水杨酸盐对大鼠听觉中枢代谢功能影响的研究
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摘要
目的通过检测耳鸣模型大鼠听觉中枢听皮层和下丘的大脑活动功能,探讨中枢可塑性在耳鸣形成中的作用。方法 24只大鼠按照给药方式分为正常对照组(生理盐水连续注射14天)、急性注射组(水杨酸钠400mg/kg单次注射)、慢性注射组(水杨酸钠200mg/kg连续注射14天,每天2次)和慢性恢复组(水杨酸钠200mg/kg连续注射14天,每天2次,然后恢复14天)四组,每组6只。各组大鼠在相应处理完毕后以听觉惊跳反射前抑制试验(gas-prepulse inhibition of austic startle reflex,GPIAS)检测耳鸣样行为,微型正电子发射断层显像/X线计算机体层成像(microPET/CT)检测听皮层和下丘的18F-FDG标准摄取值(standardized uptake values,SUV),同时以小脑脑区作为对照,比较各组间的差异。结果 GPIAS显示仅慢性注射组大鼠出现耳鸣样行为,GPIAS值在12和16kHz明显下降;microPET/CT结果显示,与正常对照组相比慢性注射组下丘和听皮层的SUV值相对性升高(P<0.01),急性注射组仅听皮层出现相对性升高(P<0.01),小脑脑区均未出现显著的相对性升高(P>0.05),说明慢性注射组下丘和听皮层神经活跃度升高,急性注射组听皮层神经活跃度升高;与正常对照组比较,急性注射组全脑区SUV值显著升高(P<0.01),说明其呈现全脑活跃状态,而慢性注射组全脑区SUV值仅轻微上升,差异无统计学意义(P>0.05);对照组和慢性恢复组间各项数据差异无统计学意义(P>0.05)。结论慢性注射水杨酸钠所诱导的耳鸣大鼠模型下丘和听皮层脑区活跃度上升,这可能是听觉中枢在中枢可塑性的引导下发生的功能性变化,最终导致持续性耳鸣。
Objective To investigate the neural activity in the central auditory pathway by using a tinnitus animal model.Methods Twenty-four rats were randomly divided into the control,acute salicylate treatment,chronic salicylate treatment,and recovery groups.The gap prepulse inhibition of acoustic startle test was used to confirm tinnitus-like behavior.After delivery of an intravenous bolus of fluorine-18 fluorodeoxyglucose(18 F-FDG),small animal positron emission tomography scans were performed on rats.Results Only rats in chronic salicylatetreatment group showed evidence of experiencing tinnitus.The SUV ratios of the AC were significantly greater in the acute salicylate treatment group than in the control group(P<0.01),suggesting relatively increased metabolism in the two brain regions of the rats in this group.The SUV ratios of the IC and AC(P<0.01),but not of the CRB(P>0.05)were greater in the chronic salicylate treatment group than in the control groups.There was a significant difference in whole brain SUVs between the control and acute salicylate treatment groups(P<0.01),the whole brain SUVs in chronic salicylate treatment group were a little higher but showed no significant difference(P>0.05).There was no significant difference in the SUVs between the control and recovery groups(P>0.05).Conclusion These findings indicate that long-term salicylate administration induced tinnitus in rats and may have enhanced neural activity corresponded to the up-regulated metabolic rate in our study.Alterations to neuroplasticity of the CNS may lead to tinnitus.
Objective To investigate the neural activity in the central auditory pathway by using a tinnitus animal model.Methods Twenty-four rats were randomly divided into the control,acute salicylate treatment,chronic salicylate treatment,and recovery groups.The gap prepulse inhibition of acoustic startle test was used to confirm tinnitus-like behavior.After delivery of an intravenous bolus of fluorine-18 fluorodeoxyglucose(18 F-FDG),small animal positron emission tomography scans were performed on rats.Results Only rats in chronic salicylatetreatment group showed evidence of experiencing tinnitus.The SUV ratios of the AC were significantly greater in the acute salicylate treatment group than in the control group(P<0.01),suggesting relatively increased metabolism in the two brain regions of the rats in this group.The SUV ratios of the IC and AC(P<0.01),but not of the CRB(P>0.05)were greater in the chronic salicylate treatment group than in the control groups.There was a significant difference in whole brain SUVs between the control and acute salicylate treatment groups(P<0.01),the whole brain SUVs in chronic salicylate treatment group were a little higher but showed no significant difference(P>0.05).There was no significant difference in the SUVs between the control and recovery groups(P>0.05).Conclusion These findings indicate that long-term salicylate administration induced tinnitus in rats and may have enhanced neural activity corresponded to the up-regulated metabolic rate in our study.Alterations to neuroplasticity of the CNS may lead to tinnitus.
