CRCNS: A mechanistic theory of serotonergic modulation of cortical processing

CRCNS：皮质处理的血清素调节机制理论

• 批准号: 10396147
• 负责人: Luca Mazzucato
• 金额: $ 31.81万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396147
• 关键词: theories

Serotonergic neuromodulation is a crucial factor in regulating several aspects of brain function, from mood disorders to appetite, reward and motivation, and in maintaining balance of sensory perception. However, the network mechanisms by which it modulates brain dynamics are elusive. In this project, we will develop and experimentally test a mechanistic theory explaining the observed modulations of cortical activity induced by the serotonergic activation via hallucinogenic agonists. Existing evidence paints an apparently contradictory picture, where a hallucinogenic HT2AR agonist increases pyramidal cells’ excitability and glutamatergic levels while, at the same time, leading to a reduction in visually evoked responses. Our central hypothesis is that these puzzling effects of serotonergic activation are due to gain modulation induced in visual cortex (V1) circuits. The proposed mechanism is counterintuitive as it leads to decreased evoked responses by way of increasing pyramidal cell excitability, due to a counterintuitive effect produced by strong recurrent dynamics in cortical circuits; it also leads to increased variability of network activity, and changes in brain-wide connectivity. By expanding the repertoire of cortical states, it may explain the onset of hallucinations driven by serotonergic activation. We will show how this mechanistic theory can reconcile the tension in the literature and we will design and perform new experiments to test the model predictions in behaving animals. Together, this project provides a link between cellular-level neuromodulation and the impact on network dynamics and, ultimately, sensory perception.

血清素能神经调节是控制大脑功能的几个方面的关键因素， 情绪障碍对食欲，奖励和动力，并保持感官感知的平衡。 但是，调节大脑动力学的网络机制是弹性的。在这个项目中， 我们将开发和实验测试一种机械理论，解释了观察到的调制 血清素能激活通过致幻激动剂引起的皮质活性。现有证据 描绘了一幅明显矛盾的图片，其中致幻ht2ar激动剂增加了金字塔 细胞令人兴奋的谷氨酸能水平，同时导致视觉上的降低 诱发的回应。我们的核心假设是，这些血清素能激活的拼图效应是 由于在视觉皮层（V1）电路中引起的增益。提出的机制是 违反直觉，因为它通过增加锥体细胞而导致诱发反应减少 兴奋，由于皮质回路中强烈的复发动力学产生的违反直觉效应； 还导致网络活动的可变性增加，以及脑宽连通性的变化。经过 扩大皮质状态的曲目，它可以解释由 血清素能激活。我们将展示这种机械理论如何调和 文献，我们将设计和执行新的实验，以测试行为的模型预测 动物。该项目一起提供了细胞级神经调节与影响之间的联系 在网络动力学以及最终感官感知上。