Cholinergic mechanisms regulating neuronal responsiveness in the optic tectum

调节视顶盖神经元反应性的胆碱能机制

• 批准号: 7407144
• 负责人: Carson A Goddard
• 金额: $ 4.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407144
• 关键词: Acetylcholine; Acute; Address; Affect; Alzheimer' s Disease; Architecture; Attention; Behavioral; Birds; Brain; Cell Nucleus; Cells; Cholinergic Agents; Cognitive; Depth; Development; Fire - disasters; Goals; Impairment; Injection of therapeutic agent; Learning; Localized; Mediating; Memory; Methods; Neurodegenerative Disorders; Neurologic; Neurons; Neurotransmitters; Output; Parkinson Disease; Physiology; Preparation; Research; Sensory; Sensory Process; Slice; Stimulus; Synapses; Tectum Mesencephali; Testing; attentional modulation; cholinergic; cholinergic neuron; insight; neural circuit; neurotransmission; novel therapeutics; pars compacta; patch clamp; pressure; response; superior colliculus Corpora quadrigemina; synaptic function; voltage/patch clamp

DESCRIPTION (provided by applicant): Acetylcholine (ACh) is crucial for the attentional modulation of brain circuits. But the question remains: What are the cellular mechanisms by which ACh increases neuronal firing in response to a stimulus? Application of ACh has been shown to paradoxically affect excitatory and inhibitory inputs onto a neuron. It has not been shown if these paradoxical effects are antagonistic or cooperative in affecting neuronal firing. A neural circuit involved with spatial attention and under the influence of cholinergic modulation is the optic tectum (called the superior colliculus in mammalian species). In avian species, the nucleus isthmi pars compacta (Ipc) provides point to point cholinergic connectivity with the optic tectum, and has been suggested to regulate the gain of tectal neurons. The focus of this proposal is to assess the function of ACh on firing in a major output neuron of the optic tectum, the layer 13 Deep Tectal Neuron (DTN). We will determine the effect of ACh on intrinsic and synaptic currents in DTNs using acute slices of the optic tectum and whole cell patch-clamp physiology. Then we will attempt to relate these changes in channel and synapse function to changes in neuronal firing. We will focally apply ACh by pressure injection to characterize the effect of ACh on intrinsic currents in DTNs. We will also characterize the effect of exogenously applied ACh on synaptic currents onto DTNs. Then we will determine the effect of localized, synaptically released ACh on the tectum by stimulating Ipc; connections Ipc and the tectum have been shown to be intact in the acute slice preparation. The long term goal of this line of research is to uncover the mechanisms by which the brain selectively modulates circuits in sensory processing. Correspondingly, ACh is crucial for proper development of sensory circuits and for learning and memory. Also, Alzheimer's disease, Parkinson's disease, and other forms of neurodegenerative disorders are associated with alterations in cholinergic function. Understanding the architecture and mechanisms that are likely to underlie ACh-mediated attention may provide insight into novel therapeutic treatments for these forms of cognitive and neurological impairments.

描述（由申请人提供）：乙酰胆碱（ACh）对大脑回路的注意力调节至关重要。但问题仍然存在：ACh增加神经元对刺激的反应的细胞机制是什么？ACh的应用已被证明矛盾地影响神经元的兴奋性和抑制性输入。尚未显示这些矛盾的效应在影响神经元放电中是拮抗的还是合作的。视顶盖（哺乳动物称为上级丘）是参与空间注意并受胆碱能调节影响的神经回路。在鸟类中，峡部核（Ipc）提供与视顶盖的点对点胆碱能连接，并被认为调节顶盖神经元的增益。该建议的重点是评估ACh在视顶盖的主要输出神经元，第13层深顶盖神经元（DTN）中的放电功能。我们将使用急性视顶盖切片和全细胞膜片钳生理学来确定ACh对DTNs内在电流和突触电流的影响。然后，我们将试图把这些通道和突触功能的变化与神经元放电的变化联系起来。我们将重点应用ACh的压力注入来表征ACh对DTN中本征电流的影响。我们还将表征外源性ACh对DTNs突触电流的影响。然后，我们将确定本地化的，突触释放乙酰胆碱顶盖刺激IPC的效果;连接IPC和顶盖已被证明是完整的急性切片制备。这项研究的长期目标是揭示大脑在感觉处理中选择性调节回路的机制。相应地，ACh对感觉回路的正常发育以及学习和记忆至关重要。此外，阿尔茨海默病、帕金森病和其他形式的神经退行性疾病与胆碱能功能的改变有关。了解乙酰胆碱介导的注意力的结构和机制可能为这些形式的认知和神经功能障碍提供新的治疗方法。