噪声暴露后豚鼠下丘可塑性和r-氨基丁酸（GABA）的改变
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摘要
目的：观察噪声暴露耳蜗损伤后豚鼠下丘神经元对纯音刺激编码机制的改变以及神经递质r-氨基丁酸(GABA)的改变,阐明噪声性耳鸣、听觉过敏、响度重振等症状发生的机理。研究分三部分：
一、正常豚鼠下丘的电生理特性。研究发现：1.大部分频率地形图(FRA)为V-shape型(84.89%),其余为non-V-shape型。2.沿背腹轴方向,随着深度的增加,特征频率(CF)呈阶梯式增加。特征频率与其阈值(MT)的函数关系呈U形即低频和高频部分阈值较高。特征频率的阈值由浅到深总体表现为“V”型。3.反应率-强度函数(RIF)有五型：a)u1型,反应率-强度函数曲线缓慢上升到最大反应程度,最后呈下降趋势；b)u2型,反应率-强度函数曲线缓慢上升到最大反应程度。c)u3型,快速上升-平缓型,函数曲线快速上升,在30dB-40dB刺激强度时,反应率达到高峰,然后维持这一高度或缓慢上升直到最后。d)ud型,函数曲线快速上升,在30dB-40dB刺激强度时,反应率达到最高峰,然后快速下降,呈倒U形。e)N型,函数曲线形状呈N、M或W形。4.刺激后时间直方图(PSTH)有五型：A.抑制型,在纯音刺激过程中抑制自发放电。B.瞬态型,在纯音刺激最初25秒之内呈现兴奋反应,随后在整个刺激过程中跟着低放电。c.长潜伏期型,类似瞬态型,但有一个22ms的潜伏期,后面的波峰较宽。D.暂停／发放型,a.起初高的放电,紧接着短暂的下降,随后跟着中等程度的持续放电；b.长潜伏期接着一个平稳的放电。E.发放型,从一开始就出现较高的反应,有平稳的放电。
二、噪声暴露后下丘的电生理改变：1.耳蜗损伤模型可靠。2.从震后1天开始,双峰型FRA和狭窄型FRA明显增多；震后11-21天,狭窄型FRA减少。3.CF与深度函数图中,在相当于4KHz的频率段有一个明显的断层,象正常组那样随着深度的增加cF呈阶梯式上升的规律被破坏,阶梯变平缓。4.cF平均持续深度比正常组明显增加。5.大多数频率段,震后组cF阈值较正常组均低。6.噪声暴露后1天内,特征频率阈上20dB带宽(BW20)没有增加,反而略降低；震后11天-21天,平均BW20比正常组明显增加。7.RIF的类型和正常组相同,但构成比例不同,随着震后时间延长,渐趋相同。8. PSTH的类型和正常组相同,但构成比例不同,随着震后时间延长,渐趋相同。
三、噪声暴露后下丘的GABA改变：GABA神经元和GABAA、GABAB受体较正常组明显减少,随着时间延长,有所增加。
结论：噪声性耳鸣、听觉过敏、言语分辨率下降的生理基础可能是下丘神经元调谐曲线变宽或变窄、发放类型改变、反应兴奋性增加,其物质基础之一是抑制递质GABA减少。
The present study aimed to shed light to the change of GABA and tone coding in guinea pig inferior colliculus (IC) after noise induced cochlea trauma, and to illustrate the mechanism of noise induced drumming in the ear, hyperacusis and loudness recruitment. The study includes three parts.
1. The normal electrophysiological characteristic in guinea pig inferior colliculus. In our study, following items were found:1) Most (84.89%) of the frequency response area (FRA) were v-shape, others were non-v-shape.2) Along the dorsoventral axis, our recording demonstrated a systematic shift in the characteristic frequency (CF) as a function of depth as a distinct staircase pattern, the minimum threshold (MT) of CF as a function of CF appeared as a Ushape, and the MT of CF as a function of depth also appeared as a Ushape.3) Rate intensity function (RIF) includes five types:a) u1:the function curve go slowly up to end then down. b) u2:the function curve go slowly up to end. c) u3:the function curve go up quickly to a height then go slowly up or go levelly. d) ud:the function curve go up quickly to the highest point then quickly down. e) Nshape:the function curve is like N or M and W.4) post-stimulus time histogram (PSTH) includes five types:A) inhibitory, the spontaneous spike were inhibited during tone stimulus. B) Transient, response to tone stimulus appeared in the first 25 seconds then less spike followed. C).long-latency, the response pattern is like the transient, but it has a latency of 22 seconds. D). Pauser/buildup, responses with an early peak in activity followed by a brief decrease in activity and a buildup of firing activity to a moderate continuous rate. E), buildup, responses early increased to a plateau.
