Behavioral and molecular responses to electroconvulsive shock differ between genetic and environmental rat models of depression
Introduction
Depression is responsible for a substantial proportion of worldwide disease burden, but clinical response to antidepressant treatments is still not satisfactory. Although pharmacotherapy has been the first-line treatment for depression, response to antidepressants varies between individuals (Keers and Uher, 2012), and more than half of patients fail to respond adequately to the first antidepressant they are prescribed (Trivedi et al., 2006). As a somatic treatment, electroconvulsive therapy (ECT) is known to be quicker and more effective than common antidepressants, but it is still not effective for up to 30% of patients with depression (Medda et al., 2009). Efficacy enhancements include exploring novel drugs and treatments, but there have been no significant advancements and robust response predictors to antidepressant treatments. ECT׳s mechanisms are complicated, and the cause of different individual responses to ECT for depression in terms of genes, environment, and their interaction are even more obscure.
Individual factors, especially depression׳s causes, play an essential role in different responses to antidepressant treatments (Uher, 2008, Keers and Aitchison, 2011, Klengel and Binder, 2013). Depression results from an interaction between genes and environments. The mainstream “diathesis-stress” hypothesis for depression׳s etiopathogenesis of depression shows that the genetic or environmental factors can lead to the occurrence and development of different depression subtypes. Previous studies indicated that those with “endogenous” depression (occurring in the absence of a prior stressor) and those with “reactive” depression (occurring in response to a stressor) responded totally differently to somatic treatments, antidepressants, or psychotherapies (Keers and Uher, 2012).
The “neurotrophic hypothesis” suggests that reduced neurotrophins, including brain-derived neurotrophic factor (BDNF), result in decreased hippocampal function and ultimately depression. Neurogenesis-related genes, including BDNF, cyclic adenosine monophosphate response element-binding protein (CREB), and the pathway are essential in gene-cognition-environment interactions in depression׳s mechanism (Juhasz et al., 2011).
In the present study, we compared behavioral and molecular responses to electroconvulsive shock (ECS, the animal analog of ECT) between a genetic [Wistar Kyoto (WKY) rats, which are genetically hypersensitive to stressors, demonstrate depressive behaviors such as anhedonia, and are deemed a valid rat model of “endogenous” depression (Tejani-Butt et al., 2003)] and environmental [rats treated with chronic unpredictable mild stress (CUMS), which have similarities to patients with depression caused by chronic, low-level stresses, and are considered to simulate patients with “reactive” depression with good predictive, face, and construct validity] rat model of depression. We wished to reveal the profile and possible mechanism of different responses to ECT in rats with different depression causes.
Section snippets
Animals
Healthy adult male Wistar rats and WKY rats (weighing 200–240 g, from the Laboratory Animal Centre of Chongqing Medical University) were used. They were maintained in a standardized environment with free access to food and water for one-week acclimatization before the experiments. All procedures were approved by the Ethical Committee of Chongqing Medical University and carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.
Groups and general procedures
Rats were
Sucrose preference
Before ECS (or sham ECS) was administered, there were significant baseline SPP differences between groups [F(5, 66)=47.854, P<0.001]. Compared with groups S and SE, the baseline SPP in groups K, C, KE or CE were less (each P<0.001), while there were no significant differences between the four depressive rat groups (in groups K, C, KE or CE). There were no significant differences between the two healthy Wistar rat groups (in groups S and SE) (Fig. 1A). After ECS (or sham ECS), there were
Discussion
The study׳s main findings are as follows: ECS impaired WKY rats׳ memories but improved CUMS rats׳ memories, elevated hippocampal BDNF and CREB proteins only in CUMS rats, improved depressive behavior and hippocampal p-CREB protein levels in both model rats, and had more effective regulations in CUMS rats. However, there were no changes in neuron number in the hippocampus in both model rats after ECS.
The core symptom of depression is anhedonia, defined as the inability to experience pleasure
Contributors
Author Su Min and Jie Luo designed the study and supervised it. Author Jie Luo, Ke Wei, Jun Cao, Yuanyuan Liu performed the protocol. Author Bin Wang, Ping Li, and Jun Dong undertook the statistical analysis, and author Jie Luo wrote the protocol and the draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors declare that there are no conflicts of interest in this work.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81271501 and 81201053), the Natural Science Foundation Project of Chongqing Science and Technology Commission (CQ CSTC) (No. cstc2012jjA10056), the National Clinical Key Subject Construction Project of China (Caishe (2011) No. 170), and the Medical Key Discipline Construction Project of Chongqing (Yuweikejiao (2007) No. 2).
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2022, Psychiatry ResearchCitation Excerpt :As shown in Table 3, it has been found that animals after chronic stress or with genetic “depression” have lower levels of BDNF than normal animals (Gersner et al., 2010, 2014; Kyeremanteng et al., 2012). In contrast, apart from a few studies (Angelucci et al., 2003; Gao et al., 2016; Kronenberg et al., 2018), BDNF was found to increase in the hippocampus of chronically stressed rats from hours to days after repeated ECS (Luo et al., 2012, 2015; Kyeremanteng et al., 2014; O'Donovan et al., 2014; Zhang et al., 2016). Increased BDNF levels are more robust in the dorsal hippocampus (Gersner et al., 2014) than in the ventral hippocampus (Gersner et al., 2010).
Effects of electroconvulsive shock on neuro-immune responses: Does neuro-damage occur?
2020, Psychiatry ResearchCitation Excerpt :Most investigations of ECS treatment in rats with chronic stresses or chronic CORT treatment found the similar results with that in unstressed animals (Table 4). The studies showed that while chronic ECS reduced stress-induced depression-like behavior and increased neurogenesis of stressed animals, the hippocampal neuron number and volume could not be affected (Hellsten et al., 2002;Luo et al., 2015;Olesen et al., 2015). Moreover, the neuron numbers did not change whenever at 1 day, several months, or at 1 year following ECS (Olesen et al., 2016), suggesting no damaging effect occurs following chronic ECS treatment.
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2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Consistent with their hypersensitivity to stress under baseline conditions, WKY rats also show enhanced physiological responses and a failure to adapt to repeated stress (Morilak et al., 2005; Tejani-Butt et al., 1994; Zafar et al., 1997). In addition, subjecting WKY rats to CMS under a two-hit model exacerbates their depression- and anxiety- like phenotypes (Luo et al., 2015; Tejani-Butt et al., 1994; Willner et al., 2018). Interestingly, early-life stress, such as neonatal handling or maternal separation, do not generally enhance the WKY phenotype, indicating a strong genetic component (Nam et al., 2014; Van Zyl et al., 2014; Zalsman et al., 2015), although some exceptions exist in the literature (Shetty and Sadananda, 2017b).