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Background: With increased social pressure, individuals face a high risk of depression. Subsequently, depression affects cognitive behaviour and negatively impacts daily life. Fortunately, the Traditional Chinese Medicine Jia Wei Xiao Yao (JWXY ) capsule is effective in reducing depression and improving cognitive behaviour. Methods: The constituents of JWXY capsule were identified by ultra-performance liquid chromatography and quad- rupole time-of-flight mass spectrometry analyses. We analysed behaviours of depression-like zebrafish in the novel tank with an automatic 3D video-tracking system and conducted the colour preference test, as well detected physi- ological changes after sertraline and JWXY capsule treatments. Results: Both sertraline and JWXY capsule rescued the decreased locomotive behaviour and depression phenotype of zebrafish caused by reserpine. JWXY capsule especially improved the inhibited exploratory behaviour caused by reserpine. In addition, with the onset of depressive behaviour, zebrafish exhibited alterations in cognitive behaviour as indicated by colour preference changes. However, compared with sertraline, JWXY capsule was more efficaciously in rescuing this change in the colour preference pattern. Moreover, an increased level of cortisol, increased expression of tyrosine hydroxylase ( TH) and decreased monoamine neurotransmitters, including serotonin (5-HT ) and noradrena- line, were involved in the depressive behaviours. In addition, sertraline and JWXY capsule rescued the depressive phenotype and cognitive behaviour of zebrafish by altering the levels of endogenous cortisol and monoamine neurotransmitters. Conclusions: JWXY capsule was more effectively than sertraline in rescuing reserpine-induced depression and cog- nitive disorder in zebrafish. Potentially, our study can provide new insights into the clinical treatment of depression and the mechanism of action of JWXY capsule. Keywords: Depression behaviour, TCM, Colour preference, Monoamines, Zebrafish *Correspondence: firstname.lastname@example.org; email@example.com; firstname.lastname@example.org Shuhui Zhang, Xiaodong Liu, Mingzhu Sun and Qiuping Zhang contributed equally to this work State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, China Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin 300071, China The Institute of Robotics and Automatic Information Systems, Nankai University, Tianjin 300071, China © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Behav Brain Funct (2018) 14:13 Page 2 of 14 Xiao Yao (JWXY) capsule, can provide a reliable clinical Background curative effect comparable to that of Western medicine. Major depressive disorder (MDD), one of the most com- In addition, TCM is much more affordable and has fewer mon brain disorders, usually has a high rate of comor- side effects. However, a lack of rigorous clinical research bidity with other psychiatric disorders . Depressive has counteracted the unique advantage of TCM and seri- disorder, characterised by decreased activity, a significant ously impeded its worldwide popularization and appli- and lasting low mood, and slowed thinking and cognitive cation. JWXY capsule can soothe the liver and reduce function [2, 3], markedly reduces quality of life. Psychi- heat, strengthen the spleen and nourish the blood. Based atric disorders such as psychosis, depression, and other on experiences with TCM, JWXY capsule exerts various mood disorders may have multigenic and multifactorial actions, including soothing the liver and improving the aetiologies . Fortunately, improvements in the diagno- circulation of qi to relieve depression. In China, JWXY sis and treatment of depression are increasing. Monoam- capsule has been commonly recognized as a safe and ines play a key role in the regulation of brain functions effective prescription in the treatment of depressive dis - in animals and humans . Monoamine neurotransmit- order [18, 21–23]. However, the effects and mechanism ters, including serotonin (5-HT), dopamine (DA) and of action of JWXY capsule remain poorly understood. noradrenaline (NA), are implicated in the regulation In the literature, several assays have been reported to of a large number of processes, such as motor control, measure behavioural learning changes in adult zebrafish social behaviour, cognition, sleep, appetite, and anxi- such as the rotating escape test, bite test, novel tank test, ety in vertebrates [6–9]. In zebrafish, 5-HT and DA are place preference test, T-maze, plus maze and Y-maze the two most studied monoamines [10, 11]. Serotonin assays [24, 25]. Most of tools used to assess learning and (5-hydroxytryptamine, 5-HT) serves as both a neuro- memory in animal models involve visual stimuli, includ- transmitter and hormone; in higher vertebrates, 5-HT ing colour preferences. Zebrafish can discriminate col - acts throughout the body, including the central nervous ours and display spontaneous approach or avoidance system (CNS), peripheral nervous system, cardiovascu- behaviours. Some studies support colour-based learning lar system, and endocrine system; it also participates in and memory paradigms or experiments involving aver- sensory perception and many behaviours . Seroto- sion, anxiety or fear in zebrafish [26, 27]. Zebrafish show nin is involved in many behavioural functions, including a preference for blue and green and avoided yellow and the organization