CELLULAR ANALYSIS OF THE VESTIBULOOCULAR REFLEX

这项研究的长期目标是了解细胞和分子机制是如何在神经元电路的背景下工作的，以调节前庭-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过程中的视觉模糊。神经元的可塑性机制使COR在面对发育、创伤和疾病时能够准确地发挥作用。尽管已确定的神经元类别对信号转换和可塑性的贡献已被阐明，但对支持VOR日常表现和适应能力的细胞机制知之甚少。这项拟议的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时的图像稳定性至关重要。特别是，这些研究旨在确定不同的细胞内钙来源在调节前庭内侧核(MVN)和舌下前置核(NPH)中特定类型神经元的放电特性中所起的作用。在活体脑干脑片细胞内记录的NPH和MVN神经元中，将研究棘波产生的动态特性(从神经元输入到动作电位的时变模式的转换)。具体的药理激动剂和电压敏感性钙通道拮抗剂，细胞内钙释放机制，以及NMDA和代谢性谷氨酸受体将被用来评估钙依赖机制如何调节自发放电频率和尖峰产生的增益和动力学。体外记录的神经元与体内自动和生理鉴定的细胞类别之间的对应关系将通过以下方式确定：用染料标记细胞内的神经元，从小脑小叶和外展核逆行标记的神经元进行记录，以及激活来自小脑和前庭神经的突触输入。这些研究将为前庭-眼反射可塑性的分子机制以及导致眼球震颤的眼球运动障碍的药物治疗提供有针对性的研究基础。

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.