Changes in Physiological and Pathological Behaviours Produced by Deep Microelectrode Implantation Surgery in Rats: A Temporal Analysis

抽象

生理行为，如睡眠 - 觉醒周期和探索行为是在完整的和假手术动物的重要参数，并通常被认为是通过在其上执行神经外科实验方案不受影响。然而，在对神经疾病的动物模型深深植入微电极手术后观察到的行为和认知效果的文献证据不足。同样，在利用神经系统疾病的动物模型研究，正在研究手术对病理现象的影响往往是最小化。基于这些考虑，我们根据拉辛规模进行的，在安静觉醒，睡眠和探索活动和病理行为大鼠海马深植入微电极手术的效果时间分析，如抽搐发作。Male Wistar rats (210-300 g) were used and grouped in sham and epileptic animals. Single doses of pilocarpine hydrochloride (2.4 mg/2 μ升;i.c.v.）分别给予动物产生自发性和反复发作。在这两个群体和快速的涟漪分析深植入微电极手术进行。生理和病理行为是通过动物的直接视频监控（24/7）记录。我们主要的研究结果表明，在癫痫动物中，受术的主要行为之一就是睡眠;因为这行为改变的结果，在探索活动的减少也被发现以及规模4和尺度4和5的癫痫发作的次数，每天发作花费的平均时间手术后增加。FR和标尺4的扣押事件的发生之间没有显著相关（RHO 0.63，value 0.25) or 5 (rho -0.7,值0.18）中观察到。最后，微电极植入手术改性一些生理学和病理学的行为;因此，当它正在与动物模型来考虑这个事实是很重要的。

1.简介

生理行为，如睡眠 - 觉醒周期和探索行为是在完整的和假手术动物的重要参数，并通常被认为是通过在其上执行神经外科实验方案不受影响。However, there is insufficient evidence in the literature on the behavioural and cognitive effects observed after deep microelectrode implantation surgery in animal models of neurological diseases compared with studies carried out in patients with various brain pathologies [1,2]。In addition, most existing studies emphasize the morphological and molecular findings after surgery, such as inflammatory response, blood brain barrier disruption, or even fine motor deficit in control versus experimental animals without regard to physiological behaviours [3–9]。同样，在利用神经系统疾病的动物模型研究，正在研究手术对病理现象的影响往往是最小化。One example is research involving seizures and epilepsy models in which electrophysiological parameters, such as high-frequency oscillations, which are known to be associated with the disease are studied without regard to the possible effects of surgery. Moreover, these surgeries typically involve specific brain areas, such as the hippocampus and cortex; these areas contain circuits that are associated with the cognitive process through theta and gamma rhythms and ripple events and with specific physiological behaviours, such as the sleep-wake cycle [10–12]。Most of these surgeries involve the implantation of electrodes or microelectrodes into the brain for the purpose of recording electrical signals and/or the implantation of guide cannulas that are used to insert dialysis probes or fine needles for drug administration [10–13]。Based on these considerations, we performed a temporal analysis of the effects of deep microelectrode implantation surgery in the hippocampus of sham and epileptic rats on physiological and pathological behaviours. The physiological behaviours studied were quiet wakefulness, sleep, and exploratory activity, and the pathological behaviours studied were convulsive seizures according to the Racine scale. These behaviours were assessed over a period extending from 15 days before to 15 days after the surgery. In addition, (a) the relationship between the latency of the first spontaneous seizures and the time that lasted rats in Racine scales 3, 4, and 5 per day before and after surgery and (b) the correlation between the number of fast ripples (FR) recorded and the number and severity of seizure events on the same day were analysed.

