摘要
研究目的：丙泊酚是临床手术常用的麻醉药物之一,该药物对手术后认知功能是否产生负面影响是临床关注的重要问题。本论文以大鼠为研究对象,以工作记忆认知功能为切入点,研究静脉注射临床关心的0.9mg/Kg.min丙泊酚在手术后不同时期大鼠工作记忆行为学特征；以及在工作记忆责任脑区(前额叶皮层)上两类不同模态的神经信号——局部场电位(local field potential, LFP)和神经元集群动作电位编码工作记忆事件的模式,研究0.9mg/Kg.min丙泊酚对工作记忆功能的影响。论文的研究为临床提供了支持。
研究方法：
1.实验动物雄性SD大鼠10只,体重300-350g,在Y迷宫中进行工作记忆任务训练。
2.将实验大鼠随机分为两组,分别记为丙泊酚组(5只)和对照组(5只)。丙泊酚组大鼠按0.9mg/kg-min剂量鼠尾静脉注射丙泊酚2小时,
3.在两组大鼠前额叶皮层在体植入16通道微电极阵列。
4.在术后每天对两组大鼠进行工作记忆能力测试,并应用Cerebus128通道信号采集系统记录两组大鼠在工作记忆过程中前额叶皮层的16通道神经电信号。直到丙泊酚组大鼠工作记忆行为达到训练标准(正确率90%)。
5.从16通道原始记录神经电信号中分离LFPs和动作电位(AP)
对所记录的原始神经电信号进行低通滤波(0.5-500Hz),得到16通道局部场电位(Local Field Potentials, LFPs);原始数据经高通滤波(500-7.5KHz),再通过阈值检测获取spikes, spikes信号经过sorting获得动作电位时空序列。
6.两组大鼠前额叶皮层16通道LFPs对工作记忆事件的编码
(1) LFPs预处理去除16通道LFPs信号中夹杂的工频干扰与基线漂移,获取零均值16通道LFPs。
(2)LFPs相关编码的时空分布
取窗口长50ms,从初始时间开始,计算一个窗口中16通道LFPs的相位相关：应用Hilbert变换获取16通道LFPs的相位；选取平均放电频率最高的通道作为参考通道；计算其余15通道LFPs对参考通道LFP的相位相关。取窗口移动步长为12.5ms,移动窗口,分别在每个窗口中计算LFPs的相位相关,获得16通道LFPs相位相关编码的时空分布模式。
(3)LFPs复杂度编码的时空分布选窗口长为200ms,应用Lem-ziv复杂度算法,计算一个窗口中LFPs复杂度平均值,窗口移动步长为50ms,获得LFPs复杂度编码的时空分布。
7.两组大鼠前额叶皮层神经元集群频率对事件的编码。选取窗口200ms,移动步长为50ms,逐个计算每个窗口中神经元集群的发放频率,获得神经元集群频率编码的时空分布。
8.从大鼠在工作记忆过程中的行为学特征、前额叶皮层LFPs相关编码和复杂度编码以及神经元集群频率编码,研究静脉注射0.9mg/kg-min丙泊酚以后不同阶段,丙泊酚对工作记忆功能的影响。
研究结果：
1静脉注射0.9mg/kg-min剂量丙泊酚对大鼠工作记忆行为学影响
(1)丙泊酚组大鼠在第1、2、3天,工作记忆测试的正确率依次为55±5%、60±5%、70±4.6%,均低于对照组大鼠89±5%、92+4.7%、90±5%(P<0.01)。丙泊酚组大鼠在第4天,工作记忆的正确率为88±5%与对照组93±4%没有显著差别(P>0.05)。
(2)第1、2天测试中、丙泊酚组大鼠工作记忆正确率没有差别(P>0.05),第2、3、4天,丙泊酚组大鼠工作记忆任务执行正确率依次提高(P<0.05)。
2静脉注射0.9mg/kg-min丙泊酚对大鼠前额叶皮层LFPs相位相关编码的影响
(1)第1、2、3天,丙泊酚组大鼠在工作记忆参考点前1秒的LFPs相位相关平均值分别为0.3149±0.0828,0.2894±0.0924,0.3470±0.0753,在工作记忆参考点后1秒的LFPs相位相关平均值依次为0.2993±0.0627,0.3203+0.1024,0.3383±0.0865,参考点前后无显著变化(P>0.05)。第4天,参考点前1秒的LFPs相位相关平均值为0.1892±0.0429,后1秒为0.4270±0.0692,参考点后相位相关平均值显著高于参考点前(p<0.01)。
(2)第1、2、3、4天,对照组大鼠在参考点后1秒LFPs的相位相关平均值分别为0.4791±0.0964、0.4801±0.0831、0.4853±0.0719、0.4361±0.0768,参考点后1秒LFPs的相位相关平均值分别为0.1687±0.0546、0.1661±0.0379、0.1663±0.0382、0.1739±0.0296,参考点后均高于参考点前(p<0.01)。
3静脉注射0.9mg/kg-min丙泊酚对大鼠前额叶皮层LFPs复杂度编码的影响
(1)第1、2、3天,丙泊酚组大鼠在工作记忆参考点前2秒的LFPs的复杂度平均值分别为0.2419+0.0864,0.2316±0.0817,0.2348±0.0941,在参考点后1秒复杂度平均值分别为0.2261±0.0314,0.2625+0.0843,0.2759±0.0847,在参考点前后无显著变化(P>0.05)。第4天,参考点后2秒16通道LFPs复杂度平均值分0.3917±0.0785,参考点前为0.2284±0.0634,参考点后的复杂度平均值高于参考点前(p<0.05)。
(2)第1、2、3、4天,对照组大鼠在参考点后LFPs的复杂度平均值为0.4437±0.0757、0.4562±0.0639、0.4692±0.0721、0.4823±0.0869,在参考点前LFPs的复杂度平均值为0.2019±0.0362、0.2548±0.0537、0.2219±0.0569、0.2465±0.0529,参考点后均高于参考点前(p<0.05)。