2. Changes of electro-physiology in guinea pig inferior colliculus after noise exposure:1) The models of acoustic trauma were successful.2) The w-shape FRA and n-shape FRA were increased from one day after noise exposure, and until 11～21days after noise exposure, the n-shape-FRA decreased.3) Noise induced hearing loss resulted in a reorganization of the normal tonotopic organization map of the IC. The distinct staircase pattern observed in normal cases was clearly altered and became more or less blurred or significantly distort, a faultage at 4KHz appeared in the staircase pattern.4) The average depth of CF remained in exposed groups increased more than that in the normal.5) The MT of CF decreased in most of the frequency bands in exposed groups.6) The bandwidths at 20 dB above the threshold at CF (BW20dB) decreased in one day and increased from 11～21 days after noise exposure.7) Types of RIF in noise exposed groups were same as it in the controlled group, but the composing ratio of every type was different.8) Types of PSTH in noise exposed groups were same as it in the controlled group, but the composing ratio of every type was different.
3) The change of GABA in guinea pig IC after noise exposure. The neurotransmisssion GABA and its receptors GABAA and GABAB decreased significantly after acoustic trauma.
According to all above, we draw a conclusion:The mechanism of noise induced drumming in the ear, hyperacusis and loudness recruitment may be related to broader or narrower tuning curve, the changed spike pattern, increased reactive activity of the neuros in inferior colliculus after noise exposure, and the reduction of GABA and its receptors was one of the reasons for the physiological changes in inferior colliculus.
一、正常豚鼠下丘的电生理特性。研究发现：1.大部分频率地形图(FRA)为V-shape型(84.89%),其余为non-V-shape型。2.沿背腹轴方向,随着深度的增加,特征频率(CF)呈阶梯式增加。特征频率与其阈值(MT)的函数关系呈U形即低频和高频部分阈值较高。特征频率的阈值由浅到深总体表现为“V”型。3.反应率-强度函数(RIF)有五型：a)u1型,反应率-强度函数曲线缓慢上升到最大反应程度,最后呈下降趋势；b)u2型,反应率-强度函数曲线缓慢上升到最大反应程度。c)u3型,快速上升-平缓型,函数曲线快速上升,在30dB-40dB刺激强度时,反应率达到高峰,然后维持这一高度或缓慢上升直到最后。d)ud型,函数曲线快速上升,在30dB-40dB刺激强度时,反应率达到最高峰,然后快速下降,呈倒U形。e)N型,函数曲线形状呈N、M或W形。4.刺激后时间直方图(PSTH)有五型：A.抑制型,在纯音刺激过程中抑制自发放电。B.瞬态型,在纯音刺激最初25秒之内呈现兴奋反应,随后在整个刺激过程中跟着低放电。c.长潜伏期型,类似瞬态型,但有一个22ms的潜伏期,后面的波峰较宽。D.暂停／发放型,a.起初高的放电,紧接着短暂的下降,随后跟着中等程度的持续放电；b.长潜伏期接着一个平稳的放电。E.发放型,从一开始就出现较高的反应,有平稳的放电。
二、噪声暴露后下丘的电生理改变：1.耳蜗损伤模型可靠。2.从震后1天开始,双峰型FRA和狭窄型FRA明显增多；震后11-21天,狭窄型FRA减少。3.CF与深度函数图中,在相当于4KHz的频率段有一个明显的断层,象正常组那样随着深度的增加cF呈阶梯式上升的规律被破坏,阶梯变平缓。4.cF平均持续深度比正常组明显增加。5.大多数频率段,震后组cF阈值较正常组均低。6.噪声暴露后1天内,特征频率阈上20dB带宽(BW20)没有增加,反而略降低；震后11天-21天,平均BW20比正常组明显增加。7.RIF的类型和正常组相同,但构成比例不同,随着震后时间延长,渐趋相同。8. PSTH的类型和正常组相同,但构成比例不同,随着震后时间延长,渐趋相同。
三、噪声暴露后下丘的GABA改变：GABA神经元和GABAA、GABAB受体较正常组明显减少,随着时间延长,有所增加。
结论：噪声性耳鸣、听觉过敏、言语分辨率下降的生理基础可能是下丘神经元调谐曲线变宽或变窄、发放类型改变、反应兴奋性增加,其物质基础之一是抑制递质GABA减少。
The present study aimed to shed light to the change of GABA and tone coding in guinea pig inferior colliculus (IC) after noise induced cochlea trauma, and to illustrate the mechanism of noise induced drumming in the ear, hyperacusis and loudness recruitment. The study includes three parts.