2. Materials and Methods

2.1。动物和毛果芸香碱管理

Male Wistar rats weighing 210-300 g ( )使用。将动物圈养在24-27℃的温度下具有12小时光照和黑暗循环的房间和被允许自由运动和获得水和食物。动物的处理和维护由当地动物保护委员会的批准，并按照规范进行研究卫生事项（墨西哥官方准则NOM 062-ZOO-1999 NOM-033-ZOO-1995）进行。将大鼠分为两组：假手术组（ )和epileptic animals ( ）。

Single doses of pilocarpine hydrochloride (2.4 mg/2 μ升;Sigma-Aldrich, USA) were administered intracerebroventricularly (i.c.v.) to the animals in the epileptic group to generate a model of induction of spontaneous and recurrent seizures [14]。For this purpose, the animals were anaesthetized with oxygen-isoflurane prior to pilocarpine injection into the right lateral ventricle (AP -4.5 mm, ML -5.2 mm, and DV -7 mm from bregma) by means of a needle connected to an injection pump attached to the stereotactic frame (Stoelting Co., IL, USA). After pilocarpine administration, the behaviour of the animals was observed until status epilepticus (SE) based on the criteria of the Racine scale [15]。SE was indicated if the animals presented seizure-like events of scale 4 or 5 (Table1）。该SE was stopped after 90 minutes by systemic injection of diazepam (5-10 mg/kg, i.p.) to ensure the animals’ survival. Following this procedure, the animals were subjected to video monitoring 24/7 to detect spontaneous and recurrent seizures until subsequent microelectrode implantation surgery.

2.2。微电极植入手术

Both sham and epileptic rats were implanted with deep microelectrodes. The epileptic animals received the surgery 15 days after the first seizure was observed. The animals were anaesthetized with isoflurane in oxygen, and an array of 10 tungsten microelectrodes 60 μ米直径被注入到右海马区。阵列中的5个双极电极通过的500的距离彼此分开 μm。迪报道背腹侧的坐标pest relative to bregma. The electrodes were arranged as follows. One bipolar microelectrode was placed in CA3 (AP: -5.04 mm, ML: -4.5 mm, and DV: -6.5 mm), and two bipolar microelectrodes for DG were placed in the molecular (AP: -6.48 mm, ML: -4.6 mm, and DV: -5.6 mm) and polymorphic (AP: -6.48 mm, ML: -4.6 mm, and DV: -4.6 mm) layers. Granular layer recording was achieved with a derivation between tips, and DG full recording was obtained through the derivation between the nearest tip to the surface and the deepest tip inside DG. Two bipolar microelectrodes for CA1 were placed in the pyramidal (AP: -6.72 mm, ML: -5.8 mm, and DV: -4.8 mm) and radial (AP: -6.72 mm, ML: -5.8 mm, and DV: -5.6 mm) layers, and the 2 surface electrodes above bregma were considered as ground and indifferent. To confirm the correct position of microelectrodes, the animals’ brains were removed and cut in coronal sections (50 μm thick) in order to proceed with an immunohistochemistry directed to neurons (NeuN, data not showed).

2.3. EEG Recordings

After allowing a three-day period for recovery from the deep microelectrode implantation surgery, the animals in both groups (sham and epileptic animals) were recorded under free movement conditions for 90 minutes on days 1, 2, 3, 7, and 14. We used AcqKnowledge Data Acquisition software 4.0 as a user interface (BIOPAC Systems, USA) with an MP150 (BIOPAC Systems, CA, USA) as an analogue-to-digital converter for the recordings, which were conducted via polygraph (Model 7D, Grass Technologies, RI, USA) at a bandwidth of 0.1 to 5 kHz and sampling at 2.5 kHz per channel (7 channels) with 12-bit precision using an iMac A1048 (Apple, USA).

2.4. Detection of Fast Ripples and Correlation with Seizure Severity

该inclusion characteristics for FR selection in the present work were as follows: (1) FR were selected visually, (2) possible FR that had or peak-to-peak amplitude greater than 150 μV were eliminated, and (3) the recordings that passed the threshold were subjected to continuous wavelet transformation to ensure that the frequency event was temporally delimited and to eliminate the presence of 60 Hz or harmonics in the signal.

