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: 7579034
• 负责人: Carson A Goddard
• 金额: $ 5.01万
• 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/7579034
• 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(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通过什么细胞机制增加神经元对刺激的反应？ACh的应用已被证明对神经元的兴奋性和抑制性输入产生矛盾的影响。目前还没有证明这些矛盾的影响在影响神经元放电方面是拮抗的还是协同的。在胆碱能调节的影响下，与空间注意有关的神经回路是视顶盖(在哺乳动物中被称为上丘)。在鸟类中，峡部致密核(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获得。本研究的重点是评估ACh在视顶盖的主要输出神经元--顶盖13层深部神经元(DTN)中的放电功能。我们将利用视顶盖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。我们将通过压力注入的方式集中施加ACh，以表征ACh对DTN中本征电流的影响。我们还将研究外源性ACh对DTN突触电流的影响。然后，我们将通过刺激IPC来确定局部的、突触释放的ACh对顶盖的影响；在急性切片准备中，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地调节感觉处理电路的机制。相应地，ACh对于感觉回路的正常发展以及学习和记忆都是至关重要的。此外，阿尔茨海默氏症、帕金森氏症和其他形式的神经退行性疾病与胆碱能功能的改变有关。了解可能构成ACh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损伤提供新的治疗方法。