听觉剥夺及耳蜗内电刺激幼鼠听皮层和下丘核CREB 和 NMDAR1蛋白表达变化

目的：观察耳聋幼鼠及其耳聋后单耳植入电极电刺激后幼鼠听皮层和下丘核环磷酸腺苷反应元件结合蛋白（cyclic AMP response element － binding protein ,CREB）和N －甲基－D－天冬氨酸受体－1（N －methyl－D－aspartic acid receptor one ,NMDAR1）表达水平的变化。方法将66只12天龄SD幼鼠随机分为2大组,分别为耳聋造模后4周组（33只）及耳聋造模后6周组（33只）。将耳聋造模后4周组再分为对照1组、耳聋造模后4周组（4周组）及耳聋造模后3周耳蜗内电刺激组1（刺激时间为1周,简称“电刺激1组”）,每组11只大鼠;将耳聋造模后6周组再分为对照2组、耳聋造模后6周组（6周组）及耳聋造模后5周耳蜗内电刺激组2（刺激时间为1周,简称“电刺激2组”）,每组11只大鼠;对照1、2组均正常饲养。除对照1、2组外,在其余4组幼鼠颈背部、两侧下腹部皮下注射庆大霉素（总量为350 mg／kg ）,半小时后于相同部位注射呋塞米（总量为200 mg／kg ）,两周后行ABR检测,于耳聋造模成功后第3、5周分别对电刺激1、2组的幼鼠植入电极,在耳蜗内进行电刺激,每天3小时,持续7天。于耳聋造模后4、6周分别处死4、6周组大鼠取听皮层和下丘组织,通过免疫组织化学方法,观察CREB和NMDAR1表达水平的变化。结果耳聋造模成功后幼鼠ABR阈值均大于93 dB SPL ,4周组听皮层、下丘CREB和NMDAR1的表达较对照1组增加,电刺激1组CREB和NMDAR1的表达较4周组增加。6周组听皮层和下丘CREB和NMDAR1的表达较对照2组下降,电刺激2组CREB和NMDAR1的表达较6周组增加。结论听觉剥夺可导致幼鼠听皮层和下丘CREB和NMDAR1早期表达增加而晚期表达下降。耳蜗植入电极电刺激可导致幼鼠听皮层和下丘CREB和NMDAR1的表达增加,反映这两个部位神经元的可塑性变化。     

正常大鼠听觉中枢四种氨基酸类神经递质测定

目的探讨并比较听觉中枢四种氨基酸类神经递质的含量。方法选取成年SD大鼠20只,采用日立835-50型氨基酸自动分析仪分别测定其耳蜗核、下丘和听皮层中r-氨基丁酸(gamma-aminobutyric acid,GABA)、甘氨酸(glycine,Gly)、谷氨酸(glutamic acid,Glu)及天冬氨酸(aspartate,Asp)的含量。结果听皮层与耳蜗核相比,GABA的含量差异无统计学意义(P>0.05),听皮层、耳蜗核分别与下丘相比,其含量差异均有显著统计学意义(P<0.01);听皮层与下丘相比,Gly的含量差异无统计学意义(P>0.05),听皮层、下丘分别与耳蜗核相比,其含量差异均有显著统计学意义(P<0.01);下丘与耳蜗核相比,Glu的含量差异无统计学意义(P>0.05),下丘、耳蜗核分别与听皮层相比,其差异均有显著统计学意义(P<0.01);听皮层、下丘及耳蜗核三者间相互比较,Asp的含量差异均无统计学意义(P>0.05)。结论听觉中枢的不同部位GABA、Gly及Glu的含量各异,可能与其神经元的活性不同有关,反映了脑神经元的功能状态。     