引文
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2 Hu SS,Mei L,Chen JY,et al.Effects of salicylate on the inflammatory genes expression and synaptic ultrastructure in the cochlear nucleus of rats[J].Inflammation,2014,37:365.
3 Hu SS,Mei L,Chen JY,et al.Expression of immediate-early genes in the dorsal cochlear nucleus in salicylate-induced tinnitus[J].Eur Arch Otorhinolaryngol,2016,273:325.
4 Elgoyhen AB,Langguth B,De Ridder D,et al.Tinnitus:perspectives from human neuroimaging[J].Nat Rev Neurosci,2015,16:632.
5 胡守森,黄治物,吴皓,等.水杨酸盐诱发大鼠听皮层中Egr-1基因表达的改变[J].听力学及言语疾病杂志,2012,20:561.
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7 Hu SS,Mei L,Chen JY,et al.Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat[J].Eur J Histochem,2014,58:2294.
8 Lockwood AH,Wack DS,Burkard RF,et al.The functional anatomy of gaze-evoked tinnitus and sustained lateral gaze[J].Neurology,2001,56:472.
9 Langguth B,Eichhammer P,Kreutzer A,et al.The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus-first results from a PET study[J].Acta Otolaryngol(Suppl),2006,556:84.
10 Schiffer WK,Mirrione MM,Biegon A,et al.Serial microPET measures of the metabolic reaction to a microdialysis probe implant[J].J Neurosci Methods,2006,155:272.
11 Baguley D,McFerran D,Hall D.Tinnitus[J].Lancet,2013,382:1600.
12 Langguth B,Kreuzer PM,Kleinjung T,et al.Tinnitus:causes and clinical management[J].Lancet Neurol,2013,12:920.
13 Eggermont JJ.The auditory cortex and tinnitus-a review of animal and human studies[J].Eur J Neurosci,2015,41:665.
14 王洪田,黄治物,李明,等.耳鸣诊治基本原则与耳鸣习服疗法[J].听力学及言语疾病杂志,2007,15:346.
15 盛海斌,黄治物,吴皓.耳蜗突触病变和隐性听力损失[J].听力学及言语疾病杂志,2016,24:614.
16 Norena AJ,Eggermont J.Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization[J].J Neurosci,2005,25:699.
17 Chen GD,Stolzberg D,Lobarinas E,et al.Salicylate-induced cochlear impairments,cortical hyperactivity and retuning,and tinnitus[J].Hear Res,2013,295:100.
18 Cazals Y,Auditory sensori-neural alterations induced by salicylate[J].Prog Neurobiol,2000,62:583.
19 Paul AK,Lobarinas E,Simmons R,et al.Metabolic imaging of rat brain during pharmacologically-induced tinnitus[J].Neuroimage,2009,44:312.
20 Roberts LE,Eggermont JJ,Caspary DM,et al.Ringing ears:the neuroscience of tinnitus[J].J Neurosci,2010,30:14972.
21 Schecklmann M,Landgrebe M,Poeppl TB,et al.Neural correlates of tinnitus duration and distress:apositron emission tomography study[J].Hum Brain Mapp,2013,34:233.
22 Huang ZW,Luo Y,Wu Z,et al.Paradoxical enhancement of active cochlear mechanics in long-term administration of salicylate[J].J Neurophysiol,2005,93:2053.
23 Jin Y,Luo B,Su YY,et al.Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus[J].PLoS One,2015,10:e0126956.
24 Cazals Y,Horner KC,Huang ZW.Alterations in average spectrum of cochleoneural activity by long-term salicylate treatment in the guinea pig:aplausible index of tinnitus[J].J Neurophysiol,1998,80:2113.
25 Lobarinas E,Hayes SH,Allman BL.The gap-startle paradigm for tinnitus screening in animal models:limitations and optimization[J].Hear Res,2013,295:150.