of defence, and its putative pathologi- red . The zebrafish visual system includes retinas cal correlate, anxiety and stress disorders . Anxiety- with cones sensitive to red, green, blue, and ultraviolet; like behaviour positively correlates with 5-HT content in moreover zebrafish are diurnal animals, which makes the novel tank test . Stress levels can be measured by them an ideal model for developing research on cognitive the whole-body cortisol concentration . Some com- responses to visual signals [29, 30]. pounds cause Parkinson’s disease-like behaviour due to In cognitive research, the zebrafish has become increas - decreased dopamine levels and locomotor activity [16, ingly popular and has advantages in behavioural brain 17]. u Th s, the study of monoamine neurotransmitters in research due to its elaborate brain structure, simplicity the brain is indispensable for the treatment of depression. and neurochemistry, which offers translational relevance For depression, the most widely used therapy is anti- to humans [31–33]. In addition, the zebrafish is an ideal depressants, including monoamine oxidase inhibitors and promising model organism for pharmacology [4, 18, (MAOIs), tricyclic antidepressants (TCAs), serotonin and 34–36], disease [35, 37], embryology and development norepinephrine reuptake inhibitors (SNRIs) and selective studies [38, 39] because it shares many genes, protein serotonin reuptake inhibitors (SSRIs) . For example, products and molecular pathways with mammals . sertraline is one a SSRI. Although these antidepressant There are also studies on the relationship between emo - drugs are effectively relieve depression, they have several tion regulation and colour preference in zebrafish . concerning side effects, such as headache, agitation or Zebrafish may become a translationally relevant study sedation, vomiting, and fatigue [19, 20]. Therefore, iden - species for the analysis of the mechanisms of learning tifying a better antidepressant is necessary; this need has and memory changes associated with psychopharmaco- led researchers to focus on natural medicine, including logical treatment of anxiety/depression . Traditional Chinese Medicine (TCM). TCM has a long Compared with 2D approaches, a 3D approach history of prevention and treatment of depression dating improves data integrity by using two videos and may as far back as 2000 years ago. When treating depression, help reduce the number of experimental subjects. We TCM starts at the whole-body level, considering not only used two cameras covering the dorsal and lateral view the psychological problems that result from a patient’s to record fish behaviour in a novel tank. A 3D approach nervous system disorder but also the changes in the integrates the position information from the top and Zang-Fu organs, qi and blood . TCM, such as Jia Wei Zhang et al. Behav Brain Funct (2018) 14:13 Page 3 of 14 front views, which is essential to measure depression- lux) arrays and a transparent platform. Two charge-cou- like behaviour in zebrafish . 2D approaches have also pled device (CCD) cameras (MV-VS078FM, Microvision, played a pivotal role in elucidating the neurobehavioural 10 frames/s) were placed to obtain the top (dorsal) view underpinnings of fish behaviour . Hence, we utilized and side (lateral) view of the moving zebrafish (Fig. 1b). a camera from the top view to record the preference of The offset cross maze and T-maze (Fig. 1c) were designed zebrafish for different colours after pharmacological based on previous research and composed of transparent manipulations. Plexiglass. Every arm of the offset cross maze is 20 cm * Reserpine causes depression by depleting monoamines 8.8 cm. The sides of the four arms are covered with four and is widely used to induce depression-like phenotypes different colours (blue, green, red and yellow) made by pharmacological manipulation in zebrafish . There - from polypropylene. The centre Section (8.8 cm * 8.8 cm) fore, in this study, we performed comparative analysis of of the cross maze is a starting place for the fish indi - the curative effect of sertraline and JWXY capsule treat - cated by None. The two opposite arms of the maze are ment for reserpine-induced depression-like behaviour in 20 cm * 8.8 cm each and are covered with two different zebrafish by examining behaviour and the concentrations colours (blue and yellow) of polypropylene on the sides. of three monoamine neurotransmitters and the hormone The last arm is 20 cm * 8.8 cm and uncoloured. The last cortisol. Sertraline and JWXY capsule rescued depres- arm and centre Section (8.8 cm * 8.8 cm) of the T-maze sive behaviour and colour preference, accompanied by is a starting place for the fish indicated by No. The maze changes in monoamines and cortisol. The purpose of our is 10 cm deep and filled with 6.5 cm system water. A study was to evaluate the effects of sertraline and JWXY CCD camera (MV-VS078FM, Microvision, 10 frames/s) capsule on behaviour, cognitive ability and biochemi- was fixed above the maze to obtain the top view of the cal parameters in zebrafish with depression induced by moving zebrafish (Fig. 1c). A daylight lamp (500 lux) or reserpine. natural light served as the light source. All apparatuses rested on a level, stable surface and were placed in a rela- Methods tively sound-proof room to minimize the effect of noise Zebrafish when behavioural tests were conducted. A big black cloak Zebrafish (AB strain) were