Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress
© Peng et al; licensee BioMed Central Ltd. 2012
Received: 24 November 2011
Accepted: 25 April 2012
Published: 6 July 2012
Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression.
We used a depressive-like state mouse model induced by unpredictable chronic mild stress (UCMS). Depressive-like behaviors were evaluated after 4 weeks of UCMS, in the presence and absence of the iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400 W) compared with the control group. Immunohistochemistry was used to check the loss of Nissl bodies in cerebral cortex neurons. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma were measured with real-time reverse transcription PCR (RT-PCR) and Griess reagent respectively.
Results showed that the 4-week UCMS significantly induced depressive-like behaviors, including decreased sucrose preference in a sucrose preference test, increased duration of immobility in a forced swim test, and decreased hole-searching time in a locomotor activity test. Meanwhile, in the locomotor activity test, UCMS had no effect on normal locomotor activities, such as resting time, active time and total travel distance. Furthermore, the levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. Neurons of cerebral cortex in UCMS-exposed mice were shrunken with dark staining, together with loss of Nissl bodies. The above-mentioned stress-related depressive-like behaviors, increase of iNOS mRNA expression in the cortex and nitrites in the plasma, and neuron damage, could be abrogated remarkably by pretreating the mice with an iNOS inhibitor (1400 W). Moreover, neurons with abundant Nissl bodies were significantly increased in the 1400 W + UCMS group.
These results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behaviors in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex.
The challenges of modern society are largely responsible for generating stress in human beings. Stress in turn engenders multiple neurochemical, neurotransmitter and hormonal changes. Studies carried out with some stress protocols (physical, psychological or mixed) show a proinflammatory response in the brain and other systems, mainly characterized by a complex release of several inflammatory mediators . In recent years, inflammation has been implicated in chronic psychiatric disorders. Cytokines such as interleukin (IL)-1β and IL-6 are elevated in the serum of depressed patients . Therefore, stress has been one of the most important pathogenic factors in several neuropsychiatric diseases such as depressive disorder. And stress exposure modifies the onset and evolution of some neurological diseases . According to a report from the World Health Organization (WHO), depression is the fourth highest contributor to the global burden of disease and is predicted to be in second place by 2020 . Therefore, it is important to reveal the mechanism of depression. However, it is still unknown that how chronic stress induces or precipitates depression.
Nitric oxide (NO), a free gaseous signaling molecule, is involved in the regulation of the nervous and immune system. It has been suggested NO is involved in depression and stress . There are three genetically different isoforms of nitric oxide synthase (NOS) that account for NO production: neuronal nitric oxide synthase (nNOS) being the isoform first identified in neurons, endothelial nitric oxide synthase (eNOS) being the isoform first identified in endothelial cells, and inducible nitric oxide synthase (iNOS), which can be synthesized following induction by proinflammatory cytokines or endotoxins . The NOS enzymes are widely distributed within the mammalian brain. NOS-positive neurons are located in the hippocampus, cerebral cortex and other encephalic regions . Various studies suggest the involvement of nNOS in the pathophysiological mechanism of depression-like behavior in rodents [7–10]. Over the last two to three decades, the ‘inflammatory depression hypothesis’ has attracted great attention. Chronic inflammation is often associated with clinical depression [11–15]. Chronic stress is associated with dysregulated immunity by overactivating the immune system, leading to low-grade inflammation . iNOS is inflammation inducible and plays no role in the brain under normal physiological conditions. However, under pathological conditions, iNOS may become important. Therefore, we chose iNOS as our focus to identify whether and how NOS is involved in the pathogenesis of the depressive behavior induced by chronic stress exposure.
Converging lines of research suggest that both functional alterations and structural changes in the volume of the hippocampal complex play roles in the pathophysiology of depressive disorder . And the effects of stress on the hippocampus are clear. The hippocampus is often considered to be the classical region to assess morphological effects related to depression. However, morphological plasticity has been less intensively studied in the cortex than in the hippocampus under stressed conditions. Furthermore, clinical and experimental evidence suggest the cortex is pathophysiologically related to depression. However, it is unknown what roles the cortex plays in stress-initiated depression. We selected the cortex for morphological assessment in our present study to investigate its potential importance in stress-related depression.
Considering that chronic stress can induce inflammatory responses and depressive behaviors in animals, and iNOS is inflammation inducible, we hypothesize that iNOS plays a critical role in stress-related depression. If the above assumption is true, the levels of iNOS and NO should be changed in stress-exposed animals. Additionally, an inhibitor of iNOS should block the alteration of iNOS and NO, followed by the recovery of depressive behaviors induced by stress exposure. The potential mechanism underlying the antidepressant effects of iNOS inhibitor may be neuron protection. Therefore, the present study was performed to verify the above hypothesis in a step-by-step manner.
