CRCNS: A mechanistic theory of serotonergic modulation of cortical processing

血清素能神经调节是调节脑功能的几个方面的关键因素，从 情绪障碍对食欲、奖赏和动机的影响，以及对维持感官知觉平衡的影响。 然而，它调节大脑动力学的网络机制是难以捉摸的。在这个项目中， 我们将开发和实验测试解释观察到的调制机制理论， 通过致幻激动剂由多巴胺能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HT 2AR激动剂增加了锥体细胞 同时，在视觉上， 诱发反应我们的中心假设是，这些令人困惑的β-肾上腺素能激活效应是 这是由于视觉皮层（V1）回路中诱导的增益调制。拟议的机制是 这是违反直觉的，因为它通过增加锥体细胞而导致诱发反应减少 兴奋性，由于皮层回路中强烈的循环动力学产生的反直觉效应;它 还导致网络活动的可变性增加，以及全脑连接的变化。通过 扩大了大脑皮层的状态，这可能解释了幻觉的发生， 肾上腺素能激活。我们将展示这种机械论如何能够调和 我们将设计和执行新的实验，以测试模型预测的行为， 动物该项目共同提供了细胞水平神经调节与影响之间的联系 网络动力学，最终，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.