CRCNS: A mechanistic theory of serotonergic modulation of cortical processing

血清素神经调节是调节大脑功能多个方面的关键因素，从 情绪障碍会影响食欲、奖励和动机，以及维持感官知觉的平衡。 然而，它调节大脑动力学的网络机制尚不清楚。在这个项目中， 我们将开发并实验测试一种机械理论，解释观察到的调制 通过致幻剂激动剂的血清素激活诱导的皮质活动。现有证据 描绘了一幅明显矛盾的画面，其中致幻性 HT2AR 激动剂增加了锥体 细胞的兴奋性和谷氨酸水平，同时导致视力下降 诱发反应。我们的中心假设是，血清素激活的这些令人费解的作用是 由于视觉皮层 (V1) 电路中引起的增益调制。提议的机制是 违反直觉，因为它通过增加锥体细胞导致诱发反应减少 兴奋性，由于皮质回路中强烈的循环动态产生的违反直觉的效应；它 还会导致网络活动的变异性增加以及全脑连接性的变化。由 扩大皮质状态的范围，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能够调和 文献，我们将设计并进行新的实验来测试模型的行为预测 动物。总之，该项目提供了细胞水平神经调节和影响之间的联系 网络动态以及最终的感官知觉。

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.