Quantscript cDNA RT kit (catalogue no. KR-103), reverse transcriptase kit and TRIzol reagent were purchased from Tiangen Biotech (Beijing, China). Real-time reverse transcription PCR (RT-PCR) primers for iNOS (catalogue no. M301149, M301150) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; catalogue no. M301155, M301156) were all obtained from Sangon Biotech (Shanghai, China). Total nitric oxide assay kit and iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400 W) were obtained from Beyotime Institute of Biotechnology (Jiangsu, China). Other reagents and chemicals were obtained from Sigma Aldrich (St. Louis, MO, USA).
Animals and chronic unpredictable mild stress model
Unpredictable chronic mild stress procedure
8:00 AM to 10:00 PM: tilted cage
10:00 AM to 12:00 AM: cage shaking for 10 minutes
17:00 PM to next day: damp bedding
9:00 AM to 11:00 AM: swimming at 4°C for 5 minutes
15:30 PM to 17:30 PM: confinement in tube for 2 h
22:00 PM to next day: food and water deprivation
21:00 PM to 22:00 PM: sucrose preference test
17:30 PM to next day: persistent illumination
9:00 AM to 11:00 AM: 45°C oven for 5 minutes
18:00 PM to next day: tilted cage
13:30 PM to 15:30 PM: confinement in tube for 2 h
19:00 PM to next day: damp bedding
20:00 PM to next day: food and water deprivation
19:30 PM to 20:30 PM: sucrose preference test
10:30 AM to 12:30 PM: confinement in tube for 2 h
17:00 PM to next day: damp bedding
8:00 AM to 10:00 PM: tilted cage
19:30 PM to next day: persistent illumination
10:00 AM to 12:00 AM: cage shaking for 10 minutes
21:00 PM to next day: food and water deprivation
20:00 PM to 21:00 PM: sucrose preference test
19:00 PM to 21:00 PM: 45° C oven for 5 minutes
8:00 AM to 10:00 PM: tilted cage
13:30 PM to 15:30 PM: confinement in tube for 2 h
9:00 AM to 11:00 AM: cage shaking for 10 minutes
17:30 PM to next day: persistent illumination
23:00 PM to next day: food and water deprivation
22:30 PM to 23:30 PM: sucrose preference test
Sucrose preference test
Anhedonia was measured by preference for a sucrose solution over water, using a two-bottle free choice method : each animal was presented simultaneously with two bottles, one containing 1% sucrose solution (w/v), the other containing tap water. Blunted sucrose intake in this test is proposed to reflect impaired sensitivity to reward and model anhedonia, a core symptom of major depression . Tap water and 1% sucrose solution were placed in premeasured bottles in the cages, and fluid intake was monitored for 1 h. Both bottles were removed and weighed after 1 h. Mice were given access to sucrose solution for 2 weeks preceding the experimental procedures to adapt to this taste. Sucrose preference tests were timetabled during the dark phase (19:00 PM to 20:00 PM) in the home cage. Mice were denied food and water for about 20 h before each sucrose preference test. The baseline preference test was performed before the onset of stress, and preference tests were then conducted weekly throughout the UCMS period. Sucrose preference was evaluated via the sucrose uptake rate, namely, the ratio of volume of sucrose consumption to the volume of sucrose consumption plus tap water consumption (sucrose preference = sucrose consumption/(sucrose consumption + water consumption) × 100%).
Locomotor activity test
On the subsequent day after the last sucrose preference test, a locomotor activity test was carried out during the night. The locomotor activity test is used to measure spontaneous activity in rodents. The apparatus consisted of a dark rectangular box with a square floor, divided into small rectangular units and holes. A single mouse was gently placed in the center of the box for 30 s of adaptation, and then allowed to freely explore the area for 5 minutes. All behaviors including the number of activities, the resting and active time, hole-searching time, and so on, were recorded automatically by DigBehv animal behavior analysis software (Jiliang Software Technology, Shanghai, China) during the 5 minutes. After each test, the floor was cleaned thoroughly with 75% alcohol solution to eliminate possible bias due to odors left by previous mice .
Forced swim test
The forced swim test (FST) was performed following the locomotor activity test at night-time, conducted as described previously . Briefly, each mouse was placed individually in a transparent cylindrical polypropylene tank (40 cm height × 30 cm diameter) containing 35 cm of water at 25 ± 1°C, without the possibility of escaping. Mice were forced to swim in the water for 6 minutes. A mouse was judged immobile when it floated in an upright position, and could only move slowly to keep its head above water. The duration of immobility during the final 5 minutes of the test was recorded. This immobile posture reflects a state of behavioral despair or helplessness . Mice were dried immediately and returned to their home cages after the swimming test.