maintained in a fish-farming forming a space covered all the experimental apparatuses system at the State Key Laboratory of Medicinal Chemi- to eliminate environmental interference. cal Biology, Nankai University. The room was maintained Briefly, the behavioural parameters were defined at a constant temperature of 28.5 °C on a constant light according to the literature and previous research [44, 45]. cycle (14 h light/10 h dark), and the water (KCl 0.05 g/L, The definitions of behavioural parameters that described NaHCO 0.025 g/L, NaCl 3.5 g/L, and CaCl 0.1 g/L) was depression in the novel tank are shown in Table 1. The 3 2 circulated continuously. The zebrafish were fed freshly definitions of behavioural parameters that described col - hatched brine shrimp twice daily. All of the experimen- our preferences in the maze are provided in Table 2. tal protocols and procedures involving zebrafish were approved by the Committee for Animal Experimentation Chemical and experimental design of the College of Life Science at Nankai University (no. Reserpine (purity ≥ 98.0%) was purchased from Shanghai 2008) and were performed in accordance with the NIH Macklin Biomedical Co., Ltd. The reserpine concentra - Guide for the Care and Use of Laboratory Animals (no. tion of 40 μg/mL in this study was chosen based on previ- 8023, revised in 1996). ous research concerning the effective doses of reserpine for the depressive behaviour of zebrafish [5, 45]. Sertra- Behavioural test apparatuses and behavioural parameters line hydrochloride (purity > 98.0%) was purchased from Behavioural apparatuses were designed according to TCI Co., Ltd. (Shanghai, China). Preliminary experi- previous studies [44, 45]. A novel tank, composed of ments proved that the effective concentration of sertra - transparent Plexiglass, was a 5 L rectangular box (23 cm line hydrochloride was 0.1 μg/mL. The experimental length * 15 cm width * 15 cm depth) used to assess the doses of reserpine (40 μg/mL) or sertraline hydrochlo- depressive behaviour of zebrafish. We divided the tank ride (0.1 μg/mL) were obtained by weighing and adding into two equal horizontal portions virtually by marking a dry powder to system water. JWXY capsule (Z10960066) midline on the outside walls. The region above this mid - was purchased from Sichuan Baoxing Pharmaceutical line indicated the “top” of the novel tank, while the area Co., LTD (Sichuang, China). The composition of JWXY below indicated the “bottom” of the novel tank. The novel capsule is as follows: Bupleuri Radix, Angelicae Sinensis tank was placed over a light source, a light-emitting diode Radix, Paeoniae Radix Alba, Atractylodis Macroceph- (LED) array, with an acrylic diffuser located above the alae Rhizoma (stir-baking with bran), Poria, Glycyr- tank. The light source was composed of white light (500 rhizae Radix Et Rhizoma, Menthae Haplocalycis Herba, Zhang et al. Behav Brain Funct (2018) 14:13 Page 4 of 14 Fig. 1 Experimental paradigm and ESI–MS spectra of JWXY capsule. a Timeline of the procedure for drug delivery and schematic diagram of the apparatus used for behavioural phenotyping in the novel tank (b) and colour preference behaviour (c). d ESI–MS spectra in the positive and negative ion voltage mode of JWXY capsule (1–15 min). Some of the constituents are labelled in the spectra Moutan Cortex, and Gardeniae Fructus (processed with 28 °C) on a 14:10 h light cycle. The 48 zebrafish were ginger juice). Based on preliminary experiments, the first tested by 3D neurophenotyping in the novel tank effective concentration of JWXY capsule was 100 μg/mL. and colour preference behaviour in the maze (defined as We opened the capsule and grinded the dry powdered control). Then, all 48 zebrafish were exposed 40 μg/mL contents. Then, the powdered medicine was weighed and reserpine for 20 min and tested by behavioural appara- dissolved in system water to obtain a solution with a con- tuses (defined as acute). Next, acute zebrafish were sep - centration of 100 μg/mL. Experimental solutions were arated into three groups according to the experimental sonicated for 30 min to dissolve the medication. design. The three groups were exposed to system water A total of 48 experimentally naïve, adult zebrafish (indicated as the model), 0.1 μg/mL sertraline hydro- (9 months old, male:female = 1:1) were used in our chloride (indicated as sertraline) and 100 μg/mL JWXY study. All zebrafish were housed in groups of 2 zebrafish capsule (indicated as JWXY) for 7 days and then sub- per 4 L tank (filled with system water maintained at jected to behavioural testing (Fig. 1a). Solutions were Zhang et al. Behav Brain Funct (2018) 14:13 Page 5 of 14 Table 1 The definitions of behavioural parameters in the novel tank Behavioural parameters Definition Total distance travelled (m) The total distance in the novel tank Average velocity (cm/s) The direction and magnitude of zebrafish speed in the novel tank Turn angle (°) The total turning angle of zebrafish in the novel tank Angular velocity (°/s) The direction and magnitude of zebrafish angular speed in the novel tank Meandering (°/s) The degree of turning vs. travel distance Average entry duration in the top (s) The amount of time spent at the top of the novel tank during each crossing Distance travelled in the top (m) The total distance moved in the defined top part in the novel tank Time spent in the top (s) The total time spent in the top part of the novel tank Latency to