5-HT (5-hydroxytryptamine, serotonin) powerfully influences cognition and mood regulation. In the medial prefrontal cortex (mPFC), the intricate balance between excitation and inhibition in celluar microcircuits allow the generation of network oscillations that encode behaviour and cognition. In particular, parvalbumin expressing interneurons (PVINs) act as key regulators of the excitatory/inhibitory balance. The precise interactions between the 5-HT system and these PVINs, however, are little understood. Using an array of modern neuroscience tools, this thesis provides a comprehensive report of interactions between the 5-HT system and different neuron subtypes in the mPFC, including PVINs.
In slice electrophysiology experiments, local application of 5-HT greatly increased the intrinsic excitability of genetically labelled PVINs in the mPFC via the 5-HT2A receptor. Such 5-HT2A receptor-mediated activation of PVINs was then demonstrated in in vivo silicon probe multi-unit recordings following the systemic
administration of the 5-HT2A receptor agonists DOI and psilocin. Pharmacological activation of the 5-HT2A receptor suppressed slow wave oscillations and elevated multi-unit activity in the mPFC, possibly via the excitation of putative PVINs and the disruption of their correlated activity with neighbouring neurons.
With an optogenetic approach, the effects of physiologically evoked 5-HT on neural activity in the mPFC were determined. This methodology was first verified with immunohistochemistry as well as in vitro and in vivo electrophysiology, which revealed diverse firing properties of optotagged 5-HT neurons. Specifically, optotagged regular-firing 5-HT neurons tended to fire action potentials following light stimuli up to 20 Hz, whereas optotagged irregular-firing 5-HT neurons were unlikely to sustain spiking at higher frequencies. Optogenetic activation of 5-HT
neurons induced frequency-dependent suppression of slow wave oscillations and increase in UP state duration. Changes in the firing rate of individual neurons, including PVINs, were mainly inhibitory, although excitatory effects and non responders were also observed. Notably, optogenetic activation of 5-HT neurons at high frequencies disrupted the spiking correlation between putative PVINs and other neurons, once again providing a potential mechanism for 5-HT modulation of excitatory-inhibitory balance and local oscillations in the mPFC.
Collectively, this thesis presents concrete evidence for 5-HT modulation of microcircuit activity, including PVINs, in the mPFC. These findings highlight the importance of elucidating the actions of 5-HT on a cellular level in gaining a better understanding of how 5-HT shapes cortical network output and, ultimately, cognition
