.

[147]. Racine RJ, Milgram NW, Hafner S. Long-term potentiation phenomena in the rat limbic forebrain[J]. Brain research, 1983, 260(2):217-31.

[148]. Hsu D, Chen W, Hsu M, et al. An open hypothesis: is epilepsy learned, and can it be unlearned?[J]. Epilepsy Behav, 2008, 13(3):511-22.