Auditory Cortex

听觉皮层
  • 文章类型: Journal Article
    背景:“语音听觉”(VH)是一种在创伤相关疾病(创伤-D)中常见的诊断经验。然而,与创伤相关的VH背后的神经底物仍未被探索。虽然听觉知觉功能障碍是精神分裂症VH中涉及的异常之一,创伤-D中的VH是否也涉及听觉知觉改变尚不清楚。
    方法:我们调查了n=65名女性的听觉皮层(AC)相关功能连接(FC),这些女性的创伤-D与童年虐待有关,VH的严重程度不同。用一本小说,计算驱动和个体特定的方法在功能上分割大脑,我们计算了两个不同的AC子区域-Heschl回的FC(HG,对应于原发性AC)和颞上回(lSTG,在非原发性AC中)-同时伴有大脑和小脑。然后,我们使用大脑内的留一交叉验证来测量VH严重程度和FC之间的关联,和小脑的体素多元回归分析。
    结果:我们发现VH严重程度与左lSTG-额叶网络FC呈正相关,而左lSTG与默认模式网络的大脑和小脑表示之间的FC呈负相关。左侧HG或右侧AC亚区的FC不能预测VH严重程度。
    结论:我们的发现指出了听觉感知过程和与自我参照和执行功能相关的更高级别的过程之间的相互作用发生了改变。这是第一项显示与创伤相关的VH中听觉皮层连通性改变的研究。虽然创伤-D中的VH似乎是由精神分裂症VH中也有牵连的大脑网络介导的,结果表明,一种独特的机制可以区分创伤中的VH-D。
    BACKGROUND: \'Voice-hearing\' (VH) is a transdiagnostic experience that is common in trauma-related disorders (trauma-D). However, the neural substrates underlying trauma-related VH remain largely unexplored. While auditory perceptual dysfunction is among the abnormalities implicated in schizophrenia VH, whether VH in trauma-D also involves auditory perceptual alterations is unknown.
    METHODS: We investigated auditory cortex (AC)-related functional connectivity (FC) in n=65 women with trauma-D related to childhood abuse with varying severities of VH. Using a novel, computationally-driven and individual-specific method of functionally parcellating the brain, we calculated the FC of two distinct AC subregions-Heschl\'s gyrus (HG, corresponding to primary AC) and lateral superior temporal gyrus (lSTG, in non-primary AC)- with both the cerebrum and cerebellum. We then measured the association between VH severity and FC using leave-one-out cross validation within the cerebrum, and voxel-wise multiple regression analyses in the cerebellum.
    RESULTS: We found that VH severity positively correlated with left lSTG-frontoparietal network FC, while it negatively correlated with FC between left lSTG and both cerebral and cerebellar representations of the default mode network. VH severity was not predicted by FC of left HG or right AC subregions.
    CONCLUSIONS: Our findings point to altered interactions between auditory perceptual processing and higher-level processes related to self-reference and executive functioning. This is the first study to show alterations in auditory cortical connectivity in trauma-related VH. While VH in trauma-D appears to be mediated by brain networks that are also implicated in schizophrenia VH, the results suggest a unique mechanism that could distinguish VH in trauma-D.
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  • 文章类型: Journal Article
    背景:左撇子是一种将运动控制的典型左脑优势逆转为非典型右脑优势的情况。这种独特的控制及其相关的神经解剖学特性对其他认知功能(如音乐处理或演奏乐器)的影响仍未被探索。先前对右手人群的研究已将音乐才能与(右)听觉皮层中的较大体积和(右)弓形束的较大体积联系起来。
    结果:在我们的研究中,我们发现左撇子音乐家(n=55),与左撇子非音乐家(n=75)相比,在左和右Heschl回中都表现出较大的灰质体积,对听觉处理至关重要。它们还在右弓形束的前段呈现更多的流线。重要的是,非典型的语言半球偏侧化(尤其在左撇子中普遍存在)与AF的向右不对称有关,与典型的横向向左不对称相反。
    结论:这些发现表明,左撇子音乐家与右撇子音乐家具有相似的神经解剖学特征。然而,非典型的言语偏侧化可能会增强正确的听觉运动途径,这与音乐才能和更好的音乐技巧有关。这可能有助于解释为什么音乐家在左撇子中更为普遍,并阐明了他们的认知优势。
    BACKGROUND: Left-handedness is a condition that reverses the typical left cerebral dominance of motor control to an atypical right dominance. The impact of this distinct control - and its associated neuroanatomical peculiarities - on other cognitive functions such as music processing or playing a musical instrument remains unexplored. Previous studies in right-handed population have linked musicianship to a larger volume in the (right) auditory cortex and a larger volume in the (right) arcuate fasciculus.