enter the top (s) The amount of time to first cross from the bottom part to the top of the novel tank Number of entries to the top The number of crosses from the bottom part to the top of the novel tank Time spent ratio of top: bottom The ratio of the time spent on top over bottom Distance travelled ratio of top: bottom The ratio of the total distance moved in the top part vs. the bottom Entries ratio of top: bottom The number of crosses from the bottom part to the top of the novel tank Freezing bouts (frequency) The total number of instances of immobility (> 1 s) during the 5 min test in the novel tank Freezing duration (s) The duration of all freezing bouts in the novel tank Table 2 The definitions of behavioural parameters in the maze Behavioural parameters Definition Time (%) The ratio of the time zebrafish spent in each arm (colour) to the total time spent in the maze Distance (%) The ratio of the distance zebrafish travelled in each arm (colour) to the total distance trav- elled in the maze refreshed every day after feeding with fresh brine into new tubes. After the diethyl ether evaporated, the shrimp. extracts were dissolved in 500 μL ELISA Buffer and ana - lysed by using the Cortisol ELISA Kit (Cayman, 500360). Behavioural testing The NA, 5-HT and DA concentrations of adult All zebrafish used in our study were acclimated to the zebrafish brains were analysed by a NA ELISA Kit laboratory environment. Before the behavioural test at (CUSABIO, Wuhan, China), 5-HT ELISA Kit (CUSA- every endpoint, zebrafish were given 1 h to acclimate BIO, Wuhan, China), and DA ELISA Kit (CUSABIO, to the tank environment. Behavioural testing was per- Wuhan, China), respectively. Zebrafish brain tissue formed between 9:00 am and 16:00 pm, i.e., the middle was rinsed with 1 × PBS, homogenised in 1 mL 1 × PBS of the light phase of the light cycle, with tanks filled with and stored overnight at − 20 °C. After two freeze–thaw system water at a temperature ranging from 26 to 28 °C. cycles, homogenates were centrifuged at 5000g for 5 min Zebrafish behaviours were recorded for 5 min by CCD at 4 °C. The supernatant was transferred into new tubes cameras and evaluated by analysing the behavioural end- and assayed immediately according to the manufacturer’s points in Tables 1 and 2. instruction. Enzyme‑linked immunosorbent assay (ELISA) Western blot Cortisol was extracted from zebrafish whole-body Total protein was extracted from adult zebrafish brain homogenates. Adult zebrafish in different treatment tissue with radioimmunoprecipitation assay (RIPA) groups were weighed and stored at − 80 °C. The whole (CWBIO, Beijing, China) buffer containing phenyl - zebrafish was dissected into small pieces on ice and methylsulfonyl fluoride (PMSF) (Sigma-Aldrich). Pro - homogenised in 500 μL ELISA Buffer, followed by soni - tein concentrations were quantified using a BCA Protein cation on ice for 30 s. Diethyl ether was added to sam- Assay Kit (CWBIO). Proteins were separated in 10% ples, which were shaken for 10 min and centrifuged at sodium dodecyl sulphate-polyacrylamide gel elec- 2000 rpm for 15 min at 4 °C. After storing the samples trophoresis (SDS-PAGE) and transferred to a polyvi- at − 80 °C for 15 min, the supernatant was transferred nylidene fluoride (PVDF) membrane that was blocked Zhang et al. Behav Brain Funct (2018) 14:13 Page 6 of 14 with Tris-buffered saline (TBS) containing 5% skim collision cell operating at two alternative energies (i.e., 20 milk for 1 h at room temperature. Membranes were and 50 eV). Leucine enkephalin (200 pg/mL) was used as − + incubated with mouse anti-TH (1:1000; Millipore) and the lock mass ([M−H] 554.2615, [M+H] 556.2771). mouse anti- glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (1:5000; Proteintech) overnight primary anti- Data analyses bodies at 4 °C. After being washed with TBS containing Data represents the mean ± SEM (standard error of the 0.05% Tween-20 (TBST), the membrane was incubated mean). One-way ANOVA was performed to assess differ - with anti-mouse HRP-conjugated secondary antibody ences between groups, followed by post hoc Tukey HSD (1:3000; CWBIO). The membrane was then washed with tests for data with a normal distribution. A nonparamet- TBS containing 0.05% Tween-20, and Super Signal West ric Kruskal–Wallis test followed by Dunn’s multiple com- Pico chemiluminescent substrate (Thermo Scientific) was parisons tests (*p < 0.05) was used for data that violated used for detection. the assumption of normality. We used GraphPad Prism 7.0 to obtain statistical charts and graphs. UPLC and QT ‑ OF‑MS analyses We opened the JWXY capsule and ground the dry pow- Results dered contents. The powdered medicine was dissolved Establishment of the experimental procedure and analyses in system water to obtain a solution. Next, we used the of JWXY capsule constituents mixed solution for ultra-performance liquid chromatog- All herbs in JWXY capsule are presented in Additional raphy (UPLC) and quadrupole time-of-flight mass spec - file 1: Table S1. We utilized a solution of capsule con- trometry (Q-TOF-MS) analyses. tents to conduct a novel tank assay and colour preference A Waters Acquity UPLC System (Waters, MA, behavioural experiment. UPLC and Q-TOF-MS analyses USA) equipped with a photodiode array detector was were conducted for JWXY capsule analysis. Protonated + − used. The system was controlled by Masslynx V4.1 [M+H] or deprotonated [M−H] ions were obtained software (Waters Co.). An Acquity BEHC18 column with as much characteristic fragment information as (2.1 × 100 mm, 1.7 μm; Waters Co.) was used for sepa- possible to deduce the molecular and elemental compo- rations. Using Rongchang capsule as an example, a gra- sitions of every constituent. The inferred chemical struc - dient elution of 0.1% formic acid in water (A) and 0.1% ture was compared with published data and reported formic acid in acetonitrile (B) was performed as follows: natural product information. The ESI–MS spectra were 2% B was obtained from 0 to 1 min, 2–10% B from 1 to acquired in both the positive and negative ion voltage 3 min, 10–15% B from 3 to 7 min, 15–30% B from 7 to modes for each capsule. Here, we show the results of 15 min, 30–50% B from 15 to 20 min, 50–80% B from 20 JWXY capsule in the positive and negative ion voltage to 23 min, and 80–100% B from 23 to 24 min; In adition, mode (Fig. 1d). A total of 57 compounds were identified 100% B was maintained from 24 to 25 min; 100–2% B was in JWXY capsule. Detailed identification results are pre - obtained from 25 to 27 min; and 2% B was maintained sented in Additional file 1: Table S2, Figures S1–S8. from 27 to 30 min. Other samples were slightly adjusted based on their ingredients and chemical polarity. The Both sertraline and JWXY capsule rescued the decreased flow rate was 0.40 mL/min, and the column temperature locomotive behaviour of zebrafish caused by reserpine was maintained at 35 °C. Accurate mass measurements The locomotive behaviour of zebrafish was measured by and MS/MS were performed on a Waters Q-TOF Pre- the total distance travelled, average velocity, turn angle mier with an electrospray ionisation (ESI) system (Xevo and angular velocity. Compared with the control, acute G2-Q Tof, Waters MS Technologies, Manchester, UK). treatment (20 min) with reserpine resulted in suppres- The electrospray ionisation mass spectrometry (ESI–MS) sion of the total distance travelled and average velocity. spectra were acquired in both the negative and positive Then, after treatment with system water for 7 days, the ion voltage modes. The capillary voltages were set to total distance travelled and average velocity were more 2.0 kV for the negative mode and 3.0 kV for the positive significantly reduced (model). The turn angle and angular mode. The sample cone voltage was set to 40 V. High- velocity showed the same trend. However, total distance purity nitrogen was used as the nebulisation and auxiliary travelled was rescued after treatment with sertraline and gas. The nebulisation gas was set at a flow rate of 800 L/h JWXY capsule for 7 days (Fig. 2b). Moreover, the average at 450 °C, the cone gas was set at a flow rate of 50 L/h, velocity revealed that sertraline and JWXY capsule signif- and the source temperature was 120 °C. The Q-TOF Pre - icantly rescued the reduced activity caused by reserpine mieracquisition rate was 0.1 s, with a 0.2-s scan delay. The (Fig. 2c). Likewise, the turn angle and angular velocity instrument was operated with the first resolving quad - demonstrated that sertraline and JWXY capsule rescued rupole in a wide pass mode (50–2000 Da) and with the the effects of reserpine on zebrafish behaviour (Fig. 2d, Zhang et al. Behav Brain Funct (2018) 14:13 Page 7 of 14 Fig. 2 Locomotion profiles of zebrafish exposed to sertraline and JWXY capsule after reserpine treatment in the novel tank test. a Diagram of locomotion behaviour recorded by a camera from a dorsal view. Histogram revealing the locomotion behaviour of adult zebrafish by the b total distance travelled, c average velocity, d turn angle, e angular velocity and f meandering. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment with reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. and were analysed by one-way ANOVA followed by the Tukey post hoc test. Significance was defined as *p < 0.05, **p < 0.01 e). Reserpine slightly increased erratic movements meas- top: bottom were significantly higher in the JWXY cap - ured by meandering in the novel tank test, and sertraline sule group than in the acute group. Reserpine induced an and JWXY capsule reduced this tendency (Fig. 2f ). obvious depressive phenotype as shown in Fig. 4. After acute treatment with reserpine, zebrafish did not show JWXY capsule rescued inhibition of exploratory behaviour changes in their freezing bouts and freezing duration. and reversed the depressive phenotype of zebrafish However, the freezing bouts and freezing duration were Exploratory behaviour, measured by the average entry enhanced after 7 days. After treatment with of sertraline duration (Fig. 3b), distance travelled in the top (Fig. 3c), and JWXY capsule for 7 days, the depressive phenotype time spent in the top (Fig. 3d), time spent ratio of top: was no longer observed. Moreover, the freezing bouts bottom (Fig. 3e), distance travelled of top: bottom and freezing duration were significantly decreased. (Fig. 3f ), latency to enter the top (Fig. 3g) and entries ratio of top: bottom (Fig. 3h), was not significantly altered in Impact of sertraline and JWXY capsule on the colour the treatment groups compared with that in the control preference behaviour of zebrafish after reserpine group, with the exception of JWXY capsule treatment treatment: JWXY capsule reversed colour preference group. However, exploratory behavioural parameters patterns were decreased in the model group. As shown in Fig. 3, Colour preference behaviour