卡铂对灰鼠中枢听觉系统的影响

目的 卡铂选择性破坏灰鼠的内毛细胞和Ⅰ型传入神经末梢已被人们所证实,但是,卡铂是否损害耳蜗核、下丘和听觉皮层还不清楚,本文旨在观察卡铂对灰鼠听觉中枢的毒性作用。方法采用恒低温冷冻连续脑组织切片,以中枢听觉系统神经元的密度来评价卡铂对灰鼠中枢听觉系统的影响。结果发现注射卡铂3和4周后,耳蜗背侧核和腹侧核神经元明显的减少,与正常动物比较有显著性差异。而下丘和听觉皮层神经元的变化与正常灰鼠比较无明显差异。结论 说明注射卡铂3和4周后对耳蜗核有明显的毒性作用,可引起耳蜗核神经元明显的减少,但是,对灰鼠下丘和听皮层未见明显的毒性作用。     

生长相关蛋白-43在听觉剥夺大鼠听皮层中的表达研究

目的探索听觉系统发育和损伤后修复的神经可塑性的分子机制,探索GAP-43与幼鼠听皮层发育和可塑性的关系;方法应用免疫组织化学方法,检测正常幼鼠(3周龄、4周龄及8周龄大鼠)及耳毒性药物致聋鼠发育的不同阶段(2周2天龄大鼠氨基糖苷类抗生素致聋后5天、12天及40天,即致聋的3周龄、4周龄及8周龄大鼠)GAP-43在听皮层的阳性神经元表达变化;结果发现GAP-43在刚出生大鼠听皮层阳性神经元高表达,随发育表达逐渐降低,出生后3周(NC P3W)的大鼠听皮层平均每高倍视野阳性神经元数为111.50±4.90,出生后4周(NC P4W)为84.17±3.24,出生后8周(NC P8W)为66.67±4.17;耳蜗损伤后早期GAP-43在幼鼠听皮层的表达反应性升高;结论 GAP-43与幼鼠听皮层发育和可塑性密切相关,GAP-43可作为听皮层乃至听觉系统发育和可塑性的重要标志。     

电针耳穴对D-半乳糖致年龄相关性听力损失豚鼠听觉中枢丙二醛表达的影响

目的探讨丙二醛在豚鼠年龄相关性听力损失发病中的作用和电针对年龄相关性听力损失的防治作用及机制。方法 4月龄豚鼠30只分为三组,每组10只,D-半乳糖模型组:豚鼠颈背部皮下注射D-半乳糖300mg.kg-1.d-1,每日1次,连续注射6周;D-半乳糖+电针组:D-半乳糖的用法用量同模型组,同时电针刺听宫、翳风两个穴位;对照组:给予等量生理盐水颈背部皮下注射,每天1次,连续6周。2年龄豚鼠10只(老年组)自然喂养。实验结束后各组行ABR检测,采用硫代巴比妥酸法(TBA)检测听皮层、下丘和耳蜗核组织中丙二醛的表达。结果①D-半乳糖模型组ABR波Ⅲ潜伏期比对照组延长(P<0.05);D-半乳糖+电针组ABR波Ⅲ潜伏期比D-半乳糖模型组缩短(P<0.05);②D-半乳糖模型组和老年组豚鼠听皮层、下丘和耳蜗核丙二醛含量明显高于对照组(P<0.05);与D-半乳糖模型组相比,D-半乳糖+电针组三个部位的丙二醛含量显著降低(P<0.05),但D-半乳糖模型组与老年组相比无明显差异(P>0.05)。结论豚鼠听觉中枢的老化可能与丙二醛含量升高所导致的脂质过氧化有关;针刺听宫和翳风两个穴位可通过降低丙二醛的表达,在一定程度上抑制D-半乳糖所致的豚鼠听觉中枢的老化过程。     