4静脉注射0.9mg/kg-min丙泊酚对大鼠前额叶皮层神经元集群频率编码的影响神经元频率编码的时空分布图显示：在参考点附近,丙泊酚组在第1、2、3天无明显集群,第4天有明显集群。第1、2、3、4天,正常组在参考点附近有明显集群。
研究结论：
本论文研究0.9mg/kg-min剂量丙泊酚对大鼠工作记忆功能的影响,分别从大鼠的工作记忆行为学实验、前额叶皮层16通道LFPs编码模式以及神经元集群频率编码进行研究,结论如下：
1对大鼠工作记忆行为学的影响
第1-3天,静脉注射0.9mg/kg-min丙泊酚降低了大鼠的工作记忆功能；大鼠的工作记忆功能可以随时间的延续而得到恢复,到第4天完全恢复到正常水平。
2大鼠前额叶皮层16通道LFPs编码工作记忆事件的影响
(1)第1-3天,静脉注射0.9mg/kg-min丙泊酚影响大鼠LFPs在参考点前后相位相关编码模式；第4天,该剂量丙泊酚不再影响LFPs在参考点前后的相位相关编码模式。
(2)第1-3天,静脉注射0.9mg/kg-min丙泊酚影响大鼠LFPs在参考点前后复杂度编码模式,第4天,该剂量丙泊酚不再影响LFPs在参考点前后的复杂度编码模式。
3对大鼠前额叶皮层神经元集群频率编码的影响在麻醉后1-3天,大鼠前额叶皮层神经元集群编码工作记忆事件的功能下降,工作记忆功能下降。在麻醉后第4天,神经元集群编码功能恢复。
Objective
Propofol is one of most common anethestic agent in clinical operations. Whether it brings negative effects in recognition ability or not after operations to patients is a widely forcused clinical problem. In the study, rats as research object, were infused with propofol according to0.9mg/Kg.min which was a interested dosage in clinic, and working memory behaviors of the rats in different post-operation periods were collected and analysed. we can get two different mode neural signals in the prefrontal cortex related to working momery:local field potential and action potentials of neurals group. We can get the effect on working momery through behavior characteristic、the coding mode of LFPs and the coding mode of action potentials of neurals group.
Methods
1. Laboratory animals
Male SD rats, weights300-350g, are trained in the Y type maze in order to grasp working momery task.
2. Separate10rats into two group. One is propofol group(5); the other is contrast group(5). The propofol groups are injected propofol as0.9mg/kg-min for two hours.
3. Implant multichannel micro-arrays in the prefrontal cortex of two group rats.
4. After the operations, the two group rats are tested working momery in the Y type maze. At the same time, records the16-channels neural signals in the prefrontal cortex of the rats, using the Cerebus-128, until the correct rate is much than90%.
5. Separate the LFPs and action potentials from the original signals.
16-channel LFPs were acquired through lowpass filtering the original data (0-500Hz).16-channel highpass signals were acquired through hrghpass filtering the original data (=500Hz). Spikes, or multi-unit, were recognized above-65μV thresholds and3.0SNR. Neuron action potential time-space series were got through sorting the16-channel valid spikes by Offline Sorter software (Plexon, USA).