After the behavioral tests, three mice from each group were deeply anesthetized and perfused with 4% paraformaldehyde for subsequent Nissl staining. The other animals were anesthetized and killed; blood was collected and brains were removed. Blood, anticoagulated with 1.5% EDTA was centrifuged at 12,000 rpm for 10 minutes, and then the supernatant was collected. All these samples were stored at −80°C for further analysis.
RNA extraction and reverse transcription
Total RNA was extracted from the brain tissue using TRIzol reagent. Total mRNA (1 μg) was reverse transcribed using Quantscript cDNA RT Kits according to the manufacturer’s manual. Briefly, RNA (1 μg) was pretreated with DNA-free DNase treatment and removal reagents. RNA samples were incubated with a mixture consisting of containing dNTPs, random primers, 10× RT mix, Quant Reverse Transcriptase, a reverse transcriptase and RNase-free water to a final volume of 10 μl at 37°C for 1 h.
cDNA was used for quantification of mRNA by real-time RT-PCR. Real-time RT-PCR was performed on an Applied Rotor-Gene 3000 (Corbett Research, China)under the following conditions: iNOS and GAPDH for 40 cycles at 94°C for 30 s, 63°C for 60 s, and 72°C for 90 s. Relative quantitative measurements of target gene levels were performed using the ΔΔCt method, where Ct is the threshold concentration. GAPDH was used as endogenous control to normalize gene expression data, and an RQ value was calculated for each sample. RQ values are presented as fold change in gene expression relative to the control group, which was normalized to 1. The following oligonucleotides were used as primers: iNOS (forward, 5'-GACTGCACAGAATGTTCCAG-3'; reverse, 5'-TGGCCAGATGTTCCTCTATT-3'), GAPDH (forward, 5'-TCCCTCAAGATTGTCAGCAA-3'; reverse, 5'-AGATCCACAACGGATACATT-3') .
Total NO production assay
Total NO production was estimated by measurement of the accumulation of nitrite and nitrate in plasma spectrophotometrically using the Griess reagent by Total Nitric Oxide Assay Kit (Beyotime, Jiangsu, China). Nitrate was measured after enzymatical conversion to nitrite by nitrate reductase. Nitrite is the stable reactive end production of NO. Briefly, 60 μl of each sample supernatant was mixed with an equal volume of dilution buffer in duplicate wells of a 96-well plate at room temperature. The mixture was incubated with 5 μl of nicotinamide adenine dinucleotide phosphate (NADPH), 10 μl of flavin adenine dinucleotide (FAD) and 5 μl of nitrate reductase for 15 minutes at 37°C. Then, 10 μl of lactate dehydrogenase (LDH) buffer and 10 μl of LDH were added in the above reaction buffer for another 5 minutes at 37°C. Finally, 50 μl of Griess reagent I and 50 μl of Griess reagent II were mixed into all the above wells before incubation for 10 minutes. Optical density at 540 nm was measured with an OPTImax multiplate reader. Concentrations were calculated by comparing absorptions with those of a standard curve (50, 20, 10, 5 and 2 μM sodium nitrite).
After behavioral tests, three mice from each group were deeply anesthetized and perfused through the left heart ventricle with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). The brain tissues were removed and post fixed immediately in the same fixative solution at 4°C for 48 h. Next, the tissues were dehydrated and immersed in paraffin, cut into 4 μm sections, mounted on slides. For Nissl staining, the sections were hydrated in 1% toluidine blue at 50°C for 20 minutes. After rinsing with double distilled water, they were dehydrated and mounted with permount. The cortex was captured and cell numbers were quantitatively analyzed with Imaging Pro-Plus (LEIKA DMLB).
To estimate the number of undamaged neurons in the cortex after treatments, photos of immunohistochemical slides were taken using a digital camera connected to a microscope at 100× and 400× magnification. Neurons with round cell bodies, visible nucleus and abundant Nissl bodies were considered undamaged, while Nissl-positive cells with dark staining in which the nucleus were not discernable were considered damaged . Detailed performance and measurements were as previously described .
For multiexperimental group analysis, data were analyzed using a one-way analysis of variance (ANOVA), followed by a post hoc pairwise multiple comparison using Fisher’s least significant difference test if the interaction was significant. The time course of sucrose preference was analyzed by repeated measures ANOVA. Statistical significance was determined as P < 0.05. All data are presented as the mean ± SEM.
To explore whether and how depressive behavior was induced by UCMS, mice were treated with UCMS for 4 weeks in the presence and absence of the iNOS inhibitor 1400 W. Depressive behaviors were measured and analyzed, and iNOS expression and neuron viability were also assayed.