外周听觉活性改变诱导在体听皮层突触NMDA受体表达变化

目的 观察听觉剥夺和耳蜗电刺激对听皮质突触N-甲基-D-天冬氨酸受体(N-methyl-D-as-partate receptor，NMDAR)表达的影响。方法 经两次不连续梯度超速离心，从初级听皮质提取高度纯化的突触体后，采用Western blotting对耳毒性聋组、听力正常组及电耳蜗内刺激0.5～2h的各实验组听皮质突触体NMDAR三个亚型的表达进行比较。结果 证实了听觉剥夺的成年或发育期大鼠耳蜗电刺激仅仅1.5小时可以诱导突触体NR2A蛋白的显著增加，但NR1和NR2B蛋白量的改变并不显著。结论 在体大鼠的听皮质存在活性依赖的突触的NR2A蛋白的表达。     

耳蜗电刺激对听觉剥夺幼鼠学习记忆能力的实验研究

目的 建立听力障碍和耳蜗电刺激模型,探讨听力障碍及耳蜗电刺激对幼鼠认知功能的影响.方法 选用健康SD幼鼠随机分成4组:①听觉剥夺组(auditory deprivation,AD);②听觉剥夺+早期耳蜗电刺激组(early intracochlear electrical stimulation,ICES1);③听觉剥夺+晚期耳蜗电刺激组(late intracochlearelectrical stimulation,ICES2);④对照组(normal control,NC).AD组、ICES1组、ICES2组在出生后第7天开始用阿米卡星500 mg/kg.d皮下注射,直到出生后第16天.对听觉剥夺的幼鼠分别于生后3周龄(早期干预组,ICES1)和生后7周龄(晚期干预组,ICES2)进行电刺激,持续3小时/天,共1周.然后对各组进行行为学检测,并与同龄对照组比较.结果 Morris水迷宫实验结果①定位航行试验:早期耳蜗电刺激组(ICES1组)逃避潜伏期于训练后第3天及第4天逐渐达正常水平(与对照组比较,P值均＞0.05),明显短于听觉剥夺组(P值均<0.05);晚期耳蜗电刺激组(ICES2)每日逃避潜伏期虽较听觉剥夺组稍有缩短,但与正常组比较,仍明显延长(均为P<0.05).②空间探索实验:早期电刺激组幼鼠在平台象限的游泳时间明显长于听觉剥夺组,穿越平台的次数较听觉剥夺组明显增多(P<0.05),达同龄正常对照组水平.而晚期电刺激组幼鼠在平台象限的游泳时间、穿越平台的次数与听觉剥夺组比较无统计学意义(P>0.05).结论 听力丧失后学习和记忆能力受损,早期耳蜗电刺激可以改善听力障碍幼鼠的学习记忆能力.     

长期注射水杨酸钠对大鼠听皮层酪氨酸受体激酶B及c－fos基因表达的影响

目的通过观察长期注射水杨酸钠后大鼠听皮层中酪氨酸受体激酶B(TrkB)及c-fos基因的表达,探讨其在水杨酸钠耳毒性机制中的作用。方法健康成年Wistar大鼠36只,分为正常组(不做任何处理)、慢性组(肌肉注射水杨酸钠175mg/kg,2次/天,时间间隔8小时,连续注射14天)、慢性恢复组(前期处理同慢性组,停药后恢复28天),每组12只。造模结束后各组大鼠均行听性脑干反应(ABR)检测,然后断头处死并迅速取出听皮层,运用实时荧光定量PCR技术及Western-blot技术分别检测三组大鼠听皮层中TrkB及c-fos的表达。结果正常组ABR反应阈为36±2.23dB SPL,慢性组反应阈升高为41.3±3.31dB SPL,与正常组比较,差异有显著统计学意义(P<0.01);慢性恢复组ABR反应阈为38.6±5.51dB SPL,与正常组比较,差异无统计学意义(P>0.05)。慢性组听皮层c-fos mRNA表达为1.24±0.09,蛋白的表达为0.70±0.12,慢性恢复组听皮层c-fos mRNA的表达为1.23±0.04,蛋白的表达为0.68±0.08,两组均高于正常组(分别为1.12±0.05、0.50±0.04),差异有统计学意义(P<0.01)。慢性组听皮层TrkB mRNA表达为1.26±0.10,蛋白的表达为1.85±0.17,慢性恢复组听皮层TrkB mRNA表达为1.23±0.07,蛋白的表达为1.80±0.08,均高于正常组(分别为1.11±0.03,1.53±0.16),差异有统计学意义(P<0.05)。结论长期注射水杨酸钠后大鼠听皮层c-fos基因表达升高,可能与听觉中枢神经活动增强有关;长期注射水杨酸钠可能通过上调大鼠听皮层TrkB的表达,增强听皮层神经营养因子的功能促进听皮层功能重塑。     

