Examining the role of serotonin on functional connectivity and neural activation using functional ultrasound imaging

Depression is a widespread disorder that affects 5.7% of adults (World Health Organization, 2025), characterized by dysfunction in monoamine systems (Chávez-Castillo et al., 2019; Hasler, 2010), neurotrophic signaling (Martinowich and Lu, 2007; Yu and Chen, 2010; Duman and Monteggia, 2006), and neuroplasticity (Player et al., 2013). Recent studies demonstrate that antidepressants facilitate synaptic plasticity by directly binding to the transmembrane region of the TrkB receptor (Casarotto et al., 2021). It has also been found that psychedelics such as psilocybin enhance neuroplasticity through direct binding to the TrkB receptor (Moliner et al., 2023), highlighting a shared mechanism of positive allosteric modulation of TrkB among pharmacologically diverse agents that promote plasticity. Given the structural similarity of psilocybin and serotonin, an important question arises as to whether serotonin itself can act as a positive allosteric modulator of the TrkB receptor. This project demonstrates that serotonin modulates neuroplasticity in vivo and in vitro. Functional ultrasound imaging data suggests serotonin reopens juvenile-like windows of plasticity in the visual cortex by shifting ocular dominance index towards the negative direction. Additionally, functional connectivity in the visuomotor pathway is altered by serotonin and control suggesting serotonin can enhance experience-dependent plasticity but is not required for network reorganization to occur. In vitro analysis shows that serotonin can modify synaptic organization in the brain through alteration of plasticity associated proteins, like total TrkB, without direct enhancement of experience-dependent plasticity after monocular deprivation. Results demonstrate that serotonin can modify plasticity, but it is still unclear if it is a positive allosteric modulator of the TrkB receptor. In conclusion, while serotonin can induce neuroplastic changes in adult mice, it does not seem to have the same mechanism of action as known PAMs of the TrkB receptor such as psilocybin. Future studies can use competitive binding assays to investigate if direct binding to the TrkB receptor is necessary for the neuroplastic effects of serotonin.