A video monitoring system Hikvision video monitoring system, Hangzhou, China was used to capture the animal behavior for later analysis. Time spent exploring each object was calculated by an observer blind to the experimental conditions and was expressed as a percentage of the total exploration time.
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Figure 2. PTZ kindling-induced cognitive impairment. A Schematic of NOR test.
Mice were habituated to the NOR arena in the absence of objects for 15 min per day for 2 consecutive days, after which they were exposed in the same arena for 10 min to two identical objects A and A' for training. After 4 days of NOR test, the mice were recovered for 24 h and then subjected to 2 days of sucrose preference test. The sucrose preference test was used to assess the taste preference of sweetened water. A diminished preference for the sweetened water is a sign of anhedonia, indicating depressive-like behavior.
The sucrose preference test was conducted as previously described Strekalova et al. To avoid place preference in drinking behavior, the position of the bottles was switched after 24 h. The consumption of tap water and sucrose solution was estimated simultaneously in control and experimental groups by weighing the bottles. The preference for sucrose was calculated as a percentage of consumed sucrose solution of the total amount of liquid drunk. The food preference is also calculated as a control to demonstrate that mice do not show a place preference.
After the sucrose preference test, the mice were recovered for 24 h and then subjected to tail-suspension test followed by forced swim test. The tail-suspension test was used to evaluate depressive-like behaviors in animals. The method is based on the observations that mice suspended by the tails show immobility, which reflects despair of hope.
The tail-suspension test was performed as previously described Steru et al. Each mouse was suspended at a height of 50 cm using a thread tied with the tip of tail. The mice were considered to be immobile when they did not show any movement of body and hanged passively. The duration of immobility was recorded throughout the 5 min test period.
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The forced swim test was created as a situation of despair and allows to assessing the depressive-like behavior. Although some studies indicate that FST reflects a passive stress coping and adaption mechanism de Kloet and Molendijk, ; Commons et al. The forced swim test was performed as previously described Porsolt et al. Mice were judged to be immobile when if floated in an upright position and made only small movements to keep its head above water for more than 2 s. The duration of immobility during the 6 min of trial was recorded using the video monitoring system Hikvision video monitoring system, Hangzhou, China.
After each test, the container was washed and refilled with fresh water. Hippocampal sections were then rinsed with PBS three times and mounted on gelatin-coated slides. Hippocampal tissues were lysed for 15 min in tissue lysis buffer Beyotime Biotechnology, China. After several washes, the membranes were incubated with HRP-linked secondary antibody Boster Bioengineering, Wuhan, China diluted , for 1 h.
Tukey's test was used for post-hoc comparisons. A Spearman rank correlation coefficient was used to determine any correlation between the immobility duration under the condition of forced swim and tail suspension and the seizure score during kindling development. PTZ-kindled mice showed a gradual increase of seizure intensity, compared with the mice in control group Figure 1B. PTZ kindling as a chronic epilepsy experimental model is usually associated with neuronal plasticity and causing psychiatric comorbidities.
To determine whether PTZ kindling affects cognition and depressive-like behavior in mice, we performed a variety of neurobehavior tests 24 h after the mice were fully kindled. During the training phase, both PTZ-kindled and vehicle control mice spent almost the same percent of time exploring the two identical objects A and A' Figure 2B. However, in the testing phase, the vehicle control mice spent more time exploring the novel object B compared to the familiar object A Figure 2C , indicating that they remembered the familiar object A from the training phase and thus had a preference for the novel object B in the testing phase.
In contrast, during the testing phase, PTZ-kindled mice spent almost the same amount of time exploring both the novel object B and the familiar object A Figure 2C , suggesting that these mice did not remember the familiar object A during the training phase and had a cognitive deficit. We examined the depressive-like behaviors by using sucrose preference, forced swim and tail suspension test.
Our data show that PTZ-kindled mice showed significantly reduced sucrose water consumption Figure 3A and the percentage of sucrose water consumption Figure 3C compared to vehicle control mice. However, the tap water Figure 3B and food consumption Figure 3D,E between these two group of mice remains similar. Immobility in forced swim and tail-suspension test represents a symptom of depression. Our data show that PTZ-kindled mice in both forced swim Figure 3F and tail-suspension test Figure 3G displayed significant increase of immobility duration, suggesting these mice had depressive-like behavior.