26 Wallhausser-Franke E,Braun S,Langner G.Salicylate alters2 -DG uptake in the auditory system:a model for tinnitus?[J].Neuroreport,1996,7:1585.
2 Hu SS,Mei L,Chen JY,et al.Effects of salicylate on the inflammatory genes expression and synaptic ultrastructure in the cochlear nucleus of rats[J].Inflammation,2014,37:365.
3 Hu SS,Mei L,Chen JY,et al.Expression of immediate-early genes in the dorsal cochlear nucleus in salicylate-induced tinnitus[J].Eur Arch Otorhinolaryngol,2016,273:325.
4 Elgoyhen AB,Langguth B,De Ridder D,et al.Tinnitus:perspectives from human neuroimaging[J].Nat Rev Neurosci,2015,16:632.
5 胡守森,黄治物,吴皓,等.水杨酸盐诱发大鼠听皮层中Egr-1基因表达的改变[J].听力学及言语疾病杂志,2012,20:561.
6 黄治物,吴皓.耳鸣中枢化机制与临床诊疗[J].临床耳鼻咽喉头颈外科杂志,2014,28:222.
7 Hu SS,Mei L,Chen JY,et al.Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat[J].Eur J Histochem,2014,58:2294.
8 Lockwood AH,Wack DS,Burkard RF,et al.The functional anatomy of gaze-evoked tinnitus and sustained lateral gaze[J].Neurology,2001,56:472.
9 Langguth B,Eichhammer P,Kreutzer A,et al.The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus-first results from a PET study[J].Acta Otolaryngol(Suppl),2006,556:84.
10 Schiffer WK,Mirrione MM,Biegon A,et al.Serial microPET measures of the metabolic reaction to a microdialysis probe implant[J].J Neurosci Methods,2006,155:272.
11 Baguley D,McFerran D,Hall D.Tinnitus[J].Lancet,2013,382:1600.
12 Langguth B,Kreuzer PM,Kleinjung T,et al.Tinnitus:causes and clinical management[J].Lancet Neurol,2013,12:920.
13 Eggermont JJ.The auditory cortex and tinnitus-a review of animal and human studies[J].Eur J Neurosci,2015,41:665.
14 王洪田,黄治物,李明,等.耳鸣诊治基本原则与耳鸣习服疗法[J].听力学及言语疾病杂志,2007,15:346.
15 盛海斌,黄治物,吴皓.耳蜗突触病变和隐性听力损失[J].听力学及言语疾病杂志,2016,24:614.
16 Norena AJ,Eggermont J.Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization[J].J Neurosci,2005,25:699.
17 Chen GD,Stolzberg D,Lobarinas E,et al.Salicylate-induced cochlear impairments,cortical hyperactivity and retuning,and tinnitus[J].Hear Res,2013,295:100.
18 Cazals Y,Auditory sensori-neural alterations induced by salicylate[J].Prog Neurobiol,2000,62:583.
19 Paul AK,Lobarinas E,Simmons R,et al.Metabolic imaging of rat brain during pharmacologically-induced tinnitus[J].Neuroimage,2009,44:312.
20 Roberts LE,Eggermont JJ,Caspary DM,et al.Ringing ears:the neuroscience of tinnitus[J].J Neurosci,2010,30:14972.
21 Schecklmann M,Landgrebe M,Poeppl TB,et al.Neural correlates of tinnitus duration and distress:apositron emission tomography study[J].Hum Brain Mapp,2013,34:233.
22 Huang ZW,Luo Y,Wu Z,et al.Paradoxical enhancement of active cochlear mechanics in long-term administration of salicylate[J].J Neurophysiol,2005,93:2053.
23 Jin Y,Luo B,Su YY,et al.Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus[J].PLoS One,2015,10:e0126956.
24 Cazals Y,Horner KC,Huang ZW.Alterations in average spectrum of cochleoneural activity by long-term salicylate treatment in the guinea pig:aplausible index of tinnitus[J].J Neurophysiol,1998,80:2113.
25 Lobarinas E,Hayes SH,Allman BL.The gap-startle paradigm for tinnitus screening in animal models:limitations and optimization[J].Hear Res,2013,295:150.
26 Wallhausser-Franke E,Braun S,Langner G.Salicylate alters2 -DG uptake in the auditory system:a model for tinnitus?[J].Neuroreport,1996,7:1585.