Auditory Cortex Plasticity and Tinnitus

描述（由申请人提供）：耳鸣，幻象听觉的主观感知（例如，耳鸣），影响大约10-15%的普通人群。目前，还没有治愈的方法，也没有已知的药物可以抑制这种疾病。慢性耳鸣最常与噪声引起的听力损失有关。虽然耳鸣的潜在机制仍然难以捉摸，但已经确定听力损失改变了整个中枢听觉通路的兴奋和抑制平衡，最终导致皮质可塑性。在动物模型中观察到的皮质可塑性的实例包括在频率特异性耳蜗损伤之后的音调定位图的重组（即，模态内皮层可塑性），并且在由耳毒性引起的深度耳聋的情况下，听觉皮层中的神经元变得对躯体感觉刺激有反应（即，跨模态皮质可塑性）。有人提出耳鸣是听力损失后模内皮层可塑性的一个负面后果;然而，耳鸣的模内皮层可塑性理论尚未得到彻底研究，因为没有研究在同一动物中进行了皮层电生理记录和耳鸣的行为评估。此外，考虑到大约三分之二的患有耳鸣的人类患者可以通过对他们的头部和颈部的体感刺激来调节其音高和响度（称为“躯体耳鸣”），可以合理地预测，除了音调图重组之外，跨模态皮质可塑性可能参与了该疾病。因此，这项建议将调查，第一次，慢性耳鸣和听觉皮层可塑性（内和跨模态）之间的关系所造成的噪音引起的听力损失。为此，将使用电生理记录来评估成年大鼠在单耳暴露于高频噪声后45天的初级听觉皮层中的神经元对听觉和体感刺激的反应性。为了确定哪些噪声暴露大鼠发展慢性耳鸣，将使用具有间隙前脉冲抑制声惊吓范例的行为测试，并且将结果与电生理学发现相关联。据推测，只有一个子集的噪声暴露大鼠将显示内和跨模态皮质可塑性，这种变化与耳鸣的行为证据。此外，预测跨模态皮层可塑性将以响应于吻侧体表的体感刺激的神经元为特征（即，头部和颈部）。第二个系列的实验将确定，如果大脑皮层可塑性和耳鸣的行为证据可以抑制住房大鼠在一个月的听觉丰富的环境。这种康复的基本原理是基于最近对听力受损动物和人类的研究，这些研究表明，在与听力损失相关的特定频率下，慢性声刺激可以抵消模态内皮层可塑性。这种治疗方法（声音疗法）的有效性尚未使用具有耳鸣行为证据的动物进行评估。 公共卫生相关性：耳鸣，一种幻觉听觉的主观感觉（例如，耳鸣），影响大约10-15%的普通人群。使用动物模型，其中耳鸣和听力损失是由极大的噪音引起的，该建议将确定耳鸣是否是由单耳听力损失引起的听觉皮层的内模态和/或跨模态可塑性引起的，以及丰富的声学环境是否可以通过逆转噪音引起的皮层可塑性来抑制耳鸣。

DESCRIPTION (provided by applicant): Tinnitus, a subjective perception of a phantom auditory sensation (e.g., ringing in the ears), affects approximately 10-15% of the general population. At present, there is no cure, and there are no drugs known that suppress the disorder. Tinnitus, in its chronic form, is most often associated with noise-induced hearing loss. Although the underlying mechanism(s) of tinnitus remain elusive, it is well established that hearing loss alters the balance of excitation and inhibition throughout the central auditory pathway, ultimately leading to cortical plasticity. Examples of cortical plasticity observed in animal models include a reorganization of the tonotopic map following a frequency-specific cochlear lesion (i.e., intramodal cortical plasticity), and in the case of profound deafness caused by ototoxicity, neurons in the auditory cortex becoming responsive to somatosensory stimulation (i.e., crossmodal cortical plasticity). It has been proposed that tinnitus emerges as a negative consequence of intramodal cortical plasticity following hearing loss; however, the intramodal cortical plasticity theory of tinnitus has not been investigated thoroughly as no studies have performed both cortical electrophysiological recordings and a behavioral assessment of tinnitus in the same animals. Furthermore, given that approximately two-thirds of human patients suffering from tinnitus can modulate its pitch and loudness by somatosensory stimulation of their head and neck (termed "somatic tinnitus"), it is reasonable to predict that, in addition to tonotopic map reorganization, crossmodal cortical plasticity may be involved in the disorder. Thus, this proposal will investigate, for the first time, the relationship between chronic tinnitus and auditory cortex plasticity (intra- and crossmodal) caused by noise-induced hearing loss. To that end, electrophysiological recording will be used to assess the responsiveness of neurons in the primary auditory cortex of adult rats to auditory and somatosensory stimulation 45 days after monaural exposure to high- frequency noise. To determine which noise-exposed rats develop chronic tinnitus, behavioral testing with a gap pre-pulse inhibition acoustic startle paradigm will be used, and the results will be correlated with the electrophysiological findings. It is hypothesized that only a subset of noise-exposed rats will show both intra- and crossmodal cortical plasticity and that such changes correlate with behavioral evidence of tinnitus. Moreover, it is predicted that the crossmodal cortical plasticity will be characterized by neurons that respond to somatosensory stimulation of the rostral body surface (i.e., head and neck). A second series of experiments will determine if cortical plasticity and behavioral evidence of tinnitus can be suppressed by housing rats in an acoustically-enriched environment for one month. The rationale for this rehabilitation is based on recent studies on hearing-impaired animals and humans which suggest that intramodal cortical plasticity can be offset by chronic acoustic stimulation at the specific frequencies associated with the hearing loss. The efficacy of this treatment approach (sound therapy) has not been evaluated using animals with behavioral evidence of tinnitus. PUBLIC HEALTH RELEVANCE: Tinnitus, a subjective perception of a phantom auditory sensation (e.g., ringing in the ears), affects approximately 10-15% of the general population. Using an animal model in which tinnitus and hearing loss are induced by extremely loud noise, this proposal will determine if tinnitus results from intramodal and/or crossmodal plasticity in the auditory cortex induced by monaural hearing loss, and whether an enriched acoustic environment can suppress tinnitus by reversing the noise-induced cortical plasticity.