CELLULAR ANALYSIS OF THE VESTIBULOOCULAR REFLEX

本研究的长期目标是了解细胞和分子机制如何在神经元回路的背景下介导前庭眼反射（VOR）的正常表现和适应性可塑性。VOR通过产生精确补偿头部运动的眼球运动来防止自我运动期间的视力模糊。可塑性的神经元m3机制使COR能够在面对发育、创伤和疾病时准确地执行。虽然已经阐明了神经元对信号转换和可塑性的贡献，但对VOR日常表现和适应能力的细胞机制知之甚少。这项研究的目的是阐明内在的细胞机制如何控制脑干神经元的放电特性，这些特性对于确保头部运动过程中的图像稳定性至关重要。特别是，这些研究的目的是确定不同来源的细胞内钙离子在调节确定的类别的神经元在前庭内侧核（MVN）和前置核舌下核（NPH）的放电特性的作用。将在活体脑干切片细胞内记录的NPH和MVN神经元中检查尖峰生成的动态特性（从神经元输入到随时间变化的动作电位模式的转换）。电压敏感性钙通道、细胞内钙释放机制以及NMDA和代谢型谷氨酸受体的特定药理学激动剂和拮抗剂将用于评估自发放电率以及峰电位生成的增益和动力学如何受钙依赖性机制调节。体外记录的神经元与体内已自动和生理学鉴定的细胞类别之间的对应关系将通过用染料在细胞内标记神经元、靶向已从小脑小叶和外展神经核逆行标记的用于记录的神经元并激活来自小脑和前庭神经的突触输入来确定。这些研究将为前庭眼反射可塑性的分子机制的靶向研究以及引起眼球震颤的眼科疾病的药物治疗提供基础。

The long-range goal of this research is to understand how cellular and molecular mechanisms operate in the context of neuronal circuitry to mediate the normal performance and adaptive plasticity of the vestibulo- ocular reflex (VOR). The VOR prevents blurred vision during self-motion by producing eye movements that precisely compensate for motion of the head. Neuronal m3echanisms of plasticity enable the COR to perform accurately in the face of development, trauma, and disease. Although the contributions of identified classes of neurons to signal transformations and plasticity have been elucidated, little is understood about the cellular mechanisms that underlie the day-to-day performance and adaptive capabilities of the VOR. The objective of the proposed research is to elucidate how intrinsic cellular mechanisms control the firing properties of brainstem neurons that are critical for ensuring image stability during head movement. In particular, the studies aim to identify the role of distinct sources of intracellular calcium in regulating the firing properties of identified classes of neurons in the medial vestibular nucleus (MVN) and nucleus prepositus hypoglossi nuclei (NPH). The dynamic properties of spike generation (the transformation from neuronal inputs into time-varying patterns of action potentials) will be examined in NPH and MVN neurons recorded intracellularly in living brainstem slices. Specific pharmacological agonists and antagonists of voltage-sensitive calcium channels, intracellular calcium release mechanisms, and NMDA and metabotropic glutamate receptors will be used to assess how the spontaneous firing rate and the gain and dynamics of spike generation are regulated by calcium-dependent mechanisms. The correspondence between neurons recorded in vitro and cell classes that have been identified automatically and physiologically in vivo will be determined by labeling neurons intracellularly with dye, targeting neurons for recording that have been retrogradely labeled from the cerebellar flocculus and abducens nucleus, and activating synaptic inputs from the cerebellum and vestibular nerve. These studies will provide foundations for targeted investigations of the molecular mechanisms that underlie vestibulo-ocular reflex plasticity as well as for pharmacological treatments for oculomotor disorders that cause nystagmus.