Three-Week Treadmill Exercise Enhances Persistent Inward Currents, Facilitates Dendritic Plasticity, and Upregulates the Excitability of Dorsal Raphe Serotonin Neurons in ePet-EYFP Mice

Abstract

Exercise plays a key role in preventing or treating mental or motor disorders caused by dysfunction of the serotonergic system. However, the electrophysiological and ionic channel mechanisms underlying these effects remain unclear. In this study, we investigated the effects of 3-week treadmill exercise on the electrophysiological and channel properties of dorsal raphe nucleus (DRN). Serotonin (5-HT) neurons in ePet-EYFP mice, using whole-cell patch clamp recording. Treadmill exercise was induced in ePet-EYFP mice of P21-24 for 3 weeks, and whole-cell patch clamp recording was performed on EYFP-positive 5-HT neurons from DRN slices of P42-45 mice. Experiment data showed that 5-HT neurons in the DRN were a heterogeneous population with multiple firing patterns (single firing, phasic firing, and tonic firing). Persistent inward currents (PICs) with multiple patterns were expressed in 5-HT neurons and composed of Cav1.3 (Ca-PIC) and sodium (Na-PIC) components. Exercise hyperpolarized the voltage threshold for action potential (AP) by 3.1 ± 1.0 mV (control: n = 14, exercise: n = 18, p = 0.005) and increased the AP amplitude by 6.7 ± 3.0 mV (p = 0.031) and firing frequency by more than 22% especially within a range of current stimulation stronger than 70 pA. A 3-week treadmill exercise was sufficient to hyperpolarize PIC onset by 2.6 ± 1.3 mV (control: −53.4 ± 4.7 mV, n = 28; exercise: −56.0 ± 4.7 mV, n = 25, p = 0.050) and increase the PIC amplitude by 28% (control: 193.6 ± 81.8 pA; exercise: 248.5 ± 105.4 pA, p = 0.038). Furthermore, exercise hyperpolarized Na-PIC onset by 3.8 ± 1.8 mV (control: n = 8, exercise: n = 9, p = 0.049) and increased the Ca-PIC amplitude by 23% (p = 0.013). The exercise-induced enhancement of the PIC amplitude was mainly

Serotonergic Modulation of Persistent Inward Currents in Serotonergic Neurons of Medulla in ePet-EYFP Mice

“…In medullar 5-HT neurons, however, PIC amplitude is 10–12 times the rheobase ( Figure 1F and Table 1 ). Similar results are also observed in 5-HT neurons of dorsal raphe nucleus in juvenile mice, where PIC amplitude is about nine times the rheobase ( Ge and Dai, 2020 ). Therefore, we speculate that these differences may be due to different types of neurons and functional roles in regulating neuronal excitabilities for different behaviors such as mental ( Meera et al, 2003 ; Kang et al, 2019 ) or physiological behaviors ( Fernandez-Fernandez et al, 2018 ; Hsu et al, 2018 ).…”

“…Study by Dai and Jordan reported that the TDR_PIC in spinal neurons activates between −20 and −30 mV, higher than Na_PIC and Ca_PIC ( Dai and Jordan, 2011 ). Although PICs in 5-HT neurons in brainstem have been studied recently in our studies ( Cheng et al, 2020 ; Ge and Dai, 2020 ), detail of PICs in 5-HT neurons of medulla, especially their modulatory properties by serotonin are still missing.…”

Pick me, Pick me! Rationale for investigating persistent inward currents (PICs) and associated exercise effects in the ageing neuromuscular system

“…further amplifying their effects) in humans or maintains their function in ageing (see Fig. 1) of serotonergic neurones in dorsal raphe nucleus increased by ∼23-28% following 3 weeks of treadmill training (30 min per day) in young mice (Ge & Dai 2020). However, it is not known if similar effects occur in MNs.…”

“…1). A possible rationale for the investigation of exercise‐related PIC adaptations in humans stems from short‐term animal models where PICs of serotonergic neurones in dorsal raphe nucleus increased by ∼23–28% following 3 weeks of treadmill training (30 min per day) in young mice (Ge & Dai 2020). However, it is not known if similar effects occur in MNs.…”

“…endurance training). Evidence of chronic exercise on monoaminergic centres and PICs in humans is currently lacking, but further research is strongly recommended given their importance to muscle contraction, and initial indication of PIC adaptive potential with short‐term exercise (see Ge & Dai 2020).…”