    RESULTS: In our study, we reveal that left-handed musicians (n = 55), in comparison to left-handed non-musicians (n = 75), exhibit a larger gray matter volume in both the left and right Heschl\'s gyrus, critical for auditory processing. They also present a higher number of streamlines across the anterior segment of the right arcuate fasciculus. Importantly, atypical hemispheric lateralization of speech (notably prevalent among left-handers) was associated to a rightward asymmetry of the AF, in contrast to the leftward asymmetry exhibited by the typically lateralized.
    CONCLUSIONS: These findings suggest that left-handed musicians share similar neuroanatomical characteristics with their right-handed counterparts. However, atypical lateralization of speech might potentiate the right audiomotor pathway, which has been associated with musicianship and better musical skills. This may help explain why musicians are more prevalent among left-handers and shed light on their cognitive advantages.
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  • 文章类型: Journal Article
    分离复杂的声音,如语音,音乐和动物发声,因为它们同时来自多个来源(称为“鸡尾酒派对问题”)是一种非凡的能力,在人类和动物中都很常见。该过程的神经基础已经在非人类动物中进行了广泛的行为和生理研究,主要是通过简化的声音(音调和噪声序列)。在人类中,利用更复杂的语音混合的隔离实验很常见;但是生理实验依赖于EEG/MEG/ECoG记录,这些记录可以从数千个神经元中采样活动,经常模糊导致观察到的偏析的详细过程。本研究将动物单单元生理学的见解与语音混合物的分离相结合。雪貂接受了训练,可以注意女性的声音并检测目标单词,在存在或不存在并发的情况下,同样突出的男性声音。从初级和次级雪貂听觉皮层区获得单神经元记录,以及额叶皮层。在任务执行期间,在所有皮质区域中,女性单词的表示相对于(干扰者)男性的表示变得更加增强,特别是在较高的听觉皮层领域。对任务执行过程中的时间和频谱响应特征的分析揭示了语音分离如何在听觉皮层中逐渐出现。在相同的语音混合物上评估的计算模型复制并将这些结果扩展到不同的注意目标(注意女性或男性的声音)。这些发现与时间相干理论是一致的,在时间相干理论中,对目标语音的关注是皮层网络中的神经活动,因此将与目标在时间上相干调制的通道结合在一起,最终形成共同的听觉流。
    Segregation of complex sounds such as speech, music and animal vocalizations as they simultaneously emanate from multiple sources (referred to as the \"cocktail party problem\") is a remarkable ability that is common in humans and animals alike. The neural underpinnings of this process have been extensively studied behaviorally and physiologically in non-human animals primarily with simplified sounds (tones and noise sequences). In humans, segregation experiments utilizing more complex speech mixtures are common; but physiological experiments have relied on EEG/MEG/ECoG recordings that sample activity from thousands of neurons, often obscuring the detailed processes that give rise to the observed segregation. The present study combines the insights from animal single-unit physiology with segregation of speech-like mixtures. Ferrets were trained to attend to a female voice and detect a target word, both in presence or absence of a concurrent, equally salient male voice. Single neuron recordings were obtained from primary and secondary ferret auditory cortical fields, as well as frontal cortex. During task performance, representation of the female words became more enhanced relative to those of the (distractor) male in all cortical regions, especially in the higher auditory cortical field. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings are consistent with the temporal coherence theory whereby attention to a target voice anchors neural activity in cortical networks hence binding together channels that are coherently temporally-modulated with the target, and ultimately forming a common auditory stream.
