The role of 5-HT dynamics in cortical population activity throughout mammalian life

Thesis

Cortical serotonin (5-HT) plays critical roles in neurodevelopment and adult behaviour, with 5-HT alterations being associated with neurodevelopmental and neuropsychiatric disorders. Despite all the research conducted on 5-HT, we have identified three major gaps: firstly, a characterization, with high temporal and spatial resolution, of cortical 5-HT dynamics is missing; secondly, the effects of 5-HT in dictating cortical population activity in development and adulthood are not well understood; and thirdly how cortical 5-HT through its effects in cortical activity shapes behaviour is unclear. To address these gaps, we use two-photon imaging of calcium and 5-HT sensors in the barrel field cortex (S1BF) of developing and adult mice, upon genetic, pharmacological and optogenetic manipulation of 5-HT dynamics. Our results show that 5-HT fluctuates with sensation, saliency, reward, and novelty in the adult S1BF. While in the developing S1BF, we observe 5-HT buffering through transient SERT overexpression. Blocking this developmental 5-HT buffering system (SERT-KO or SSRI exposure) can result in early hypoactivity, alterations in interneuron subpopulations (i.e., VIP and Nkx2-1 interneurons) and subsequent hyperexcitability. In the adult cortex of wildtype mice, we observe that 5-HT inhibits bottom-up inputs in layer 4 of S1BF, while producing a mixture of excitation and inhibition in layer 2/3. Optogenetically increasing 5-HT in S1BF can decrease learning from misleading trials during an air puff discrimination task, illustrating that 5-HT gating of bottom-up inputs decreases learning. Pharmacologically decreasing cortical 5-HT with psilocin correlates with increases in learning rate during a reversal learning task. Finally, we capture all these results in a theoretical model using a gated deep neural network. Thus, this project identifies cortical 5-HT as a critical regulator of bottom-up and top-down activity, to control neuroplasticity throughout mammalian life, with consequences for translationally relevant contexts (i.e., developmental SSRI dosing and adult psychedelic exposure).

Authors: Ocaña Santero, G

• DOI: 10.5287/ora-8r2g4pkdb
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: neuroscience; neurodevelopment; serotonin
• Subjects: Neuroscience