c-fos及NR2A在耳鸣大鼠听皮层中的表达

目的通过检测神经元功能可塑性标记物快反应基因c-fos和N-甲基-D-天门冬氨酸受体（N-methyl-D-aspartate receptor,NMDAR）亚型NR2A在耳鸣大鼠听皮层中的表达探讨听皮层的可塑性变化及其在耳鸣产生中所起的作用.方法将30只白色Wistar大鼠随机分为3组,耳鸣模型组（12只）、生理盐水组（12只）和空白对照组（6只）.注射水杨酸钠造模并用行为学方法证实动物感受到耳鸣后,利用免疫组化技术检测动物听皮层中c-fos和NR2A的表达,并用数字图像分析系统进行分析.结果12只注射水杨酸钠的耳鸣模型组大鼠全部造模成功.c-fos基因的表达产物FOS蛋白主要存在于皮层神经元的胞核,其阳性细胞的数量及所占面积的百分比在耳鸣组显著高于对照组（P值均＜0.01）;NR2A受体主要表达在锥形细胞的胞膜上,其阳性细胞的数量、染色强度和面积百分比均显著强于对照组（P值均＜0.01）.结论耳鸣大鼠听皮层中c-fos和NR2A的表达明显增多,一方面表明神经递质及受体可能参与了耳鸣的发生;另一方面提示耳鸣大鼠听皮层中发生了功能可塑性改变,这种改变可能在耳鸣的发生发展中起重要作用.     

NADPH氧化酶在D-半乳糖诱导的老化大鼠听觉系统氧化损伤过程中的作用

目的研究NADPH氧化酶（NADPH oxidase,NOX）在D-半乳糖诱导的老化大鼠外周听觉系统耳蜗和中枢听觉系统听皮层组织中的表达,探讨老年性耳聋氧化性损伤的发生机制。方法 48只1个月龄雄性Spragua-Dawley大鼠按数字随机法分成两组,每组各24只。D-半乳糖组：每日颈背部皮下注射D-半乳糖（500 mg/kg）,连续8周;对照组：每日颈背部皮下注射同体积的生理盐水,连续8周。造模完成后,取两组大鼠外周听觉系统耳蜗和中枢听觉系统听皮层组织,利用免疫组织化学法检测DNA氧化损伤生物标记物8-羟基-2-脱氧鸟苷（8-hydroxy-2-deoxyguanosine,8-OHdG）;利用实时定量PCR检测线粒体DNA（mitochondrial DNA,mtDNA）普遍缺失（common deletion,CD）和NOX基因的表达;利用Western blot检测NOX蛋白表达;应用Taqman PCR检测mt DNA CD。所有实验数据采用两样本的t检验进行分析。结果 D-半乳糖组和对照组大鼠相比较,D-半乳糖诱导的老化大鼠8-OHdG的表达在耳蜗和听皮层组织中明显增多,两组比较差异具有统计学意义（t分别为6.341、10.589,P均〈0.05）;NOX3基因和蛋白的表达在耳蜗组织中明显增强,两组比较差异具有统计学意义（t分别为8.491、18.983,P均〈0.05）;NOX2基因和蛋白的表达在听皮层组织中明显增强,两组比较差异具有统计学意义（t分别为3.548、8.219,P均〈0.05）;mtDNA CD的累积在耳蜗和听皮层组织中明显增多,两组比较差异具有统计学意义（t分别为9.796、7.901,P均〈0.05）。结论在听觉系统老化过程中,NOX是活性氧的重要来源,可能是导致老年性耳聋氧化性损伤发生的重要原因。     

