Abstract
The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors.
Highlights
The prefrontal cortex (PFC) plays an essential role in many higher brain functions such as goal-directed behavior, action planning, learning, attention, mnemonic processes, inhibitory control, and task switching (Miller, 2000; Fuster, 2001; Miller and Cohen, 2001; Andrade, 2011b)
We have shown, from single neuron to neuronal circuits, how DA and 5-HT, with their multiple receptors and combinations, can tonically modulate the PFC neural activity, resulting in a variety of complex behaviors
Due to the different affinities and opposing effects of the 5-HT1A and 2A receptors, the neuronal firing activity of a PFC excitatory neuron coexpressing these two receptors can be inhibited before being enhanced as 5-HT concentration increases
Summary
The prefrontal cortex (PFC) plays an essential role in many higher brain functions such as goal-directed behavior, action planning, learning, attention, mnemonic processes, inhibitory control, and task switching (Miller, 2000; Fuster, 2001; Miller and Cohen, 2001; Andrade, 2011b). D1-like receptor is found to directly depress excitatory interaction between pyramidal cells, increase the excitability of fast-spiking interneurons, and enhance inhibitory (GABAergic) synaptic transmission (Zhou and Hablitz, 1999; Gao et al, 2001; Gulledge and Jaffe, 2001; Gonzalez-Burgos et al, 2002; Gorelova et al, 2002; Kroner et al, 2007) These can be attributed to D1-like receptors’ ability to trigger a variety of ionic channel activities, e.g., enhancement of sodium current, and attenuation of slowly-inactivating potassium currents and glutamate mediated synaptic currents (Yang and Seamans, 1996; Gao et al, 2001; Seamans et al, 2001a; GonzalezIslas and Hablitz, 2003; Tseng and O’Donnell, 2004).
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