Electroconvulsive stimulation results in long-term survival of newly generated hippocampal neurons in rats

Abstract

Electroconvulsive stimulation (ECS) is one of the strongest stimulators of hippocampal neurogenesis in rodents that represents a plausible mechanism for the efficacy of electroconvulsive therapy (ECT) in major depressive disorder. Using design-based stereological cell counting, we recently documented an initial 2.6-fold increase in neurogenesis following a clinical relevant schedule of ECS, a treatment also rescuing depression-like behavior in rats. However, these results gave no demonstration of the longevity of newly generated neurons. The present study is a direct continuation of the previous work aiming to test the hypothesis that rats subjected to ECS in combination with chronic restraint stress (CRS) display increased formation of new hippocampal neurons, which have a potential for long-term survival. Furthermore, using mediation analysis, we tested if an ECS-induced increase in neurogenesis facilitates the behavioral outcome of the forced swim test (FST), an animal model of depression. The results showed that ECS in conjunction with CRS stimulates hippocampal neurogenesis, and that a significant quantity of the newly formed hippocampal neurons survives up to 12 months. The new BrdU-positive neurons showed time-dependent attrition of ∼40% from day 1 to 3 months, with no further decline between 3 and 12 months. ECS did not affect the number of pre-existing dentate granule neurons or the volume of the dentate granule cell layer, suggesting no damaging effect of the treatment. Finally, we found that, while ECS increases neurogenesis, this formation of new neurons was not associated to ameliorated immobility in the FST. This implies that other ECS-induced effects than neurogenesis must be part of mediating the antidepressant action of ECS. Taken together, the results of the present study contribute to the basic understanding of the neurogenic effects of ECT, and demonstrate that ECS, neurogenesis and anti-depressant behavior are not directly linked. © 2016 Wiley Periodicals, Inc.

Electroconvulsive treatment prevents chronic restraint stress‐induced atrophy of the hippocampal formation—A stereological study

“…Finally, ECS and CRS + ECS have no effects on the total number of neurons and volume in the CA1, CA2/3 and hilus, or the volume of the entire hippocampus. In the context of our previous findings in the exact same animals (Olesen et al, , ), our compiled results show that CRS induces depression‐like behavior and hilar atrophy in rats, effects that are rescued following a clinical relevant schedule of ECS. Furthermore, CRS do not affect basal neurogenesis, the number of preexisting neurons in any hippocampal regions examined, or the volume of granule cell layer, CA1, CA2/3, or the entire hippocampus.…”

“…The present study is a direct continuation of two previous stereological studies from our laboratory subjecting rats to three weeks of chronic restraint stress (CRS) and/or a clinical relevant schedule of ECS (Olesen et al, ). Data from these studies showed that CRS induces a depressive‐like phenotype blocked by ECS (CRS + ECS).…”

“…Supporting these findings in humans is the extensive literature in rodent models of depression-like behavior and antidepressant treatment. Accordingly, rodents treated with a range of antidepressant drugs or electroconvulsive stimulation (ECS, the animal model of ECT) show increased hippocampal volume, neurogenesis, angiogenesis, and synaptic differentiation (Chen, Madsen, Wegener, & Nyengaard, 2009Hellsten et al, 2005;Kaae, Chen, Wegener, Madsen, & Nyengaard, 2012;Madsen et al, 2000;Olesen, Wörtwein, Folke, & Pakkenberg, 2017;Olesen, Wortwein, & Pakkenberg, 2015;Santarelli et al, 2003). The molecular mechanisms underlying the beneficial effects of antidepressant medication or ECT/ECS are thought to involve alterations in neurotransmitter systems, growth factors, and neurotropic factors (Lee & Son, 2009;Malberg, Eisch, Nestler, & Duman, 2000;Samuels & Hen, 2011;Segi-Nishida, 2011).…”

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus

“…A recent study by Olesen and colleagues also suggested that ECS promotes long‐term survival of newly generated hippocampal neurons in rats (Olesen et al . ). However, in their study, BrdU was administered multiple times during ECS, so it could not be precisely distinguished whether the increase in BrdU(+) cells in the DG was because of the increase in proliferation or survival.…”

Repetitive enhancement of serum BDNF subsequent to continuation ECT

“…Preclinical studies involving rodents have sought to exploit the neuroplastic processes associated with ECS for antidepressant treatment. Such studies have demonstrated that ECS increases BDNF levels in the hippocampus and prefrontal cortex in rodents and induces hippocampal neurogenesis, enduring for up to 12 months . Treatment regimens that differ in frequency have been investigated to disentangle the impacts of these parameters on hippocampal neurogenesis.…”