Stimulation-dependent gene expression in the central auditory system

Acoustic or electrical stimulation activate specific populations of neurons in specific regions of the central auditory system to prepare for a molecular, structural, and functional remodeling within hours. Among the indicators for the initiation of neuronal remodeling is the expression of immediate early genes (IEGs). The IEG c-fos is one of the first genes to be expressed following sensory-evoked neuronal activity. In order to investigate activity-dependent neuroplasticity in the central auditory system we applied acute unilateral electrical intracochlear stimulation (EIS) in a rat model. By using different stimulation parameters we found that laterality, intensity, and frequency effect different kinds of neurons in different regions. We investigated the ventral and dorsal cochlear nucleus (VCN and DCN), the lateral superior olive (LSO), the central inferior colliculus (CIC), and the medial geniculate body (MGB). In each region a unique dynamic pattern of c-Fos expression was found.     

Expression of NMDA, AMPA and GABA(A) receptor subunit mRNAs in the rat auditory brainstem. II. Influence of intracochlear electrical stimulation

We investigated the effects of intracochlear electrical stimulation (ICES) on auditory pathways of neonatal rat deafened by daily amikacin injections. Expression of mRNAs encoding ionotropic glutamate receptor subunits such as alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid type A (GABA(A)) receptor subunits was assessed by in situ hybridization in the dorsal (DCN) and the ventral cochlear nucleus (VCN) and in the central nucleus of the inferior colliculus (CNIC). After 15 days of daily unilateral ICES, the expressions of NR1, NR2b and NR2c subunits of NMDA receptor, that of GluRA, B, C, D flop isoforms of AMPA receptor and that of some GABA(A) subunits (alpha1, beta1, gamma1, gamma2) were increased bilaterally in the DCN, VCN and the CNIC. These changes last over a week after stimulation for only NR1 and NR2c. These modifications might be related to long lasting synaptic plasticity of brainstem auditory pathways. As far as analogy to deaf children can be made, early electrical stimulation might be of interest to maintain neuronal networks.     

Expression of NMDA, AMPA and GABAA receptor subunit mRNAs in the rat auditory brainstem. II. Influence of intracochlear electrical stimulation

We investigated the effects of intracochlear electrical stimulation (ICES) on auditory pathways of neonatal rat deafened by daily amikacin injections. Expression of mRNAs encoding ionotropic glutamate receptor subunits such as α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and N-methyl- -aspartate (NMDA), and γ-aminobutyric acid type A (GABA_A) receptor subunits was assessed by in situ hybridization in the dorsal (DCN) and the ventral cochlear nucleus (VCN) and in the central nucleus of the inferior colliculus (CNIC). After 15 days of daily unilateral ICES, the expressions of NR1, NR2b and NR2c subunits of NMDA receptor, that of GluRA, B, C, D flop isoforms of AMPA receptor and that of some GABA_A subunits (α1, β1, γ1, γ2) were increased bilaterally in the DCN, VCN and the CNIC. These changes last over a week after stimulation for only NR1 and NR2c. These modifications might be related to long lasting synaptic plasticity of brainstem auditory pathways. As far as analogy to deaf children can be made, early electrical stimulation might be of interest to maintain neuronal networks.     