该analysis included the band from 250 to 600 Hz and was normalized to the highest wavelet energy coefficient in the recording channels; if the frequencies of possible FR coincided with the expected frequencies, the events were evaluated and classified as FR.

Signal and data analysis was realized offline using personalized programs written in MATLAB (MathWorks, Inc., USA), Python (License of Python Software Foundation, USA), or R (R Foundation for Statistical Computing, GNU General Public License, USA). A total of 346 events classified as FR were obtained in the different registration areas; these were correlated with different scales to determine the linear relationship of FR occurrence to the severity of seizures and indirectly relate it to the effects of surgery. For this purpose, we performed a Pearson correlation between the mean FR registered per day of EEG recording and the mean number of FR events of scales 4 and 5 that occurred on the same day of EEG recording (1, 2, 3, 7, and 14 days after surgery).

2.5。生理行为分析

动物的生理行为sham and epileptic groups were analysed according to episodes of sleep, wakefulness, and exploration. The analysis was performed over a period extending from 15 days before to 15 days after the deep electrode implantation surgery. Physiological behaviour was recorded through direct video monitoring of animals (24/7). Episodes in which the rat remained lying down with closed eyes were recorded as sleep; in quiet wakefulness, rats remained motionless but with open eyes. Scratching behaviours and episodes of movement related to eating or drinking were not included in the analysis. During exploratory episodes, the animals were in constant motion, continuously sniffing in the box with the presence of vibrissa movements, grooming, and raising. The purpose of this analysis was to compare the physiological behaviours of sham and epileptic rats before and after surgery.

2.6. Analysis of Convulsive Behaviour

To analyse the animals’ convulsive behaviour, the epileptic rats were subjected to continuous observation by video monitoring (24/7), and the latency to the appearance of the first spontaneous seizure of scale 4 or 5 on the Racine scale was recorded. The ranking of convulsive behaviour according to the Racine scale is as follows: scale 1, movement of lips and tongue, vibrissae movement, and salivation; scale 2, head clonus and eye clonus; scale 3, forelimb clonus, “wet dog shakes”; scale 4, raising of the forelimbs with clonic convulsions; and scale 5, raising of the forelimbs with clonic convulsions and loss of posture. Once the first seizure was presented, the behaviours of scales 3, 4, and 5 and their duration were quantified. This analysis was performed over a period extending from 15 days before to 15 days after the surgical implantation of deep electrodes.

2.7。统计分析

Comparisons between groups and surgery effects (pre- vs. postsurgery and intragroup) were performed using Student’s -test after Q-Q plots and the Shapiro-Wilk test for normality had confirmed that the -试验是合适的。统计显着性定义为获得values < 0.05. Pearson correlation was performed to correlate FR occurrence with seizure severity.

3. Results

In the analysis of deep EEG recordings obtained from the epileptic group, a total of 346 FR events were observed in the registration areas. When these were correlated with different scales to determine whether there was a linear relationship between FR occurrence and the severity of seizures and indirectly relate it to the effects of surgery, no significant correlations between the occurrence of FR and events of scale 4 (rho 0.63,value 0.25) or 5 (rho -0.7,观察值0.18）（图1）。

Epileptic animals showed a significant decrease in sleep time after surgery ( -测试， ),but their periods of quiet wakefulness and exploratory behaviours were not modified by surgery (Figure2(a)）。On the other hand, a reduction in the duration of the quiet wakefulness period was observed in animals in the sham group after surgery ( -测试， ),和the time spent by these animals in exploratory behaviour increased ( -测试， )(Figure2(b)）。癫痫和假动物的生理行为的比较显示在安静觉醒状态时假手术组在手术前一个显著上升（ -测试， )并增加了睡眠和探索行为时间在手术后（ -测试， 和 ,respectively) (Figure2(c)）。