Decrease of sucrose preference was induced by UCMS in a time-dependent manner
Increase of iNOS mRNA expression induced by UCMS was abrogated by the iNOS inhibitor 1400 W
Decrease of sucrose preference induced by UCMS was modulated by the iNOS inhibitor 1400 W
1400 W abrogated the increase of immobility time in forced swim test by UCMS
1400 W abrogated the decrease of hole-searching time but had no effect on central time and total travel distance in locomotor activity test by UCMS
Locomotor activity was not modulated by UCMS and the iNOS inhibitor 1400 W
1400 W protected cortical neurons from damage induced by UCMS
The results of the present study demonstrated that chronic stress significantly induced depressive-like behaviors in mice. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. The neurons of the cerebral cortex in UCMS-exposed mice were shrunken, together with loss of Nissl bodies. However, the stress-related depressive-like behaviors, the increase of iNOS mRNA expression and nitrites, and neuron damage were remarkably abrogated by pretreating the mice with an iNOS inhibitor (1400 W).
The relationship between NO and depression has been noticed clinically. Plasma nitrate concentrations, an index of NO production, are prominently higher in depressed patients . Additionally, some antidepressants inhibit the enzymatic activity of NOS in animals and humans [34, 35]. The above facts implied a possible involvement of NO in depression. In the past few years, several groups have consistently reported that nNOS indeed plays a crucial role in depression. The evidence for nNOS involvement in depression includes nNOS expression increasing in the hippocampus  and nNOS inhibition preventing and reversing depressive-like behaviors [37, 38]. Recently, Wang et al. reported that iNOS also made contributions to the mechanism of depression by using intrahippocampal injections of the iNOS inhibitor aminoguanidine . This research did not explore whether systemic injection of iNOS inhibitor has the similar effect on depressive-like behavior, and how the iNOS inhibitor functions, which is our focus in this study. Mice were treated with UCMS for 4 weeks consecutively in the presence or absence of the specific iNOS inhibitor 1400 W. The results showed that treatment of mice with the iNOS inhibitor 1400 W prevented the decrease of sucrose preference (P < 0.05), the increase of immobility time in FST (P < 0.01), and the decrease of exploring time in the locomotor activity test (P < 0.01) induced by UCMS. These actions are specific to depressive-like behavior and have no effect on locomotor activity such as active time and resting time, which reflects sickness behavior.
In accordance with the change of depressive-like behavior, the iNOS inhibitor 1400 W exhibited a significant protection on neurons compared with UCMS group (P < 0.01). UCMS caused the loss of Nissl bodies in the cerebral cortex neurons, and 1400 W pretreatment prevented this loss. Namely, blocking NO abrogated neuronal damage caused by UCMS. This protection by 1400 W might be related to neuronal functional impairment and structural damage caused by excessive NO. In fact, stress-related events including depression are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators . It has been shown that repeated and unpredictable stress situations increase generation of reactive oxygen species (ROS) in the brain, which in turn results in oxidative damage in the central nervous system [40, 41]. Recent findings indicate a key role for NO and an excess of pro-oxidants in various brain areas is responsible for both neuronal functional impairment and structural damage . Nevertheless, the effects of oxidative stress in this present system require further study, such as the measurement of some oxidative/antioxidative parameters.
Over the last two to three decades, inflammatory depression has attracted increasing attention in the field of depression [43, 44]. The main theory of inflammatory depression is that the activation of the inflammatory immune system may influence neurochemicals or damage neurons and contribute to depression . Under physiological conditions, these proinflammatory cytokines enhance neurogenesis. However, excessive or prolonged cytokine exposure may damage the brain (including affecting the metabolism of neurotransmitter and neuropeptide, neuroendocrine and neural plasticity, decreasing neurogenesis, increasing glutamatergic activation, oxidative stress, and induction of apoptosis) [46–50]. Chronic inflammation is often associated with clinical depression [51–53]. Chronic stress dysregulates immunity by overactivating the immune system, leading to low-grade inflammation. iNOS is inflammation inducible. Therefore, we conclude that iNOS may play an important role in the depressive behavior induced by chronic stress exposure. Based on our experimental results, chronic stress leads to a prominent increase of inflammatory mediators (data not shown), which is consistent with reports from other groups [42, 54, 55]. These results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behavior in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex. A dose course is recommended in future studies to further establish the rationale between UCMS-related depressive behavior and iNOS/NO. Additionally, complete measurement of the alteration of iNOS in individual brain regions is also suggested, so that the key regions related to UCMS-induced depression based on iNOS/NO can be identified and located.
In summary, the present study supports the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behavior in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex. These studies provide new insights into the mechanisms underlying the responses of depression to UCMS. A better understanding of the role of key signaling mediators in depression could aid the development of novel pharmacological agents. Further studies on detailed and in-depth molecular mechanisms of iNOS in UCMS-induced depressive-like behavior are recommended.
The authors have no conflicting financial interests. This work was supported by NSFC (30971190, 81171124), Innovation Program of Shanghai Municipal Education Commission (11ZZ74) and Shanghai Pujiang Program (10PJ1412400) to Y-XW.
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