Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study

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.

Keywords: computational model; dopamine DA; nonlinear dynamics; prefrontal cortical circuit; selective dopamine and serotonin receptor agonist and antagonist; serotonin 5-HT.

Figure 1

Concentration dependent modulation factor of DA and 5-HT. Black (red) line: gain modulation factor due to D1 (D2) receptors as a function of DA concentration (A); modulation factor due to 5-HT1A (5-HT2A) receptors as a function of 5-HT concentration (B).

Figure 2

Examples of synaptic current modulations. (A) Modulation factor of GABA mediated current from an inhibitory interneuron to a pyramidal cell, both expressing D1 and 5-HT2A receptors. (B) Modulation factor of an NMDA- or AMPA-mediated synaptic current by a presynaptic inhibitory neuron expressing D1 and 5-HT1A receptors and a postsynaptic pyramidal cell expressing D1 and 5-HT2A receptors.

Figure 3

Non-monotonic modulation of serotonin on the firing rate of a 5-HT1A and 5-HT2A coexpressing pyramidal cell given a fixed synaptic input, I_syn. Colors denote different constant I_syn values: 0.5, 0.55, 0.6 and 0.65 nA.

Figure 4

Modulation of DA and 5-HT on a network consisting of Pyr1-type (D1+5-HT1A) and Int1 (D1+5-HT1A) neurons. (A) Firing rate time course of pyramidal cells with [DA] = 7 nM and [5-HT] = 0.3 nM (dotted) or 2 nM (solid). (B) Oscillation frequency decreases with increasing [DA]. [5-HT] = 0.3 nM (dotted) and 2 nM (solid).

Figure 5

Modulation of [DA] and [5-HT] on excitatory-inhibitory neuronal networks. Pyr1 (D1+5-HT1A) neurons paired with: (A) Int1 (D1+5-1HT1A), (B) Int2 (D1+5-HT2A), (C) Int3 (D2+5-HT1A), (D) Int4 (D2+5-HT2A) neurons. Left: Stability or bifurcation diagrams with respect to [DA] given [5-HT] = 0.3 nM (dotted) or 2, 1, 2,and 2.95 nM 1(solid) for (A–D), respectively. Black (red) lines: stable (unstable) steady states; top/bottom green: maximum/minimum firing rates during oscillation. Right: Phase diagrams with respect to [DA] and [5-HT]. OSC: oscillatory behavior; SFP: only one stable asynchronous steady state (or fixed point). Inset: oscillation frequency vs [DA] with fixed [5-HT] values (in left).

Figure 6

Modulation of [DA] and [5-HT] on excitatory-inhibitory neuronal networks. Pyr3 (D1+5-HT1A+5-HT2A) neurons paired with: (A) Int1 (D1+5-1HT1A), (B) Int2 (D1+5-HT2A), (C) Int3 (D2+5-HT1A), (D) Int4 (D2+5-HT2A) neurons. Left: Stability or bifurcation diagrams with respect to [DA] given [5-HT] = 0.3 nM (dotted) or 2 nM (solid). Right: phase diagrams. Label as in Figure 5.

Figure 7

Dependence of the heterogeneous network behavior on [DA]. Oscillation of the network emerges from a Hopf bifurcation at [DA] = 3.21 nM. (A–C) The amplitude of the oscillation increases with increasing [DA] before the activation of D2 receptors reduce (A,C) or suppress it (B). (D) The frequency of the oscillation decreases with increasing [DA] due to the D1 receptors before it increases slightly again upon activation of D2 receptors. [DA]₁ = 4 nM, [DA]₂ = 8 nM, [5-HT]₁ = 1 nM, [5-HT]₂ = 2 nM, and [5-HT] = 0.3 nM.

Figure 8

Dependence of the heterogeneous network behavior on [5-HT]. The network oscillates only for low [5-HT] (<1.08 nM) or high [5-HT] (>2.22 nM). (A) Activity of pyramidal cells expressing 5-HT1A is almost totally suppressed by the activation of 5-HT1A when [5-HT] exceeds [5-HT]₁ (note: log scale). (B) Activity of pyramidal cells expressing D1, 5-HT1A, and 5-HT2A receptors. (C) Activity of interneurons expressing D1 and 5-HT2A receptors. (D) Dependence of the oscillation frequency on [5-HT]. Insets: firing rates of Pyr 3 and Int 2 given [5-HT] = 0.5 nM and 2.5 nM. [DA]₁ = 4 nM, [DA]₂ = 8 nM, [5-HT]₁ = 1 nM, [5-HT]₂ = 2 nM, and [DA]= 5 nM.

Figure 9

Heterogeneous network behavior with respect to [DA] and [5-HT]. Black region: Only asynchronous tonic stable firing states. Above the regions, oscillations can occur. Color bar denotes the oscillation frequencies (from 15 to 36 Hz) which depend on the combination of [5-HT] and [DA] levels. For [DA] > 10.946 nM, there exists an optimal [5-HT] value where the network can attain the maximum frequency oscillation.

Figure 10

D1 selective agonist/antagonist on the heterogeneous network. Increasing [DA]₁ will decrease the amplitude of oscillation but increase the frequency of oscillation. (A) Dependence of firing rate of pyramidal cell (D1+5-HT1A) on [DA]₁. The amplitude of the oscillation, the difference between the green lines, decreases with increasing [DA]₁. (B) Dependence of firing rate of pyramidal cell (D2+5-HT1A) on [DA]₁. (C) The firing rate of interneurons (D1+5-HT1A) depends on [DA]₁. (D) Frequency of oscillation increases with the increase of [DA]₁ before the agonist/antagonist shuts off the oscillation. Insets: firing rates of two types of pyramidal cells over time with [DA]₁ = 1 nM (left), and [DA]₁=3 nM (right).

Figure 11

D2 selective agonist/antagonist affects the oscillation amplitudes of D2-expressing neurons. [DA]₂ increases from 4 to 9 nM slightly decrease the frequency of oscillation. (A) Firing rate of pyramidal cell expressing D1 and 5-HT1A receptors. (B) Firing rate of pyramidal cells expressing D2 and 5-HT1A receptors. (C) Firing rate of interneuron expressing D1 and 5-HT2A receptors. (D) Firing rate of interneurons expressing D2 and 5-HT1A receptors.

Figure 12

5-HT1A selective agonist/antagonist effects on the network behavior. The oscillation merges through Hopf bifurcation at [5-HT]₁ = 0.516 nM. The amplitude increases with increasing [5-HT]₁ and reaches a plateau after almost all of 5-HT1A receptor are blocked. Firing rate of pyramidal cell (D1+5-HT1A) (A), pyramidal cell (D2+5-HT1A) (B), and interneuron (D1+5-HT1A) (C). (D) Oscillation frequency decreases with increasing [5-HT]₁ and approaches a stable value. Insets: firing rate timecourse of pyramidal cell (D1+5-HT1A) and interneuron (D2+5-HT2A) with [5-HT]₁ = 0.6 nM (left) and [5-HT]₁ = 1.1 nM (right).

Figure 13

5-HT2A selective agonist/antagonist on the network behavior. Increasing [5-HT]₂ from 0.5 to 2.0 nM, the amplitude of the firing rate oscillation decreases, but the frequency of the oscillation slightly increases. Firing rate of pyramidal cell (D1+5-HT1A) (A), pyramidal cell (D2+5-HT1A) (B), interneuron (D1+5-HT2A) (C), and interneuron (D2+5-HT1A) (D).