Mechanisms of efferent synaptic modulation in vestibular peripheral sensation

 描述(申请人提供)：内耳的外周前庭系统由三个半规管、椭圆囊和球囊组成。它在将头部运动转化为大脑信号的过程中发挥着关键作用。前庭外周感觉由起源于脑干的传出输入调节。传出神经的激活已被证明会导致 前庭传入神经活动改变。然而，传出功能的确切性质仍然难以捉摸。大体而言，前庭感觉对于稳定凝视、控制姿势和平衡相关功能至关重要。前庭疾病在40岁及以上的成年人中发病率很高，会严重影响生活质量。双侧传入活动的不平衡是许多前庭功能障碍的基础。有趣的是，传出信息整合了来自中枢神经系统和前庭外周的信息，并向前庭周围器官提供双向反馈输入，因此是补偿传入活动不对称的理想选择。然而，在细胞水平上，这种功能的证据在很大程度上是缺乏的。在细胞/突触水平上更好地了解前庭外周的传出输入不仅将阐明传出功能的重要方面，而且有助于设计更好的前庭疾病的治疗方法。因此，我们建议研究外周传出调节的突触机制。在哺乳动物中，传出信号在包裹I型毛细胞(HCS)和II型毛细胞的花帽状传入末梢上形成突触，根据定义，II型毛细胞由bouton形状的传入末梢和bouton传入联系。我们已经建立了在切除的啮齿动物眉骨(半规管的感觉器官)中进行II型HCS和肾盏传入的全细胞记录的方法。我们将开发新的方法来研究不同类型的传出输入的特性，以及它们是如何整合来修改传入活动的。在目标1中，为了刺激切除的Crist组织中的传出纤维，我们建议开发和改进电刺激和光遗传刺激方法。初步数据表明，这两种方法各有优缺点。在目标2中，我们建议描述II型HCS和花环传入的传出突触反应。以往的研究和初步数据表明，II型HCS和花盏传入的传出反应由不同的机制介导，如不同的受体和递质释放模式。我们将确定不同传出行为背后的机制，以提供区分特定传出输入的方法。在目标3中，研究了当II型HIR细胞通过谷氨酸能信号进入传入活动时，传出对II型HC输入对传入活动的特殊贡献。综上所述，本研究的目的是在单个突触水平和外周整合回路水平上更好地了解前庭外周的传出功能。

 DESCRIPTION (provided by applicant): The peripheral vestibular system in the inner ear consists of three semicircular canals, utricle and saccule. It plays a key role in transforming head motions into signals to the brain. The vestibular peripheral sensation is modulated by efferent inputs originating in the brain stem. Activation of efferents has been shown to results in altered activity in vestibular afferents. However, the exact nature of the efferent function remain elusive. The vestibular sensation is critical for stabilizing gaze, controlling postural and balane related functions in general. Vestibular disorders, which have high prevalence among adults at age 40 and higher, can severely impact life quality. The bilateral imbalance of afferent activity underlies many vestibular disorders. Interestingly, efferents integrate information from the central nervous system as well as from the vestibular periphery and provide bilateral feedback inputs to the vestibular peripheral organs, hence are ideal for compensating for asymmetry in afferent activity. However, at the cellular level, evidence for such a function is largely missing.A better understanding of efferent inputs to the vestibular periphery at the cellular/synaptic level will not only elucidate important aspects of efferent function, but also help to design better treatments for vestibular disorders. We therefore propose to investigate synaptic mechanisms underlying peripheral efferent modulation. In mammals, the efferents form synapses on calyx-shaped afferent endings that ensheath type I hair cells (HCs), type II HCs, which are by definition contacted by bouton-shaped afferent endings and bouton afferents. We have established methods to perform whole-cell recordings from type II HCs and calyx-afferents in the excised rodent crista, the sensory organ of semicircular canals. We will develop novel methods to investigate properties of different types of efferent inputs and how they are integrated to modify afferent activity. In Aim 1, for stimulating efferent fibers in excised crist tissue, we propose to develop and refine electrical and optogenetic stimulation methods. Preliminary data show that both methods have advantages and disadvantages. In Aim 2, we propose to characterize efferent synaptic responses in type II HCs and calyx- afferents. Previous studies and preliminary data suggest that the efferent responses in type II HCs and calyx- afferents are mediated by distinct mechanisms, such as different receptors and transmitter release modes. We will identify the mechanisms underlying differential efferent actions, to provide means to distinguish specific efferent inputs. In Aim 3, the specific contribution of the efferent to type II HC input on afferent activity is investigated, as type II hir cells feed into afferent activity via glutamatergic signaling. In Summary, the proposed study aims to provide a better understanding of efferent function in the vestibular periphery, at the level of individual synapses as well as the level of peripheral integrating circuitry.