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: 7813813
• 负责人: Carson A Goddard
• 金额: $ 5.22万
• 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/7813813
• 关键词: Acetylcholine; Acute; Address; Affect; Alzheimer' s Disease; Architecture; Attention; Behavioral; Birds; Brain; Cell Nucleus; Cells; Cognitive; Development; Goals; Impairment; Injection of therapeutic agent; Learning; 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）对于大脑回路的注意力调节至关重要。但问题仍然存在：ACh 增加神经元放电以响应刺激的细胞机制是什么？乙酰胆碱的应用已被证明会矛盾地影响神经元的兴奋性和抑制性输入。尚未证明这些矛盾效应在影响神经元放电方面是拮抗还是协同。与空间注意力相关并受胆碱能调节影响的神经回路是视顶盖（在哺乳动物中称为上丘）。在鸟类中，峡部致密部核 (Ipc) 提供与视顶盖的点对点胆碱能连接，并被认为可以调节顶盖神经元的增益。该提案的重点是评估视顶盖主要输出神经元（第 13 层深顶盖神经元 (DTN)）中 ACh 放电的功能。我们将使用视顶盖的急性切片和全细胞膜片钳生理学来确定 ACh 对 DTN 中固有电流和突触电流的影响。然后我们将尝试将通道和突触功能的这些变化与神经元放电的变化联系起来。我们将重点通过压力注入应用 ACh 来表征 ACh 对 DTN 中固有电流的影响。我们还将描述外源应用的 ACh 对 DTN 突触电流的影响。然后我们将通过刺激 Ipc 来确定局部突触释放的 ACh 对顶盖的影响；在急性切片制备中，IPC 和顶盖的连接已被证明是完整的。这一系列研究的长期目标是揭示大脑选择性调节感觉处理回路的机制。相应地，乙酰胆碱对于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。了解乙酰胆碱介导注意力的结构和机制可能有助于深入了解这些形式的认知和神经功能障碍的新型治疗方法。