Electroconvulsive Shock, but Not Transcranial Magnetic Stimulation, Transiently Elevates Cell Proliferation in the Adult Mouse Hippocampus

Abstract

Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic electroconvulsive shock (ECS) strongly promotes neurogenesis, less is known about its acute effects and little is known about the neurogenic effects of other forms of stimulation therapy, such as repetitive transcranial magnetic stimulation (rTMS). Here, we investigated the time course of acute ECS and rTMS effects on markers of cell proliferation and neurogenesis in the adult hippocampus. Mice were subjected to a single session of ECS, 10 Hz rTMS (10–rTMS), or intermittent theta burst stimulation (iTBS). Mice in both TMS groups were injected with BrdU 2 days before stimulation to label immature cells. One, 3, or 7 days later, hippocampi were collected and immunostained for BrdU + cells, actively proliferating PCNA + cells, and immature DCX + neurons. Following ECS, mice displayed a transient increase in cell proliferation at 3 days post-stimulation. At 7 days post–stimulation there was an elevation in the number of proliferating neuronal precursor cells (PCNA + DCX +), specifically in the ventral hippocampus. iTBS and rTMS did not alter the number of BrdU + cells, proliferating cells, or immature neurons at any of the post-stimulation time points. Our results suggest that neurostimulation treatments exert different effects on hippocampal neurogenesis, where ECS may have greater neurogenic potential than iTBS and 10–rTMS.

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fibre plasticity in male but not female mice

“…Future studies should examine neurons born during early development to determine whether the current results reflect accelerated neuronal maturation or general trophic effects of iTBS. Given the clinical relevance of other types of noninvasive stimulation, such as 10 Hz repetitive iTBS, slow gamma stimulation and ECS (Adaikkan & Tsai, 2019; Gaynes et al, 2014), it will be important to examine whether they also promote mossy fibre plasticity in a sex‐specific fashion (Zhang et al, 2021).…”

“…The stimulation was done in an open room, without a grounded faraday cage. The stimulation intensity was set to 115% motor threshold, and stimulation cycle was set according to prior experiments described in Zhang et al, 2021 (see also Figure 1). The magnetic pulse is biphasic with a pulse width of 280 μs and a field strength of 80kT/s.…”

“…Here, we performed the first investigation of the effects of repeated sessions of iTBS on neurogenesis rates, finding that iTBS did not alter immature neuronal numbers (DCX + cell density) or affect the survival of cells born 1 week prior to stimulation onset. Based on our recent study of acute iTBS effects (Zhang et al, 2021), however, it remains possible that repeated sessions of iTBS could alter the turnover of cells that were not captured by the timing of our BrdU injection. Since a theta-dependent associative-learning paradigm (Darling et al, 2011) is accompanied by increased survival of 1 week old cells (same age as the cells examined here) (Anderson et al, 2011), this suggests that there may be substantial neurogenic differences between natural theta oscillations and external iTBS stimulation.…”

“…In a previous study, we found that a single session of iTBS may decrease the survival of adult‐born neurons that were born just prior to stimulation (Zhang et al, 2021), potentially increasing hippocampal neuroplasticity by enhancing cell turnover (Sairanen et al, 2005). However, iTBS effects were minor and not statistically different from sham‐stimulated animals.…”

“…Since clinical treatment involves multiple sessions, this raises the question of whether chronic iTBS might have more potent neurogenic effects. Indeed, repeated sessions are necessary for rTMS and long‐term use of pharmacological antidepressants to increase hippocampal neurogenesis (Malberg et al, 2000; Santarelli et al, 2003; Ueyama et al, 2011; Zhang et al, 2021).…”