1. The normal electrophysiological characteristic in guinea pig inferior colliculus. In our study, following items were found:1) Most (84.89%) of the frequency response area (FRA) were v-shape, others were non-v-shape.2) Along the dorsoventral axis, our recording demonstrated a systematic shift in the characteristic frequency (CF) as a function of depth as a distinct staircase pattern, the minimum threshold (MT) of CF as a function of CF appeared as a Ushape, and the MT of CF as a function of depth also appeared as a Ushape.3) Rate intensity function (RIF) includes five types:a) u1:the function curve go slowly up to end then down. b) u2:the function curve go slowly up to end. c) u3:the function curve go up quickly to a height then go slowly up or go levelly. d) ud:the function curve go up quickly to the highest point then quickly down. e) Nshape:the function curve is like N or M and W.4) post-stimulus time histogram (PSTH) includes five types:A) inhibitory, the spontaneous spike were inhibited during tone stimulus. B) Transient, response to tone stimulus appeared in the first 25 seconds then less spike followed. C).long-latency, the response pattern is like the transient, but it has a latency of 22 seconds. D). Pauser/buildup, responses with an early peak in activity followed by a brief decrease in activity and a buildup of firing activity to a moderate continuous rate. E), buildup, responses early increased to a plateau.
2. Changes of electro-physiology in guinea pig inferior colliculus after noise exposure:1) The models of acoustic trauma were successful.2) The w-shape FRA and n-shape FRA were increased from one day after noise exposure, and until 11～21days after noise exposure, the n-shape-FRA decreased.3) Noise induced hearing loss resulted in a reorganization of the normal tonotopic organization map of the IC. The distinct staircase pattern observed in normal cases was clearly altered and became more or less blurred or significantly distort, a faultage at 4KHz appeared in the staircase pattern.4) The average depth of CF remained in exposed groups increased more than that in the normal.5) The MT of CF decreased in most of the frequency bands in exposed groups.6) The bandwidths at 20 dB above the threshold at CF (BW20dB) decreased in one day and increased from 11～21 days after noise exposure.7) Types of RIF in noise exposed groups were same as it in the controlled group, but the composing ratio of every type was different.8) Types of PSTH in noise exposed groups were same as it in the controlled group, but the composing ratio of every type was different.
3) The change of GABA in guinea pig IC after noise exposure. The neurotransmisssion GABA and its receptors GABAA and GABAB decreased significantly after acoustic trauma.
According to all above, we draw a conclusion:The mechanism of noise induced drumming in the ear, hyperacusis and loudness recruitment may be related to broader or narrower tuning curve, the changed spike pattern, increased reactive activity of the neuros in inferior colliculus after noise exposure, and the reduction of GABA and its receptors was one of the reasons for the physiological changes in inferior colliculus.
引文
[1]Manuel S. Malmierca, Marco A. Izquierdo, Salvatore Cristaudo, et al. A Discontinuous Tonotopic Organization in the Inferior Colliculus of the Rat. J Neurosci.2008,28(18):4767-4776.
[2]Izquierdo MA, Gutierrez-Conde PM, Merchan MA, et al. Non-plastic reorganization of frequency coding in the inferior colliculus of the rat following noise-induced hearing loss. Neurosci.2008,154 (1):355-369.
[3]O.Hernandez, N.Espinosa, D.Perez-Gonzalez, M.Malmierca. The inferior colliculus of the rat:A quantitative analysis of monaural frequency response areas. Neurosci.2005,132 (1):203-217.
[4]Paul G, Finlayson.Post-stimulatory suppression, facilitation and tuning for delays shape responses of inferior colliculus neurons to sequential pure tones. Hear Res. 1999,131 (1-2):177-194.
[5]Liang-Fa Liu, Alan R. Palmer, Mark N, et al. Phase-Locked Responses to Pure Tones in the Inferior Colliculus. J Neurophysiol.2006,95(3):1926-1935.
[6]Fitzpatrick DC, Kuwada S, Batra R. Transformations in processing interaural time differences between the superior olivary complex and inferior colliculus: beyond the Jeffress model. Hear Res.2002,168 (2):79-89.
[7]McAlpine D, Jiang D, Shackleton TM, et al. Convergent input from brain stem coincidence detectors onto delay-sensitive neurons in the inferior colliculus. J Neurosci.1998,18 (15):6026-6039.