In addition, the results showed that scale 4 events persisted for a long time after surgery ( -测试， ）;增加的数量秤4的事件和5中也观察到（ -测试， 和 ,respectively) (Figures3(a)和3(b)）。然而，事件的持续时间，并且每个尺度的事件的数量之间的比率仅表现为标尺4的癫痫发作的增加（图3(c)）手术后（ -测试， ）。当我们分析每手术在每个动物的前后期间，由15天延长期的每一天观察到15天的总发作事件的平均持续时间，我们发现，手术并没有改变癫痫的日常模式在动物中观察到（数字4）。具有短延时到第一次自发性发作（≤60天）的大鼠在拉辛规模前和手术后的标尺4的癫痫发作的持续时间呈高可变性。相比之下，动物长的等待时间（≥90天）图前和手术后（显示在此参数稳定格局4）。

4。讨论

我们发现在手术前的15天假癫痫组的平均睡眠时间没有差异;然而，应该指出的是，尽管随着深水动物每天花费时间都在睡觉的相同金额，癫痫大鼠进行了更多的睡眠时间。这与睡眠片段化的现象，其中增加的光睡眠和降低的睡眠效率，深度睡眠，快速眼动（REM）睡眠发生相符;这个现象已经在人类[被描述都16] and in animal models [17–19]。同样，癫痫大鼠在安静觉醒和探索行为与假手术组相比，花了更少的时间。类似这些改变患者的颞叶癫痫的观察和参与学习和记忆[18,20,21]。However, 15 days after implantation surgery, decreased sleep time and exploratory behaviour were observed in the epileptic rats. This could be evidence of decreased sleep quality in these animals [19,21–23] and may indicate that various diurnal symptoms such as excessive sleepiness or attention disorders were present in the animals during the time of quiet wakefulness, resulting in the decrease in exploratory behaviour observed in the epileptic animals. This effect in place could be similar to a phenomenon that has been observed in patients with TLE [18,19,23]。However, one limitation of our study was not comparing intact versus epileptic animals without implantation surgery. However, this result is consistent with the results of a previous study in which the implantation of deep electrodes for EEG recording modified the circadian cycle in rats with epileptic seizures, first decreasing their motor activity and subsequently increasing it [24]。我们研究的一个优点是，行为被列为安静觉醒，探索和睡眠，而不是仅仅作为活动相关的光暗周期。我们能够排除通过手术对癫痫组所产生的行为影响是由致病过程本身造成的，因为同样的行为进行了分析比手术前的15天期限的可能性。与此相反，假手术组，在平均时间显著上升的精力去探索和睡眠，以及在时间在安静觉醒状态所花费的金额手术后观察到的减少。这种类型的生理行为密切相关的海马振荡活动，如r和θ节律[24,25], as well as to various types of learning, such as spatial learning, planning [26,27]和存储器[28,29]。此外，有证据表明，皮层和海马病变导致神经元丢失和广泛的破坏影响不同的行为[30]。该refore, the injury generated by surgery could alter the rhythmic control of hippocampal activity and, at the same time, affect related behaviours through inflammatory responses and the death of distinct inhibitory interneurons in the hilus of the dentate gyrus [24]。该effect of this altered inhibition on pyramidal cells in the hippocampus was also observed in other studies in which spatial and nonspatial learning and memory tests were performed during epileptogenesis and TLE [20,26,27,31–33]。

