CRCNS: A mechanistic theory of serotonergic modulation of cortical processing

5-羟色胺能神经调节是调节大脑功能的几个方面的关键因素，从 情绪障碍导致食欲、奖励和动机，以及维持感官知觉的平衡。 然而，它调节大脑动态的网络机制仍然难以捉摸。在这个项目中， 我们将开发并实验测试一种机械理论来解释观察到的 5-羟色胺能通过致幻激动剂激活所诱导的皮质活动。现有证据 描绘了一幅明显矛盾的图景，其中一种致幻的HT2AR激动剂增加了锥体 细胞的兴奋性和谷氨酸水平，同时导致视觉功能下降 唤起的反应。我们的中心假设是，5-羟色胺能激活的这些令人费解的效应 由于在视觉皮层(V1)回路中诱导的增益调制。建议的机制是 违反直觉，因为它通过增加锥体细胞的方式导致诱发反应减少 兴奋性，由于皮层回路中强烈的反复动力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，以及全脑连接的变化。通过 扩展大脑皮层状态的曲目，它可能解释由 5-羟色胺能激活。我们将展示这一机械论如何调和 文献，我们将设计和执行新的实验来测试模型预测的行为 动物。总之，这个项目提供了细胞水平的神经调节和影响之间的联系 网络动态，并最终影响到感官感知。

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.