6. The differents of the two group rats'LFPs coding working momery
(1) Local linear regression based on the weighted least square method was used to remove the baseline drift and power-line interference on LFPs.
(2) The phase synchronization pattern of16-channel LFPs Instantaneous phase extraction of16-channel LFPs:The method of instantaneous phase extraction was the commonly used Hilbert transform; Selecting a reference channel:The reference channel is of the fastest average firing rate in all channels; Sliding window and step parameter:The length of sliding widow is50ms and step is12.5ms; The synchronous phase activity of16-channel LFPs were obtained by calculating cross-correlation measure between the reference channel and other channels.
(3) The complex pattern of16-channel LFPs Select windows wide as200ms, using Lem-ziv complex method, calculates the average value of very window. Sliding step is50ms.
7. The coding pattern of neural ensemble's action potentials The rate code method of neuronal ensemble were scored in a selected window (200ms) with a moving step (50ms). The neuronal ensemble was performed by counting spikes in the window from the initial point to the end of the spatiotemporal sequences of neuronal firing.
8. Research the results from the behavior character、LFPs coding pattern and neural ensemble's rate code; summarize the effects on the rats'working momery affected by0.9mg/kg-min propofol.
Results:
1The effect on rats'behavior character
(1)At the first three days, the propofol groups'correct rate is55±5%、60±5%、70±4.6%in respectively, saller than the contrast groups'89±5%、92±4.7%90±5%(P＜0.01)。 At the fourth day the propofol group is88±5%, the same as the contrast group,93±4%(P＞0.05)。
(2) At the first two days, the propofol group is the same, from the second day,the correct rate is much than proxima luce (P＜0.05)。
2The effect on LFPs phase synchronization pattern
(1) At the first three days, mean of LFPs phase synchronization of the propofol group befor reference point are0.3149±0.0828,0.2894±0.0924,0.3470±0.0753in respectively, the same as the mean of LFPs phase synchronization of the propofol group after reference point0.2993±0.0627,0.3203±0.1024,0.3383±0.086(P>0.05)。 At the fourth day, mean of LFPs phase synchronization of the propofol group befor reference point is0.1892±0.0429, saller than the mean of LFPs phase synchronization of the propofol group after reference point (0.4270±0.0692)(p＜0.01)。
(2) In the contrast group the mean of LFPs phase synchronization after reference point is much larger than the mean befer the reference point, after reference point0.4791±0.0964、0.4801±0.083、0.4853±0.0719、0.4361±0.0768, befer the reference point0.1687±0.0546、0.1661±0.0379、0.1663±0.0382、0.1739±0.0296,(p＜0.01)。
3The complex pattern of16-channel LFPs
(1) At the first three days, mean of LFPs complex of the propofol group befor reference point are0.2419±0.0864,0.2316±0.0817,0.2348±0.0941, the same as the mean after reference point0.2261±0.0314,0.2625±0.0843,0.2759±0.0847,(P＞0.05)。 At the fourth day, mean of LFPs complex of the propofol group after reference point is0.3917±0.0785, much larger than the mean of LFPs complex of the propofol group befor reference point0.2284±0.0634,(p＜0.05)。
(2) In the contrast mean of LFPs complex after reference point are0.4437±0.0757、0.4562±0.0639、0.4692±0.072、0.4823±0.0869, much larger than mean of LFPs complex befor reference point0.2019±0.0362、0.2548±0.0537、0.2219±0.0569、0.2465±0.0529,(p＜0.05)。
4The coding pattern of neural ensemble's action potentials At the first three days, the propofol group dose not form the neural ensemble, at the fourth day, it dose. The contrast group forms the neural ensemble every day.
Conclusions
This paper aimed at the propofol effect on working momey among behavior character,16-channel LFPs, neuron action potentials and the conclusions as follows:
1The effect on the behavior character At the first three days,0.9mg/kg-min propofol decrease the rats'working momery. It can recovery at the fourth day.
2The effect on LFPs coding pattern
(1) At the first three days,0.9mg/kg-min propofol affect the rats'LFPs phase synchronization pattern. It can recovery at the fourth day.
(2) At the first three days,0.9mg/kg-min propofol affect the rats'LFPs complex pattern. It can recovery at the fourth day.
3The coding pattern of neural ensemble's action potentials
At the first three days, the propofol group dose not form the neural ensemble, It can recovery at the fourth day.
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