was demonstrated by the zebrafish treated with JWXY capsule exhibited improve - time spent (Fig. 5) and distance travelled (Additional ments in exploratory behaviour; the average entry dura- file 1: Figure S9) in every colour arm using a remoulded tion, distance travelled in the top, time spent in the top, offset cross maze (Fig. 5a). The control group (Fig. 5b) time spent ratio of top: bottom and distance travelled of spent the most time in the blue area, followed by the Zhang et al. Behav Brain Funct (2018) 14:13 Page 8 of 14 Fig. 3 Exploratory profiles of zebrafish exposed to sertraline and JWXY capsule after reserpine treatment in the novel tank test. a Diagram of the exploratory behaviours recorded by a camera from a lateral view. The histograms demonstrated the exploratory behaviours of adult zebrafish by the b average entry duration to the top, c distance travelled in the top, d time spent in the top, e time spent top: bottom ratio, f distance travelled top: bottom, g latency to enter the top and h entries top: bottom ratio. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment with reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. and were analysed by one-way ANOVA followed by the Tukey post hoc test. Significance was defined as *p < 0.05, **p < 0.01 Fig. 4 Histogram of the a freezing bouts and b freezing duration of zebrafish. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment with reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. and were analysed by one-way ANOVA followed by the Tukey post hoc test. Significance was defined as *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 Zhang et al. Behav Brain Funct (2018) 14:13 Page 9 of 14 Fig. 5 Colour preference profiles of zebrafish exposed to sertraline and JWXY capsule after reserpine treatment in the remoulded offset cross maze test. a Diagram of the remoulded offset cross maze and distribution of colours. The centre of the cross maze was denoted as None, and zebrafish started in that location. b The duration (time) of control zebrafish in every colour arm. c The duration (time) of zebrafish treated with reserpine for approximately 20 min (acute) in every colour arm. d The duration (time) of zebrafish exposed to system water after reserpine treatment (model) in every colour arm. e The duration (time) of zebrafish exposed to sertraline after reserpine treatment in every colour arm. f The duration (time) of zebrafish exposed to JWXY capsule after reserpine treatment at every colour arm. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment with reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. One-way ANOVA with post hoc Tukey HSD tests was used to analyse data with a normal distribution, and a nonparametric Kruskal–Wallis test followed by Dunn’s multiple comparisons tests was used for data that violated the assumption of normality. Significance was defined as *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 red, green, and yellow areas (listed from most to least same over time. Based on the abovementioned results, time spent). The most and least preferred colours were we concluded that zebrafish preferred blue the most and unchanged, but the time spent in green area was higher yellow the least. Following treatment with sertraline and than that in the red area in the acute group (Fig. 5c). In JWXY capsule, the colour preference order was restored, the model group (Fig. 5d), the amounts of time spent and JWXY capsule was more effective than sertraline in in blue, red and green were not significantly different. restoring colour preference behaviour. Zebrafish continued to spend the least amount of time Based on colour preference behaviour in the remoulded in the yellow area. After sertraline treatment (Fig. 5e), offset cross maze, we chose two colours (blue and yel - zebrafish recovered their preference for blue. However, low) to conduct a concise test using a T-maze. Colour the time spent in the red and green areas was not differ - preference behaviour was demonstrated by time (Fig. 6) ent. Notably, the JWXY group and control group had the and distance (Additional file 1: Figure S10) travelled in same colour preference (Fig. 5f ). The distance (Additional every colour arm using a T-maze (Fig. 6a). In the con- file 1: Figure S9) travelled in every colour arm was the trol (Fig. 6b) and acute (Fig. 6c) groups, zebrafish spent Zhang et al. Behav Brain Funct (2018) 14:13 Page 10 of 14 Fig. 6 Colour preference profiles of zebrafish exposed to sertraline and JWXY capsule after reserpine treatment in the T-maze test. a Diagram of the T-maze and distribution of colours. The centre of the T-maze was denoted as No, and zebrafish started in that location. b The duration (time) of WT zebrafish in every colour arm. c The duration (time) of zebrafish treated with reserpine for approximately 20 min (acute) in every colour arm. d The duration (time) of zebrafish exposed to system water (model) after reserpine treatment in every colour arm. e The duration (time) of zebrafish exposed to sertraline after reserpine treatment in every colour arm. f The duration (time) of zebrafish exposed to JWXY capsule after reserpine treatment in every colour arm. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment of reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. and were analysed by one-way ANOVA followed by the Tukey post hoc test. Significance was defined as *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 significantly more time in the blue area than in the yellow sertraline group. However, compared with the model and area. However, the time zebrafish spent in every colour sertraline groups, the JWXY group showed a significant arm was not different in the model group (Fig. 6d). After increase in the NA concentration (Fig. 7b). 5-HT was sertraline (Fig. 6e) and JWXY capsule (Fig. 6f ) treatment, significantly increased in the acute group but increased the same colour preference tendency as that of the con- only slightly in the model group. Sertraline elevated the trol was observed. The distance (Additional file 1: Figure 5-HT level, but JWXY capsule did not (Fig. 7c). Sertraline S10) travelled in every colour arm was consistent with decreased TH expression 7 days after acute exposure, the time spent. and sertraline and JWXY capsule treatments improved TH to a degree (Fig. 7d). However, the DA level did not Cortisol and monoamine levels influenced zebrafish change after sertraline and JWXY treatments (Additional neurobehaviour file 1: Figure S11). Whole-body cortisol, monoamines, including NA, 5-HT, DA, and TH were detected in zebrafish brain tissues Discussion after different treatments. The cortisol level in the model JWXY capsule contains nine herbal medicines, and 57 group was significantly higher than that in the acute and compounds were identified in its extraction by UPLC and control groups. After sertraline and JWXY capsule treat- Q-TOF-MS. As previously described, TCM posits that ments, the cortisol level was markedly decreased, espe- depression involves in multiple organs. TCM focuses on cially in the JWXY group (Fig. 7a). NA in the model the overall effect of medicines contained in a prescrip - group was significantly lower than that in the control and tion, and it also plays a role in health care and disease Zhang et al. Behav Brain Funct (2018) 14:13 Page 11 of 14 Fig. 7 The effects of sertraline and JWXY capsule treatment on cortisol and monoamines in zebrafish. The levels of cortisol (a), noradrenaline (b), 5-HT (c) and tyrosine hydroxylase (d) in zebrafish after different treatments. Control: untreated AB strain zebrafish. Acute: acute treatment with reserpine for 20 min. Model: after acute treatment with reserpine, zebrafish were exposed to system water for 7 days to generate the depression model. Sertraline: after acute treatment with reserpine, zebrafish were exposed to sertraline for 7 days. JWXY: after acute treatment with reserpine, zebrafish were exposed to JWXY capsule for 7 days. The data are expressed as the mean ± S.E.M. and were analysed by one-way ANOVA followed by the Tukey post hoc test. Significance was defined as *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 prevention through the treatment of multiple targets. All with our study. After 20 min of reserpine exposure, herbal medicines in the prescription work synergistically zebrafish showed a slight decrease in locomotive activ - and can yield stable and comprehensive curative effects, ity but did not show obvious changes in exploratory greatly reducing the side effects of drug treatment. Deter - behaviour and freezing behaviour. Zebrafish displayed mining the main components of TCM prescriptions and significantly decreased locomotive activity and a wors - their mechanisms of action is difficult. However, char - ened depressive phenotype after 7 days, along with acterising the multiple constituents, targets and path- hypoactive exploratory behaviour, which proved that ways of TCM prescriptions is of greater importance, and the establishment of zebrafish depression model first requires further research. introduced by Kyzar et al. was successful in our experi- We employed a 3D video-tracking system to detect ment. However, compared with zebrafish in the model changes in the swimming behaviour of lesioned group, zebrafish in the sertraline and JWXY capsule zebrafish in novel tank. Zebrafish demonstrated long- groups treated for 7 days expressed different behav - term depressive symptoms, including elevated baseline iours. Sertraline treatment increased locomotive activ- whole-body cortisol, social withdrawal and locomotor ity and rescued the depressive phenotype induced by retardation after reserpine exposure . Reserpine reserpine. Moreover, JWXY capsule increased locomo- does not induce overt acute behavioural effects but tive activity, more effectively reversed the depressive markedly reduces activity after 7 days , consistent phenotype, and improved exploratory behaviour. Zhang et al. Behav Brain Funct (2018) 14:13 Page 12 of 14 The colour preference test could serve as a useful pro - reserpine-induced zebrafish model of depression showed tocol for memory evaluation, cognitive dysfunction, increased whole-body cortisol and 5-HT, decreased NA assessment of neurodegenerative disorders, preclinical and reduced TH. Compared with the model, sertraline appraisal of drug efficacy and behavioural evaluation of prevented the increase in cortisol and NA and increased toxicity . Here, we evaluated cognitive impairment 5-HT and TH. However, JWXY capsule prevented the by the colour preference test. Studies have demonstrated increase in cortisol and 5-HT, consistent with the res- the natural colour preference of zebrafish. Zebrafish cued depressive phenotype. In addition, compared with prefer colours of short wavelengths. Zebrafish exhibit the model, JWXY capsule improved the levels of NA and a strong