Xiaochaihutang attenuates depressive/anxiety-like behaviors of social isolation-reared mice by regulating monoaminergic system, neurogenesis and BDNF expression
Graphical abstract
Introduction
The social isolation (SI) rearing model is commonly considered as an early life stressor in animals, where post-weaning animals are raised in single-housed conditions (Fone and Porkess, 2008, Yorgason et al., 2016). It is often used to model childhood neglect leading to behavioral changes indicative of depression/anxiety in adulthood. These behavioral changes include hyper-locomotor activity under a novel environment (Koponen et al., 1989), raised anxiety-like performance, increased despair statement and aggressive behaviors (Koike et al., 2009, Kokare et al., 2010), which are similar to those observed in depressive individuals with early life stress. SI has been known to significantly influence the adult brain function, such as the activity of monoaminergic system, hippocampal neurogenesis and neurotrophin expression (Ibi et al., 2008, Lukkes et al., 2009).
Xiaochaihutang (XCHT) is a classic Chinese herbal formula for the treatment of “Shaoyang syndrome”, which is recorded in “ShangHan Lun” written by Zhang Zhongjing (150–219 A.D.) of the Chinese Eastern Han Dynasty. It has been reported that XCHT could treat clinical depressive disorders (Jia et al., 2009, Li and Gao, 1996). Our previous studies suggested that XCHT exerted antidepressant effects in the forced swimming test, tail suspension test and improved depressive-like behaviors in model of chronic unpredictable mild stress and neuroendocrine model of anxiety/depression (Su et al., 2014a, Zhang et al., 2015, Zhang et al., 2016). Furthermore, we demonstrated that XCHT could regulate depressive/anxiety-like behaviors of adult rats induced by social isolation stress (Ma et al., 2016).
The monoamine deficiency hypothesis proposes that depressive symptoms arise from the deficiency of monoamine neurotransmitters, such as 5-HT, NE, and/or DA (Delgado, 2000). The monoaminergic system is mostly implicated in the pathophysiology of depression and in the mechanisms of antidepressants therapy. Studies have discovered that agents altering monoamine metabolism, such as serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA) relieve depressive symptoms. At present, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), NE reuptake inhibitors (NRIs) and the dual reuptake inhibitors (SNRIs) are commonly used for the treatment of depression. Our previous study found that XCHT could alter monoamine neurotransmitter levels in several brain regions (Su et al., 2014b), but XCHT's effects in altering the synthesis, transport and degradation of monoamine neurotransmitters have never been investigated. In addition, neurotrophic factors and adult neurogenesis have been shown to mediate the behavioral responses to antidepressants. The brain-derived neurotropic factor (BDNF) is regulated by antidepressants and is associated with antidepressant-like behavioral response in animal models of depression (Duman and Monteggia, 2006, Monteggia et al., 2004). Neurogenesis is also considered to modulate hippocampal function to produce antidepressant effects (Sahay and Hen, 2007). Our group has demonstrated that XCHT promoted hippocampal neurogenesis of non-stressed mice and depressive animals including socially isolated adult rats and depressive mice exposed to chronic corticosterone stress. Yet, it is still unknown whether neurotrophic factors and adult neurogenesis are underlying mechanisms that mediate XCHT's regulation on depressive/anxiety-related behaviors of SI-reared mice.
Therefore, in order to further evaluate the antidepressant effect of XCHT and the possible mechanism of action from distinct perspectives, we adopted social isolation-reared mice model of depression to investigate the consequences of XCHT on depressive/anxiety-related behaviors and elucidate the potential neurobiological mechanisms underlying these changes by investigating monoaminergic system, neurogenesis and neurotrophin expression in hippocampus.
Section snippets
Drugs
XCHT is an herbal formula comprising seven drugs (Su et al., 2014a, Wu et al., 2015): Radix Bupleuri (12 g; Latin name: Bupleurum chinense DC.; no. 1012002), Radix Scutellariae (9 g; Latin name: Scutellaria baicalensis Georgi; no. 1101002), Ginseng (9 g; Latin name: Panax ginseng C.A. Meyer; no. 20111001), Rhizoma Pinelliae (9 g; [Latin name: Pinellia ternata (Thunb.) Breit.]; no. 110303), Radix Glycyrrhizae (6 g; Latin name: Glycyrrhiza uralensis Fisch.; no. 1101002), Rhizoma Zingiberis recens (6 g;
XCHT alleviates depressive-like behaviors of SI-reared mice
Depressive-like behaviors were tested in TST and FST. Fig. 2 shows that the immobility time of social isolation-reared mice was significantly increased compared with the control group in TST and FST (P < 0.01 and P < 0.05, respectively). Treatment with XCHT (7.0 g/kg) for 6 weeks significantly reduced the immobility time in TST compared with SI group (P < 0.05). Similarly, XCHT (2.3 g/kg) administration significantly shortened the prolonged immobility time in FST that was induced by post-weaning
Discussion
In this study, we found that SI-reared mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the TST and FST, decreased time spent in open arms of the EPM test and enhanced aggressive behaviors, of which these behavioral alternations were significantly reversed after XCHT treatment, suggesting that XCHT could remarkably alleviate depressive/anxiety-related behaviors of post-weaning mice resulting from chronic social isolation stress.
The
Conclusion
Our study demonstrated that chronic social isolation stress after weaning produced profound depressive/anxiety-like behaviors with decreased function in the monoaminergic system and decreases in neurogenesis/neurotrophin-associated proteins expression. XCHT attenuated depressive/anxiety-like behaviors of social isolation-reared mice, and the plausible neurobiological mechanism underlying these behavioral changes may be related to improving the monoaminergic activity, neurogenesis and
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgments
This research was supported by the Key Project of National Natural Science Foundation of China, P.R. China (81130071), the Project of Innovation Team of Liaoning of P.R. China (LT2013021) and Doctoral Scientific Research Foundation of Liaoning Province (2013010582-401).
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