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  • 文章类型: Journal Article
    echolocating蝙蝠是所有哺乳动物中最具社交性和嗓音的。鉴于这些动物的相对肥大的边缘和听觉神经结构以及听到MRI梯度噪声的能力降低,这些动物是听觉社交交流功能MRI(fMRI)研究的理想对象。然而,没有与社会认知相关的静息状态网络(例如,默认的类似模式的网络或DMLN)已经在蝙蝠中被识别出来,因为很少,如果有的话,功能磁共振成像研究在肩科目。这里,我们从9只轻度麻醉的浅矛鼻蝙蝠(毛竹变色)获得了7特斯拉的功能MRI数据。我们应用独立成分分析(ICA)来揭示静息状态网络和测量的神经活动,该活动由跨越该物种的超声波听觉范围(20至130kHz)的噪声波纹(开:10ms;关:10ms)引起。静息状态网络遍布听觉,顶叶,和枕骨皮质,以及海马体,小脑,基底神经节,和听觉脑干。两个中线网络形成了明显的DMLN。此外,我们发现了四个主要的听觉/顶叶皮层网络,其中两个是左偏侧的,两个是右偏侧的。已知四个听觉/顶叶皮层网络内的区域响应于社交呼叫。连同听觉脑干,这四个皮层网络中的区域对超声噪声波动做出了反应。迭代分析显示一致,左端之间的显著功能连接,但不对,听觉/顶叶皮层网络和DMLN节点,尤其是最前扣带皮质.因此,一个涉及社会认知的静息状态网络在左边显示出更多的分布式功能连通性,相对于权利,在这种高度社交和声乐的物种中,听觉和交流的半球皮质基质。
    Echolocating bats are among the most social and vocal of all mammals. These animals are ideal subjects for functional MRI (fMRI) studies of auditory social communication given their relatively hypertrophic limbic and auditory neural structures and their reduced ability to hear MRI gradient noise. Yet, no resting-state networks relevant to social cognition (e.g., default mode-like networks or DMLNs) have been identified in bats since there are few, if any, fMRI studies in the chiropteran order. Here, we acquired fMRI data at 7 Tesla from nine lightly anesthetized pale spear-nosed bats (Phyllostomus discolor). We applied independent components analysis (ICA) to reveal resting-state networks and measured neural activity elicited by noise ripples (on: 10 ms; off: 10 ms) that span this species\' ultrasonic hearing range (20 to 130 kHz). Resting-state networks pervaded auditory, parietal, and occipital cortices, along with the hippocampus, cerebellum, basal ganglia, and auditory brainstem. Two midline networks formed an apparent DMLN. Additionally, we found four predominantly auditory/parietal cortical networks, of which two were left-lateralized and two right-lateralized. Regions within four auditory/parietal cortical networks are known to respond to social calls. Along with the auditory brainstem, regions within these four cortical networks responded to ultrasonic noise ripples. Iterative analyses revealed consistent, significant functional connectivity between the left, but not right, auditory/parietal cortical networks and DMLN nodes, especially the anterior-most cingulate cortex. Thus, a resting-state network implicated in social cognition displays more distributed functional connectivity across left, relative to right, hemispheric cortical substrates of audition and communication in this highly social and vocal species.
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  • 文章类型: Journal Article
    大脑皮层是如何处理信息的?在大多数情况下,记录的大脑活动在许多(刺激)重复中平均,消除神经信号的精细结构。然而,大脑显然是一个单一的试用处理器。因此,我们在此证明,无监督机器学习方法可用于在单次试验基础上从电生理记录中提取有意义的信息.我们使用自动编码器网络来减少单个局部场势(LFP)事件的维度,以创建不同神经活动模式的可解释集群。引人注目的是,某些LFP形状对应于不同记录通道中的延迟差异。因此,LFP形状可用于确定大脑皮层中信息通量的方向。此外,聚类后,我们对集群质心进行了解码,以对底层原型LFP事件形状进行反向工程。为了评估我们的方法,我们将其应用于啮齿动物的细胞外神经记录,和人类的颅内脑电图记录。最后,我们发现,在自发活动期间,单通道LFP事件形状来自可能的刺激诱发事件形状的领域。到目前为止,仅针对多通道种群编码进行了研究。
    How is information processed in the cerebral cortex? In most cases, recorded brain activity is averaged over many (stimulus) repetitions, which erases the fine-structure of the neural signal. However, the brain is obviously a single-trial processor. Thus, we here demonstrate that an unsupervised machine learning approach can be used to extract meaningful information from electro-physiological recordings on a single-trial basis. We use an auto-encoder network to reduce the dimensions of single local field potential (LFP) events to create interpretable clusters of different neural activity patterns. Strikingly, certain LFP shapes correspond to latency differences in different recording channels. Hence, LFP shapes can be used to determine the direction of information flux in the cerebral cortex. Furthermore, after clustering, we decoded the cluster centroids to reverse-engineer the underlying prototypical LFP event shapes. To evaluate our approach, we applied it to both extra-cellular neural recordings in rodents, and intra-cranial EEG recordings in humans. Finally, we find that single channel LFP event shapes during spontaneous activity sample from the realm of possible stimulus evoked event shapes. A finding which so far has only been demonstrated for multi-channel population coding.
