Long- and short-range connectivity and neuronal types affect prefrontal dorsal raphe circuit dynamics differently

The prefrontal cortex (PFC) plays a major role in high-level cognitive functions, which can be modulated through long-range innervation by serotonin (5-HT) neurons from the dorsal raphe nucleus (DRN). Reciprocally, the PFC, particularly the medial PFC (mPFC), sends long-range inputs to DRN, controlling 5-HT activity and regulating emotion. Additionally, there exists different PFC and DRN neuronal types, constituting their local micro-circuitries. Hence, it is unclear how the PFC-DRN’s long- and short-range connections and neuronal types contribute to its collective network dynamics. To systematically address this, we developed the first biologically realistic spiking neuronal circuit model of a closed-loop PFC-DRN system, while focusing on layer-V prelimbic (PL) cortex, a subregion of the mPFC. Our model demonstrates that baseline PL-DRN neural activities, including multiple network frequency bands, can co-exist. Brief excitation of DRN 5-HT and GABAergic neurons affect PL neuronal types differently, while stimulation of PFC pyramidal, but not PFC GABAergic, neurons transiently activates DRN 5-HT and GABAergic neurons. Stronger long-range PL-to-5-HT or local short-range DRN 5-HT-to-GABAergic connections, enhances higher DRN frequency oscillations, primarily mediated by DRN GABAergic neurons. Overall, our computational modelling work lays the foundation towards developing more realistic closed-loop neuronal circuits for systematic understanding of chemical neuromodulation.