Expression of the c-fos transcription factor in the rat auditory pathway following postnatal auditory deprivation

As an animal model for inborn hearing loss rat pups were reared in a sound-proof chamber from birth until age 21 days. In addition, pinnae were bilaterally sutured closed to reduce any influence of ambient sound. At the end of the sound deprivation, outer ear channals were reopened. Since previous studies failed to show any difference in the number or morphology of neurons in the auditory pathway in bilaterally sound-deprived animals, expression of c-fos protein was used as a functional marker to map trans-synaptic information transfer in the auditory pathway with cellular resolution. At day 21 sound-deprived rats and untreated controls were stimulated with pure tones of 8kHz for 5min at different sound pressure levels. Acoustic stimulation induced c-fos in both parts of the cochlear nucleus, superior olivary complex and inferior colliculus. Compared to untreated rats, deprivation reduced the number of c-fos labeled neurons in the dorsal and ventral part of the cochlear nucleus and inferior colliculus by 58% and 30%, respectively, following low sound pressure levels (90dB). In contrast, high sound pressure levels (120dB) increased the number of c-fos labeled neurons in these areas and evoked only minor differences in the number of labeled neurons in both untreated and sound-deprived rats.     

Plasticity in central representations in the inferior colliculus induced by chronic single- vs. two-channel electrical stimulation by a cochlear implant after neonatal deafness

The goal of this research is to examine the functional consequences of patterned electrical stimulation delivered by a cochlear implant in the deafened developing auditory system. In previous electrophysiological experiments conducted in the inferior colliculus (IC), we have demonstrated that the precise cochleotopic organization of the central nucleus (ICC) develops normally in neonatally deafened unstimulated cats and is unaltered despite the lack of normal auditory input during development. However, these studies also showed that chronic electrical stimulation delivered at a single intracochlear location by one bipolar channel of a cochlear implant induces significant expansion of the central representation of the stimulated cochlear sector and degrades the cochleotopic organization of the IC. This report presents additional data from a new experimental series of neonatally deafened cats that received chronic stimulation on two adjacent bipolar intracochlear channels of a cochlear implant. Results suggest that competing inputs elicited by electrical stimulation delivered by two adjacent channels can maintain the selective representations of each activated cochlear sector within the central auditory system and prevent the expansion seen after single-channel stimulation. Alternating stimulation of two channels and use of highly controlled electrical signals may be particularly effective in maintaining or even sharpening selectivity of central representations of stimulated cochlear sectors. In contrast, simultaneous stimulation using two channels of a model analog cochlear implant processor in one experimental animal failed to maintain channel selectivity and resulted in marked expansion and fusion of the central representations of the stimulated channels. This potentially important preliminary result suggests that under some conditions the central auditory system may be unable to discriminate simultaneous, overlapping inputs from adjacent cochlear implant channels as distinct.     

Effects of age at onset of deafness and electrical stimulation on the developing cochlear nucleus in cats

This study examined the effects of deafness and intracochlear electrical stimulation on the anatomy of the cochlear nucleus (CN) after a brief period of normal auditory development early in life. Kittens were deafened by systemic ototoxic drug injections either as neonates or starting at postnatal day 30. Total CN volume, individual CN subdivision volumes, and cross-sectional areas of spherical cell somata in the anteroventral CN (AVCN) were compared in neonatally deafened and 30-day deafened groups at 8 weeks of age and in young adults after approximately 6 months of electrical stimulation initiated at 8 weeks of age. Both neonatal and early acquired hearing loss resulted in a reduction in CN volume as compared to normal hearing cats. Comparison of 8- and 32-week old groups indicated that the CN continued to grow in both deafened groups despite the absence of auditory input. Preserving normal auditory input for 30 days resulted in a significant increase in both total CN volume and cross-sectional areas of spherical cell somata, as compared to neonatally deafened animals. Restoring auditory input in these developing animals by unilateral intracochlear electrical stimulation did not elicit any difference in CN volume between the two sides, but resulted in 7% larger spherical cell size on the stimulated side. Overall, the brief period of normal auditory development and subsequent electrical stimulation maintained CN volume at 80% of normal and spherical cell size at 86% of normal ipsilateral to the implant as compared to 67% and 74%, respectively, in the neonatally deafened group.     

The auditory midbrain implant: a new auditory prosthesis for neural deafness-concept and device description.