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  • 文章类型: Journal Article
    最近的研究表明,成年人的大脑在感官处理方面非常适应。在这种情况下,也有人认为,结构“蓝图”可能从根本上限制神经可塑性变化,例如,对感觉剥夺的反应。这里,在10周的时间里,我们对12名盲人参与者和14名有视力的参与者进行了回声定位培训,并在pre-post设计中使用MRI来测量大脑功能和结构的变化。我们发现,盲人参与者和有视力的参与者一起显示出训练引起的左,右V1的激活增加,以响应回声,这一发现很难与感觉皮层严格按模态组织的观点相协调。Further,盲人参与者和有视力的参与者表现出训练诱导的右A1激活增加,以响应声音本身(即不是回声特定的),伴随着盲人参与者右侧A1和视力参与者相邻声学区域的灰质密度增加。视力参与者和盲人参与者之间功能结果的相似性与重组可能受两组相似原则支配的想法一致,然而,我们的结构分析还显示了组间的差异,这表明可能需要更细致入微的观点。
    Recent work suggests that the adult human brain is very adaptable when it comes to sensory processing. In this context, it has also been suggested that structural \"blueprints\" may fundamentally constrain neuroplastic change, e.g. in response to sensory deprivation. Here, we trained 12 blind participants and 14 sighted participants in echolocation over a 10-week period, and used MRI in a pre-post design to measure functional and structural brain changes. We found that blind participants and sighted participants together showed a training-induced increase in activation in left and right V1 in response to echoes, a finding difficult to reconcile with the view that sensory cortex is strictly organized by modality. Further, blind participants and sighted participants showed a training induced increase in activation in right A1 in response to sounds per se (i.e. not echo-specific), and this was accompanied by an increase in gray matter density in right A1 in blind participants and in adjacent acoustic areas in sighted participants. The similarity in functional results between sighted participants and blind participants is consistent with the idea that reorganization may be governed by similar principles in the two groups, yet our structural analyses also showed differences between the groups suggesting that a more nuanced view may be required.
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  • 文章类型: Journal Article
    外周和中枢听觉系统之间的生理相互作用对于听觉信息传递和感知至关重要,虽然目前缺乏可靠的听觉神经回路模型。为了解决这个问题,利用碳纳米管纳米纤维系统产生小鼠和人的神经通路。支架的超对齐图案使得双极和多极神经元的轴突在平行方向上延伸。此外,支架的导电性维持小鼠初级听觉神经元的电生理活动。然后将来自系统中外周和中枢听觉单元的小鼠和人类原代神经元共培养,并表明这两种神经元形成突触连接。此外,耳蜗和听觉皮层的神经祖细胞来源于人类胚胎以产生特定区域的类器官,并且这些类器官在纳米纤维组合的3D系统中组装。使用光遗传学刺激,钙成像,和电生理记录,揭示了外周神经元和中枢神经元之间形成功能性突触连接,钙掺杂和突触后电流证明了这一点。听觉回路模型将使听觉神经通路的研究成为可能,并促进对感觉神经性听力损失中神经元连接障碍的治疗策略的寻找。
    The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.
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  • 文章类型: Journal Article
    耳鸣和高音,可能是由听力损失引发的,可归因于听觉感知中的适应不良可塑性。然而,由于它们的共存,解开它们的神经机制证明是困难的。我们假设耳鸣的神经相关因素与低强度音调触发的神经活动有关,而高音与对中等和高强度音调的反应有关。
    为了检验这些假设,我们在大鼠创伤后2至8天进行了行为和电生理实验。
    在行为实验中,预脉冲和间隙抑制倾向于表现出不同的频率特性(尽管没有达到足够的统计水平),这表明暴露于创伤性音调会导致不同频率范围内的急性音高和耳鸣。当检查丘脑皮层受体层的听觉皮层时,我们观察到耳鸣症状与杂乱无章的音调图相关,通常以对低强度音调的反应为特征。在多单位活动(MUA)水平的皮层募集功能中发现了运动过度的神经相关性,但不在局部场电位(LFP)水平,响应中等和高强度的音调。从LFP到MUA的这种转变与单调性的丧失有关,表明抑制性突触的关键作用。
    因此,在创伤性音调暴露的急性症状中,我们的实验成功地解开了耳鸣和听觉皮层的丘脑皮层受体层的神经相关性。他们还认为耳鸣与中枢噪音有关,而高音与异常的增益控制有关。动物实验和临床研究之间的进一步相互作用将提供对神经机制的见解,耳鸣和高音的诊断和治疗,特别是在慢性症状的长期可塑性方面。
    UNASSIGNED: Both tinnitus and hyperacusis, likely triggered by hearing loss, can be attributed to maladaptive plasticity in auditory perception. However, owing to their co-occurrence, disentangling their neural mechanisms proves difficult. We hypothesized that the neural correlates of tinnitus are associated with neural activities triggered by low-intensity tones, while hyperacusis is linked to responses to moderate- and high-intensity tones.