In the same way, surgery increased the average duration of seizure events of scale 4 and the number of seizure events of scales 4 and 5. Although postsurgical modifications in the intensity of seizure events according to the Racine scale have not been described in the literature, a modification of the circadian cycle in animals subjected to surgery has been described [24]。我们的结果与在其中外科电极植入后观察到的增加的数量和癫痫发作持续时间等的研究的结果是一致的[17–19]。However, the observed increase in the number of seizure events was not accompanied by an increase in the average amount of time during which the rat experienced seizures of scale 5; seizures of scale 3 were not altered during the 30-day period (the number of events and the duration of seizures of scale 3 remained at a ratio of approximately 1 : 1). These results may be because it is easy to differentiate behaviours related to scale 3, such as shaking, because they persist for a longer time than physiological behaviours, such as scratching, grooming, and behaviours related to discomfort of the animal. The fact that there are technical difficulties associated with determining the loss of posture of epileptic animals during the video monitoring and thereby distinguishing between seizures of scales 4 and 5 could explain why events of scale 4 were the only class of events that showed a significant increase in duration after surgery.

To determine whether the observed change in seizure severity was due to surgery or was a direct effect of epileptogenesis, an intragroup analysis was performed in which the relationships between the latency to the first spontaneous seizure, the total duration of seizures of scales 3, 4, and 5, and the total number of seizure events per day per animal were assessed. The results showed a high variability in animals with compared with animals with latencies of ≥90 days. The epileptic animals with long latencies showed 4 s of seizures per day, very similar to the parameter of average time per event of scale 4, and this pattern remained after surgery and did not influence [34] or modify epileptogenesis; in addition, these animals displayed a better established pathological process in which there was less variability over time. Therefore, the changes observed inside the group of epileptic animals after surgery could be due to the intrinsic relationship between sleep and epilepsy [35,36] as well as to the impact of the sleep-wake cycle on the development of seizures. This is consistent with evidence found in human patients [37,38]。

最后，根据拉辛规模和FR活性癫痫发作的严重程度之间没有相关性，在本研究中发现，可能是因为它很难一次脑电图记录与动物的癫痫发作不谋而合。这是可以通过扩展在此期间，脑电图记录由与时间得到改善的技术限制。此外，很难以确定对FR手术植入的效果，因为它们只能被观察，并通过深EEG电极分析;因此，即使我们试图通过规模的严重程度之前和植入手术后间接确定它植入的效果是有限的。虽然我们无法比较文学与我们类似的数据结果，布拉金及其同事[33,39,40]表明与由红藻氨酸诱导的一个TLE模型早期自发性和复发性癫痫发作FR的早期发生和FR发生之间的直接关系。

5. Conclusions

我们的结论是在癫痫动物，受微电极植入手术的主要行为之一就是睡眠;因为这行为改变的结果，在探索活动的减少也被发现。此外，平均时间标尺4的发作，每天花费在癫痫大鼠接受微植入手术增加，在这些动物中观察到增加秤4和5的癫痫发作的次数手术后。与此相反，假手术组的动物显示在安静觉醒状态的减少和手术后增加睡眠和探索活动。在我们的研究中提出的另一项重要发现是，潜伏期首检和其变异的动物在其中等待时间大于90天后发现，一个稳定的格局。这阐明了在细胞，分子和电生理改变必须发生，以允许建立和癫痫的广义过程中抽搐的发展进程。在视频监控30天的24/7分析，我们观察到，对于规模5的癫痫发生，标尺4个癫痫发作是必要的，并且它是在本标尺4在其改变中观察到数和时间的事件;此外，这些变化在手术后15天依然存在。最后，观察到FR和不同尺度的发作事件的发生之间没有显著相关性。

Data Availability

该data used to support the findings of this study are available from the corresponding author upon request.

利益冲突

该authors declare that they have no competing interests.

作者的贡献

LMC participated in the design and supervision of the experiments, the analysis and discussion of the results, and the preparation and final revision of the manuscript. GACT and MANO contributed to the experiments, the analysis and discussion of the results, and the preparation of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

这项研究是通过在LMC，国家科学技术委员会，Secretaría教育协会Publica 250930的资助。

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版权© 2020 Gustavo A. Chiprés-Tinajero et al. This is an open access article distributed under theCreative Commons Attribution License，其允许在任何介质无限制地使用，分发和再现时，所提供的原始工作正确的引用。