The auditory midbrain implant (AMI) is a new central auditory prosthesis designed for penetrating stimulation of the human inferior colliculus. The major group of candidates for the AMI consists of neurofibromatosis type 2 (NF2) patients who develop neural deafness because of growth and/or surgical removal of bilateral acoustic neuromas. Because of the absence of a viable auditory nerve, these patients cannot benefit from cochlear implants. An alternative solution has been the auditory brainstem implant (ABI), which stimulates the cochlear nucleus. However, speech perception performance in NF2 ABI patients has been limited. The fact that the ABI is able to produce high levels of speech perception in nontumor patients (with inaccessible cochleae or posttraumatic damage to the cochlear nerve) suggests that limitations in ABI performance in NF2 patients may be associated with cochlear nucleus damage caused by the tumors or the tumor removal process. Thus, stimulation of the auditory midbrain proximal to the damaged cochlear nucleus may be a better alternative for hearing restoration in NF2 patients. We propose the central nucleus of the inferior colliculus (ICC) as the potential site. A penetrating electrode array aligned along the well-defined tonotopic gradient of the ICC should selectively activate different frequency regions, which is an important elementfor supporting good speech understanding. The goal of this article is to present the ICC as an alternative site for an auditory implant for NF2 patients and to describe the design of the first human prototype AMI. Practical considerations for implementation of the AMI will also be discussed.     

Evidence for tinnitus-related plasticity in the auditory and limbic system, demonstrated by arg3.1 and c-fos immunocytochemistry

Distributions of arg3.1 and c-fos immunoreactive neurons (IRN) in gerbil auditory cortex (AC) and amygdala showed characteristic differences when comparing systemic application of the tinnitus-eliciting drug salicylate with acoustic stimulation or saline injections. In AC, arg3.1 IRN induced by stimulation focused in regions corresponding to the frequency content of the stimulus. Injections of salicylate (350 mg/kg body weight) led to accumulation of arg3.1 IRN in the high frequency domain, while saline injections produced a diffuse distribution. After all treatments, c-fos IRN outnumbered arg3.1 IRN in AC and showed a broad distribution. In subcortical auditory structures arg3.1 IRN were absent in all but one brain. In ventral cochlear nucleus, c-fos IRN were always found after stimulation and often also after saline injections, whereas none were present when injecting salicylate. Similarly, in inferior colliculus, numbers of c-fos IRN were lowest after salicylate injections. In the amygdala, c-fos and arg3.1 IRN were increased substantially after salicylate injections compared to auditory stimulation or saline injections. In particular in its central nucleus, c-fos and arg3.1 IRN were found exclusively after the tinnitus-inducing treatment, suggesting that coactivation of the AC and the amygdala may by an essential feature of tinnitus-related activation.     

Neurochemistry of the peripheral and central auditory system after ototoxic drug exposure: implications for tinnitus

Platinum-containing drugs, such as cisplatin and carboplatin, are known to have ototoxic side effects causing hearing loss that may be accompanied by tinnitus. This study reviews recent studies on the ototoxicity of cisplatin and carboplatin and summarizes the effects of protective agents that may prevent hearing loss and tinnitus. The primary locus of ototoxicity is in the cochlea, but oxidative stress to the inferior colliculus has been reported recently with carboplatin. Enhanced spontaneous activity within the dorsal cochlear nucleus has been correlated with loss of outer hair cells in animal experiments using cisplatin. This may result from disinhibition of neurons within the dorsal cochlear nucleus caused by reduced input from spiral ganglion cells. Carboplatin may cause tinnitus by oxidative stress within the inferior colliculus or by loss of inhibition within the inferior colliculus resulting from cochlear damage. This could lead to compensatory gain and enhanced responses in neurons within the auditory cortex. Protective agents may prevent tinnitus by preventing damage to the cochlea, thereby obviating the development of disinhibition within central auditory pathways.