Cholinergic Gain Control and the Short-term Dynamics of Cortical Synapses

大脑中的神经细胞(神经元)形成一个网络，处理来自感觉器官的输入，创造外部世界的内部表征。通过网络的信息流取决于行为状态：例如，当动物醒着时，感觉输入的处理会增强，而在睡眠时则会受到抑制。每个神经元与它的邻居形成数以千计的连接(突触)，当大脑在行为状态之间切换时，连接的强度必须有协调的变化。这是如何发生的，目前还不完全清楚。这项拟议的研究考察了乙酰胆碱(ACh)的作用，乙酰胆碱是一种渗透到大脑中的自然物质，似乎可以促进清醒和警觉。已知ACh会影响突触强度以及神经元的其他特性。我们的目标是了解ACh在细胞水平上的影响如何转化为清醒时感觉输入的增强处理。特别是，这项工作将解决依赖ACh的突触变化如何与短期突触动力学(连接强度的快速、可逆变化，取决于每个神经元最近的活动)相互作用以影响感觉处理的问题。实验方法将涉及基于从活的脑组织获得的药理学数据的计算机模拟。首先，将从啮齿动物的脑组织中连接成对的神经元进行电子录音。然后，该组织将暴露在ACh中，以测试其对突触强度和动力学的影响。一台计算机将被编程模拟一个包含不同类型相互连接的神经元的网络，从实验结果得出突触连接强度和动力学。模拟的感官输入将被输入计算机，以测试它在通过网络传播时是如何转换的(例如，放大或退化)。通过改变模型的参数(模拟的连接强度和动力学)，将有可能检验ACh作为控制网络中感觉放大(增益)的全局开关的假设。这将是第一个将不同细胞类型与现实的短期动态结合在一起的ACH行动模型，这些因素对真实大脑中的感觉信息处理至关重要。首席调查员与高中生、本科生和研究生一起工作，既是项目导师，也是临时的。他与纽约大学教学部门合作，向当地学校的教师介绍了他正在进行的研究，这些学校的学生主要来自弱势少数群体，研究机会非常有限。拟议的研究包括一些组成部分，将作为后一类学生和/或教师的独立项目，或西门子科学竞赛的高中生、纽约大学本科生和夏季本科生研究计划的参与者，该计划优先考虑女性和代表性不足的少数族裔。首席调查员还参加了纽约大学教育学院开设的课程，该课程向当地大学预科教师通报当前的研究情况。

Nerve cells (neurons) in the brain form a network that processes input from the sense organs, creating an internal representation of the outside world. The flow of information through the network depends on behavioral state: for example, processing of sensory input is enhanced when an animal is awake, and suppressed during sleep. Each neuron forms thousands of connections (synapses) with its neighbors, and when the brain switches between behavioral states there must be coordinated changes in the strength of the connections. How this happens is not fully understood. The proposed study examines the role of acetylcholine (ACh), a natural substance that permeates the brain and seems to promote wakefulness and alertness. ACh is known to affect synapse strength as well as other properties of neurons. The goal is to understand how the effects of ACh at the cellular level translate into enhanced processing of sensory input during wakefulness. In particular, the work will address the question of how ACh-dependent synaptic changes interact with short-term synaptic dynamics (rapid, reversible changes in connection strength that depend on the recent activity of each neuron) to influence sensory processing.The experimental approach will involve computer simulations based on pharmacological data obtained from living brain tissue. First, electrical recordings will be made from pairs of connected neurons in brain tissue from rodents. The tissue will then be exposed to ACh in order to test its effect on synaptic strength and dynamics. A computer will be programmed to simulate a network containing different types of interconnected neurons, with synaptic connection strengths and dynamics derived from the experimental results. Simulated sensory input will be fed into the computer, to test how it is transformed (for instance, amplified or degraded) as it is propagated through the network. By changing the parameters (simulated connection strengths and dynamics) of the model, it will be possible to test the hypothesis that ACh acts as a global switch controlling sensory amplification (gain) in the network. This will be the first model of ACh action that incorporates different cell types with realistic short-term dynamics, factors that are critical for sensory information processing in real brains. The principal investigator has worked with high school, undergraduate, and graduate students, both as a project mentor and on an ad-hoc basis. In conjunction with the NYU Department of Teaching and Learning, he has presented his ongoing research to teachers from local schools whose students are predominantly from disadvantaged minority groups, with very limited research opportunities. The proposed research includes components that will serve as stand-alone projects for students and/or teachers from the latter group, or for high school students in the Siemens science competition, NYU undergraduates, and participants in the Summer Undergraduate Research Program, which gives priority to women and under-represented minorities. The principal investigator also participates in the course run by the NYU School of Education, which informs local pre-college teachers about current research.