[8]Satoshi Seki, Jos J. Eggermont. Changes in cat primary auditory cortex after minor-to-moderate pure-tone induced hearing loss. Hear Res.2002,173 (1-2): 172-186.
[9]Russell L. Snyder, Donal G. Sinex b, JoAnn D. McGee c, et al. Acute spiral ganglion lesions change the tuning and tonotopic organization of cat inferior colliculus neurons. Hear Res.2000,147 (1-2):200-220.
[10]Richard J. Salvi, Jian Wang, Dalian Ding. Auditory plasticity and hyperactivity following cochlear damage. Hear Res.2000,147 (1):261-274.
[11]Krogsgaard-Larsen P, Johnston GA, Lodge D, et al. A new class of GABA agonist. Nature.1977,268 (5615):53-55.
[12]G. W. Price, G. P. Wilkin*, M. J. Turnbull, et al. Are ba-clofensensitive GABAB receptors on primary afferent lerminals of the spinal cord? Nature.1984, 307(5946):71-73.
[13]魏继业,王海龙,杨雄里.新型r-氨基丁酸受体：GABAC受体.生理科学进展,1995,26(1)：7-11.
[14]Pollak G.D., Park T.J. Inferior colliculus.ln.Popper A N, Fay R R.Hearing by Bats.Berlin:Springer-Verlag.1995:229-320.
[15]冯瑞本,孙心德.N-甲基-D-天冬氨酸(NMDA)及荷包牡丹碱对不同年龄蝙蝠下丘神经元听反应的影响.生物物理学报,1998,14(4)：673～678.
[16]Jen P H-S, Feng RB. Bicuculline application affects dis-charge pattern and pulse-duration tuning characteristics of bat inferior collicular neurons. J.Comp.Physiology.1999,184 (2):185-194.
[17]Wu MI, Jen P H-S. Temporally patterned sound pulses affect directional sensitivity of inferior collicular neurons of the big brown bat, Eptesicus fuscus. J Comp Physi A.1996,179 (3):385-393.
[18]Hall JC. GABAergic inhibition shapes frequency tuning and modifies responses properties in the auditory midbrain of theleopard frog. J Comp Physiol A.1999,185 (5):479-491.
[19]Lu Y, Jen P H-S, Wu M. GABAergic disinhibition affects response of bat inferior collicular neurons to temporally patterned sound pulses. J.Neurophsiol.1998, 79 (5):2303-2315.
[20]Sun H, Wu SH. The physiological role of pre-and postsynaptic GABA (B) receptors in membrane excitability and synaptic transmission of neurons in the rat's dorsal cortex of the inferior colliculus. Neurosci.2009,160 (1):198-211.
[21]Benoit Pouyatos, Georges Morel, Anne-Marie Lambert-Xolin, et al. Consequences of noise-or styrene-induced cochlear damages on glutamate decarboxylase levels in the rat inferior colliculus. Hear Res.2004,189 (1-2):83-91.
[22]王勤瑛,华清泉,汪审清,et al.大鼠单侧耳蜗损毁后下丘r2氨基丁酸及其神经元的变化.临床耳鼻咽喉头颈外科杂志.2007,21(7)：321-323.
[23]JONES E G. Cortical and subcortical cont ributions to activity2dependent plasticity in primate somatosensory cortex. J Annu Rev Neurosci.2000,23:1-37.
[24]SAPOLSKY R M. The possibility of neurotoxicity in the hippocampus in major depression:a primer on neuron death. J Biol Psychiat ry.2000,48:755-765.
[25]VARJU P, KATAROVA Z,MADARASZ E, et al. GABA signalling during development:new data and old questions.J Cell Tissue Res.2001,305:239-246.
[26]Andrea Lelli, Yukako Asai, Andrew Forge, et al. Tonotopic Gradient in the Developmental Acquisition of Sensory Transduction in Outer Hair Cells of the Mouse Cochlea. J Neurophysiol.2009,101 (6):2961-2973.
[2]Izquierdo MA, Gutierrez-Conde PM, Merchan MA, et al. Non-plastic reorganization of frequency coding in the inferior colliculus of the rat following noise-induced hearing loss. Neurosci.2008,154 (1):355-369.
[3]O.Hernandez, N.Espinosa, D.Perez-Gonzalez, M.Malmierca. The inferior colliculus of the rat:A quantitative analysis of monaural frequency response areas. Neurosci.2005,132 (1):203-217.
[4]Paul G, Finlayson.Post-stimulatory suppression, facilitation and tuning for delays shape responses of inferior colliculus neurons to sequential pure tones. Hear Res. 1999,131 (1-2):177-194.