preference for blue relative to all other colours TH, consistent with the increased locomotive activity. (red, yellow and green), with yellow being less preferred Interestingly, DA levels in zebrafish brains were unaf - than red and green [26, 48]. In our study, blue was the fected by any treatments. Those changes in monoamine favourite colour of control zebrafish, and yellow was the neurotransmitters were related to the colour preference least favourite. Control zebrafish exhibited a significantly disorder caused by reserpine and were consistent with stronger preference for blue than for red and green. How- the restored cognitive ability. ever, compared with control zebrafish, zebrafish exhibit - ing depressive behaviour lost certain colour preferences. Conclusion Yellow was the least preferred colour of model zebrafish, The novel tank test recorded by a 3D method in this but the preference for green and red increased simulta- experiment revealed the similar anti-depression effects neously and was not significantly different compared of two treatments for chronic reserpine exposure. This with that for blue, indicating that the normal colour pref- validation was based on the successful establishment of a erence pattern was disturbed. However, Zebrafish treated depressive zebrafish model, which was first introduced by by JWXY capsule regained this colour preference pat- Kyzar et al. The depressive effects of reserpine decrease tern. Sertraline also restored the colour preference pat- locomotion, increase erratic movements, reduce explora- tern to a degree, but its efficacy was not as obvious and tory behaviour to the top and enhance depressive phe- clear as that of JWXY capsule. To minimize the effects notype. Furthermore, colour preference testing in a of place preference on the results and further verify this remoulded offset cross maze and T-maze indicated that preference in zebrafish, we chose to test blue and yellow the natural colour preference pattern (zebrafish prefer in T-maze. All groups except the model group exhibited blue to red, green and yellow and show a strong aver- a preference for blue. However, different from the other sion to yellow) was disturbed due to depression induced groups, the model group also showed an increased pref- by reserpine. However, sertraline treatment improved erence for yellow and the same preference for all three depression-like behaviours by increasing locomotion arms, illustrating the colour preference disorder in and decreasing erratic movements and the depressive depressed zebrafish. In contrast, sertraline and JWXY phenotype. Sertraline also restored the colour prefer- capsule restored the colour preference pattern. These ence in zebrafish. Notably, JWXY capsule was a more results showed that the cognitive dysfunction accompa- effective treatment than sertraline. JWXY capsule treat - nying with depression in zebrafish could be reversed by ment reversed depression-like behaviours by increasing sertraline and JWXY capsule. locomotion, decreasing erratic movements, increasing Depression is usually comorbid with anxiety, which exploratory behaviour to the top and rescued the depres- leads to behavioural alterations. The effects of chronic sive phenotype. Zebrafish also exhibited their natural col - depression and anxiety on the hypothalamic–pitui- our preference after JWXY capsule treatment. tary–interrenal (HPI) axis have been studied previously Depression-like behaviours and cognitive disorder in zebrafish. Benzodiazepines (anxiolytics) and antide - (measured by colour preference) resulted from changes in pressants completely prevent increased cortisol levels in hormone and monoamine neurotransmitters in the brain. zebrafish . The decreases in total distance travelled Increased whole-body cortisol and decreased NA and TH and velocity in zebrafish are related to the decreased were observed in the zebrafish depression model. Sertraline levels of DA and NA . SSRIs were developed and prevented the increase in cortisol, inhibited the reuptake entered clinical trials as a new class of antidepressant in of 5-HT, and improved the expression of TH. Compared the 1980s. Six SSRIs, including fluoxetine, paroxetine, with the model, JWXY capsule also prevented the increase sertraline, fluvoxamine, citalopram and escitalopram in cortisol, recovered NA and improved the expression of are commonly used for clinical treatment. SSRIs selec- TH. Overall, these results show that changes in cortisol tively inhibit the reuptake of 5-HT by the presynap- and monoamines accounted for the reversal of depressive tic membrane. SSRIs have little impact on NA and behaviours and cognitive dysfunction. The high sensitivity hardly affect the reuptake of DA . In our study, the of zebrafish to the effects of Western medicine and TCM Zhang et al. Behav Brain Funct (2018) 14:13 Page 13 of 14 2. Richelson E. Pharmacology of antidepressants. Mayo Clin Proc. can help improve our understanding of the psychophar- 2001;76(5):511–27. macological profiles of these drugs and related CNS drugs, 3. Perrine SA, Ghoddoussi F, Michaels MS, Sheikh IS, Mckelvey G, Galloway as well contribute to further development of TCM as an MP. Ketamine reverses stress-induced depression-like behaviour and increased GABA levels in the anterior cingulate: an 11.7 T 1H-MRS study antidepressant. in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51(1):9–15. 4. 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