Furber, Steve

Joshi, Alok

Rhodes, Oliver

Sharp, Trevor

Wong-Lin, KongFatt

English

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. <br/

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Long- and short-range connectivity and neuronal types affect prefrontal dorsal raphe circuit dynamics differentlyAlok JoshiIntelligent Systems Research CentreUlster UniversityUKPrefrontal cortexCredit- UCD Neuropsychology labPrefrontal cortex (PFC) plays a key role in high-level cognitivefunctions such as attention, memory, decision-making, andmood regulation.Prefrontal cortexCredit- UCD Neuropsychology labPrefrontal cortex (PFC) plays a key role in high-level cognitivefunctions such as attention, memory, decision-making, andmood regulation.Medial prefrontal cortex (mPFC): Brodmann areas 12, 24, 25, 32, 33Dorsal raphe nucleus (DRN)▪ PFC receives dense serotonergic (5-HT) innervation from DRN.▪ DRN is located in the midbrain and pons.PFC-DRN interaction (closed loop)(Celada, Puig and Artigas 2013)Medial prefrontal cortex- Prelimbic cortex (PL)Bicks et al., 2015Research Questions▪ What is the collective dynamics of PFC-DRN interaction? With the focus on PL-DRN system?▪ How the long- and short-range connections in PL-DRN contribute to its collective dynamics? ▪ What is the role of PL and DRN neuronal types? PL-DRN interactionPL-DRN interactionL-V# of Py neurons ~ 6300# of FS1/FS2 neurons ~389# of nFS neurons ~81DRN# of 5-HT neurons ~ 13250# of GABA neurons ~ 6625SpiNNaker(University of Manchester)Computational model𝑑𝑉𝑑𝑡= 0.04𝑉2 + 5𝑉 + 140 − 𝑈 + 𝐼𝐷𝐶,𝑖 + 𝐼𝐵𝑎𝑐𝑘𝑔𝑟𝑜𝑢𝑛𝑑,𝑖 + 𝐼𝑆𝑦𝑛,𝑖𝑑𝑈𝑑𝑡= a b𝑉 − 𝑈 If 𝑉 ≥ 𝑉𝑃𝑒𝑎𝑘, then 𝑉 = 𝑐 and U = 𝑈 + 𝑑𝐼𝑆𝑦𝑛 = 𝑤𝑓 𝑒ൗ−𝑡 1 − 𝑒 ൗ−𝑡2 , w is synaptic weight, f is scaling factor1, 2 are time constants estimated from experiments for different synapsesSingle neuron model: Izhikevich type model:Synaptic current:Baseline PL-DRN neural activities with multiple network frequency bands can co-exist. Baseline PL-DRN neural activities with multiple network frequency bands can co-exist. Multiple network frequency bands co-exist for distinct neuronal populationsStimulation of PL pyramidal neurons transiently activatesDRN 5-HT and GABAergic neuronsStimulation of PL interneurons have negligible impact on DRN5-HT and GABAergic neuronsStimulation of PL interneurons have negligible impact on DRN5-HT and GABAergic neuronsStimulation of PL interneurons have negligible impact on DRN5-HT and GABAergic neurons5-HT stimulation activates 5-HT neurons and inhibits Py neuronsGABAergic stimulation is stronger than 5-HT and inhibits significant Py and 5-HT neuronsStronger long-range PL-to-5-HT or local short-range 5-HT-to-GABA connections, enhances higher DRN frequency oscillationsConclusion▪ Developed the first closed-loop model of the PFC-DRN, focusing on PL.▪ Model supports co-existence of baseline firing activities and multiple networkfrequency bands observed in various separate experimental studies.▪ Stimulation of PL pyramidal, but not PL GABAergic, neurons transiently activatesDRN 5-HT and GABAergic neurons.▪ Stronger long-range PL-to-5-HT or local short-range 5-HT-to-GABA connections,enhances higher DRN frequency oscillations, primarily mediated by DRNGABAergic neurons.▪ Computational model lays the foundation towards developing more realisticclosed-loop neuronal circuits for systematic understanding of chemicalneuromodulation and its links to cognition and brain disorders.AcknowledgementsUniversity of Manchester▪ Oliver Rhodes▪ Steve Furber▪ Andrew Rowley▪ Michael Hopkins▪ Alan StokesUlster University▪ KongFatt Wong-LinUniversity of Oxford▪ Trevor Sharp

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

https://pure.ulster.ac.uk/ws/files/78841787/Presentation_Neuromatch.pdf

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

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