[5]Liang-Fa Liu, Alan R. Palmer, Mark N, et al. Phase-Locked Responses to Pure Tones in the Inferior Colliculus. J Neurophysiol.2006,95(3):1926-1935.
[6]Fitzpatrick DC, Kuwada S, Batra R. Transformations in processing interaural time differences between the superior olivary complex and inferior colliculus: beyond the Jeffress model. Hear Res.2002,168 (2):79-89.
[7]McAlpine D, Jiang D, Shackleton TM, et al. Convergent input from brain stem coincidence detectors onto delay-sensitive neurons in the inferior colliculus. J Neurosci.1998,18 (15):6026-6039.
[8]Satoshi Seki, Jos J. Eggermont. Changes in cat primary auditory cortex after minor-to-moderate pure-tone induced hearing loss. Hear Res.2002,173 (1-2): 172-186.
[9]Russell L. Snyder, Donal G. Sinex b, JoAnn D. McGee c, et al. Acute spiral ganglion lesions change the tuning and tonotopic organization of cat inferior colliculus neurons. Hear Res.2000,147 (1-2):200-220.
[10]Richard J. Salvi, Jian Wang, Dalian Ding. Auditory plasticity and hyperactivity following cochlear damage. Hear Res.2000,147 (1):261-274.
[11]Krogsgaard-Larsen P, Johnston GA, Lodge D, et al. A new class of GABA agonist. Nature.1977,268 (5615):53-55.
[12]G. W. Price, G. P. Wilkin*, M. J. Turnbull, et al. Are ba-clofensensitive GABAB receptors on primary afferent lerminals of the spinal cord? Nature.1984, 307(5946):71-73.
[13]魏继业,王海龙,杨雄里.新型r-氨基丁酸受体：GABAC受体.生理科学进展,1995,26(1)：7-11.
[14]Pollak G.D., Park T.J. Inferior colliculus.ln.Popper A N, Fay R R.Hearing by Bats.Berlin:Springer-Verlag.1995:229-320.
[15]冯瑞本,孙心德.N-甲基-D-天冬氨酸(NMDA)及荷包牡丹碱对不同年龄蝙蝠下丘神经元听反应的影响.生物物理学报,1998,14(4)：673～678.
[16]Jen P H-S, Feng RB. Bicuculline application affects dis-charge pattern and pulse-duration tuning characteristics of bat inferior collicular neurons. J.Comp.Physiology.1999,184 (2):185-194.
[17]Wu MI, Jen P H-S. Temporally patterned sound pulses affect directional sensitivity of inferior collicular neurons of the big brown bat, Eptesicus fuscus. J Comp Physi A.1996,179 (3):385-393.
[18]Hall JC. GABAergic inhibition shapes frequency tuning and modifies responses properties in the auditory midbrain of theleopard frog. J Comp Physiol A.1999,185 (5):479-491.
[19]Lu Y, Jen P H-S, Wu M. GABAergic disinhibition affects response of bat inferior collicular neurons to temporally patterned sound pulses. J.Neurophsiol.1998, 79 (5):2303-2315.
[20]Sun H, Wu SH. The physiological role of pre-and postsynaptic GABA (B) receptors in membrane excitability and synaptic transmission of neurons in the rat's dorsal cortex of the inferior colliculus. Neurosci.2009,160 (1):198-211.
[21]Benoit Pouyatos, Georges Morel, Anne-Marie Lambert-Xolin, et al. Consequences of noise-or styrene-induced cochlear damages on glutamate decarboxylase levels in the rat inferior colliculus. Hear Res.2004,189 (1-2):83-91.
[22]王勤瑛,华清泉,汪审清,et al.大鼠单侧耳蜗损毁后下丘r2氨基丁酸及其神经元的变化.临床耳鼻咽喉头颈外科杂志.2007,21(7)：321-323.
[23]JONES E G. Cortical and subcortical cont ributions to activity2dependent plasticity in primate somatosensory cortex. J Annu Rev Neurosci.2000,23:1-37.
[24]SAPOLSKY R M. The possibility of neurotoxicity in the hippocampus in major depression:a primer on neuron death. J Biol Psychiat ry.2000,48:755-765.
[25]VARJU P, KATAROVA Z,MADARASZ E, et al. GABA signalling during development:new data and old questions.J Cell Tissue Res.2001,305:239-246.
[26]Andrea Lelli, Yukako Asai, Andrew Forge, et al. Tonotopic Gradient in the Developmental Acquisition of Sensory Transduction in Outer Hair Cells of the Mouse Cochlea. J Neurophysiol.2009,101 (6):2961-2973.