    UNASSIGNED: To test these hypotheses, we conducted behavioral and electrophysiological experiments in rats 2 to 8 days after traumatic tone exposure.
    UNASSIGNED: In the behavioral experiments, prepulse and gap inhibition tended to exhibit different frequency characteristics (although not reaching sufficient statistical levels), suggesting that exposure to traumatic tones led to acute symptoms of hyperacusis and tinnitus at different frequency ranges. When examining the auditory cortex at the thalamocortical recipient layer, we observed that tinnitus symptoms correlated with a disorganized tonotopic map, typically characterized by responses to low-intensity tones. Neural correlates of hyperacusis were found in the cortical recruitment function at the multi-unit activity (MUA) level, but not at the local field potential (LFP) level, in response to moderate- and high-intensity tones. This shift from LFP to MUA was associated with a loss of monotonicity, suggesting a crucial role for inhibitory synapses.
    UNASSIGNED: Thus, in acute symptoms of traumatic tone exposure, our experiments successfully disentangled the neural correlates of tinnitus and hyperacusis at the thalamocortical recipient layer of the auditory cortex. They also suggested that tinnitus is linked to central noise, whereas hyperacusis is associated with aberrant gain control. Further interactions between animal experiments and clinical studies will offer insights into neural mechanisms, diagnosis and treatments of tinnitus and hyperacusis, specifically in terms of long-term plasticity of chronic symptoms.
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  • 文章类型: Journal Article
    Deepfakes是数字环境的病毒成分,它们可以欺骗人类的认知,误认为假的是真实的。这里,我们测试了25名参与者接受或拒绝在音频deepfakes中重现的个人身份的神经认知敏感性.我们通过使用先进的deepfake技术从自然扬声器中生成高质量的语音身份克隆。在身份匹配任务期间,参与者用深度虚假的声音表现出中级表现,表明欺骗程度和对深度伪造身份欺骗的抵抗力。在大脑层面,单变量和多变量分析一致地揭示了一个中央皮质纹状体网络,该网络解码了声音声学模式和deepfake-level(听觉皮层),以及自然的说话者身份(伏隔核),因其社会相关性而受到重视。该网络嵌入在更广泛的神经身份和对象识别网络中。因此,人类可以部分地被深度假货欺骗,但是在深度伪造处理过程中确定的神经认知机制为增强人类对虚假信息的抵抗力打开了窗口。
    Deepfakes are viral ingredients of digital environments, and they can trick human cognition into misperceiving the fake as real. Here, we test the neurocognitive sensitivity of 25 participants to accept or reject person identities as recreated in audio deepfakes. We generate high-quality voice identity clones from natural speakers by using advanced deepfake technologies. During an identity matching task, participants show intermediate performance with deepfake voices, indicating levels of deception and resistance to deepfake identity spoofing. On the brain level, univariate and multivariate analyses consistently reveal a central cortico-striatal network that decoded the vocal acoustic pattern and deepfake-level (auditory cortex), as well as natural speaker identities (nucleus accumbens), which are valued for their social relevance. This network is embedded in a broader neural identity and object recognition network. Humans can thus be partly tricked by deepfakes, but the neurocognitive mechanisms identified during deepfake processing open windows for strengthening human resilience to fake information.
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  • 文章类型: Journal Article
    即使是在发育关键时期的短暂听力损失也会导致时间和频谱感知的长期缺陷。这些感知缺陷与人类的语音感知相关。在沙鼠中,这些听力损失引起的知觉缺陷与听觉皮层中离子型GABAA和代谢型GABAB受体介导的突触抑制的减少有关,但是大多数关于关键时期可塑性的研究都集中在GABAA受体上。因此,我们开发了病毒载体来表达会上调沙鼠突触后抑制性受体亚基(GABAA,Gabra1;GABAB,Gabbr1b)在锥体神经元中,和在表达小白蛋白的中间神经元中突触前介导GABA合成(GAD65)的酶。在听觉临界期期间,发展性听力损失的短暂时期显着损害了两个听觉任务的感知性能:幅度调制深度检测和频谱调制深度检测。然后,我们测试了每个向量恢复这些听觉任务的感知性能的能力。虽然两种GABA受体载体都增加了皮质抑制性突触后电位的幅度,只有病毒表达突触后GABAB受体将感知阈值提高到对照水平.同样,突触前GAD65表达改善了光谱调制检测的感知性能。这些发现表明,恢复听觉感知任务的表现取决于听觉皮层小清蛋白到锥体突触的GABAB受体依赖性传递,并指出了发育感觉障碍的潜在治疗目标。
    Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.
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