Furthermore, we examined the immobility duration under the conditions of the forced swim and tail suspension correlated with the severity of behavioral seizures during kindling process in individual mice. Our data show a strong positive correlation between the duration of immobility and the seizure score during PTZ kindling development in forced swim as well as tail-suspension test Figure 3H.
Taken together, these results suggest that PTZ kindling induced cognitive impairment and depressive-like behaviors.
Figure 3. PTZ kindling-induced depressive-like behavior. The coefficient of correlation r is calculated using the Spearman test. In contrast, during the testing phase, the wildtype kindled mice spent almost the same amount of time exploring both the novel object B and the familiar object A Figure 4B , indicating that these mice did not remember the familiar object A during the training phase and had a cognitive deficit.
These data suggests that PTZ kindling induced cognitive impairment. Figure 4. We then examined the depressive-like behaviors by using sucrose preference, forced swim and tail suspension test.
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In forced swim and tail-suspension test, we found that wildtype kindled mice displayed significant increase of immobility duration compared to wildtype control mice in both forced swim Figure 4E and tail-suspension test Figure 4F. These data suggests that PTZ kindling induced depressive-like behavior.
http://vapiere.com/sitemap2.xml Taken together, these results indicated that PTZ kindling-induced cognitive impairment and depressive-like behavior is dependent on nNOS activity. Figure 5. The MAPK signaling pathway is involved in modulation of various physiological and pathological events.
Our results revealed that phosphorylation of p38 and ERK in the hippocampus of wildtype kindled mice was significantly increased compared to wildtype control mice. Our results showed that PI3K level and phosphorylation of AKT in the hippocampus of wildtype kindled mice was significantly increased compared to wildtype control mice.
Cognitive dysfunction and depressive like behavior have been reported as main neurobehavioral comorbidities of chronic epilepsy, which significantly impact the outcomes and affects the life quality of epilepsy patients. Cognitive impairment in is evident in children with epilepsy. It is reported that children with generalized nonabsence seizures were at increased risk for learning abilities Zalachoras et al.
Furthermore, Children who have pharmacoresistant seizures appear to have lower IQ scores than children with well controlled seizures Guo and Commons, Adults with chronic epilepsy are also reported to have cognitive impairment Hutton et al. Moreover, the incidence of depression is remarkably higher in epilepsy patients than that in the normal people Cramer et al.
PTZ Kindling is a well-established chronic epilepsy model that has been extensively studied to understand the pathological mechanisms of epilepsy. Here in this study, we found that PTZ kindling triggered cognition impairment and depressive like behavior, which is in agreement with previous reports Russo et al. Although epilepsy is known to be relevant to a high incidence of cognition deficits and depressive-like behavior, the responsible underlying mechanisms remains elusive.
NO has been recognized as a neuronal messenger, which is involved in regulation the balance of neurotransmission West et al.
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It is suggested that alterations of NO signaling may contribute to the pathophysiology of cognition deficits Walton et al. When nNOS knockout mice are subjected to focal ischemia, they have smaller infarcts, suggesting a protective role of nNOS against neurotoxicity Huang, To define a primary role of nNOS on PTZ kindling-induced psychiatric comorbidities, we measured the cognition function and depressive-like behavior in nNOS deficient mice and their wildtype littermates under normal and PTZ kindling conditions.
We demonstrated that PTZ kindling-induced cognition deficit and depressive-like behavior is dependent on nNOS activity. Redox homeostasis is essential for maintain normal function of brain. Excessive production of ROS, a hallmark of redox homeostasis impairment in the brain, appears to be involved in the pathogenesis of epilepsy Rowley et al. Mounting evidence suggests that increased oxidative stress in the brain was usually accompanied with cognition deficit and depressive-like behavior.
In summary, here we have used a PTZ kindling epilepsy model, supported by a genetic nNOS deficient mice, to demonstrate nNOS as a critical signaling in PTZ kindling -induced comorbidities including cognitive impairment and depressive-like behavior. Our understanding of the role of nNOS signaling in PTZ kindling-induced cognition deficit and depressive-like behavior may provide insight into the molecular mechanism for psychiatric comorbidities in chronic epilepsy patients. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.