丘脑NMDA受体在麻醉鼠大脑网络处理感觉信息中的作用
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摘要
目的：NMDA受体是中枢神经系统内非常重要的兴奋性突触受体,其分布广泛,大脑及脊髓都被证实有NMDA受体存在。研究表明NMDA受体是多种全身麻醉药物作用于中枢神经系统产生麻醉作用的效应靶点。然而在网络与系统水平,通过调节丘脑-皮层环路中的NMDA受体而产生对感觉信息处理的影响及其作用机制,仍然是一个有待研究的问题。基于此,在本研究中我们通过在大鼠丘脑腹后内侧核(ventral posteromedial nucleus, VPM)注射氯胺酮,记录注射前后初级体感皮层(Primarysomatosensory cortex, S1)的自发局部场电位(Spontaneous local field potentials, sLFPs)与体感诱发电位(Somatosensory evoked potentials, SEPs),观察脑区局部调节NMDA受体对大鼠丘脑-皮层环路感觉信息处理的影响。
方法：采用丙泊酚(propofol)对大鼠进行全身麻醉后,手术建立大鼠胞外电神经生理记录模型。在大鼠初级体感皮层内植入胞外记录金属电极。并通过气动装置偏转大鼠胡须刺激产生所需记录的SEPs。实验中利用特制玻璃微电极在分别在各组大鼠VPM内注射NMDA受体阻断剂AP-51μl (5μg/μl)、氯胺酮1μl (25μg/μl或12.5μg/μl)及生理盐水1μl。采集注射前300秒、注射后0-300秒、300-600秒、600-900秒等各时段的SEPs与注射前600秒注射后600秒的sLFPs,并分析比较其在用药前后的变化与差异。
结果：
1.在丘脑VPM中微量注射AP-51μl(5μg/μl)后,S1区内的δ(1-4Hz)、θ(4-8Hz)、β(12-25Hz)及γ(25-60Hz)四个频段电活动较注射前显著降低。另外注射AP-5后各时段的SEPs的反应电压幅度较注射前也明显降低；
2.在丘脑VPM中微量注射氯胺酮1μl (25μg/μl)后,S1区内的β(12-25Hz)及γ(25-60Hz)两个频段电活动及SEPs的反应电压幅度均显著降低；
3.在丘脑VPM中微量注射氯胺酮1μl (12.5μg/μl)后,S1区内的δ(1-4Hz)、α(8-12Hz)、β(12-25Hz)及γ(25-60Hz)两个频段电活动及SEPs的反应电压幅度均显著降低；
4.在丘脑VPM中微量注射生理盐水(1μl),对S1区内记录到的sLFPs各频段电活动及SEPs的反应电压幅度均无显著影响；
结论：通过阻断丘脑VPM内的兴奋性NMDA受体,可使外周传入大脑皮层的感觉信息量减少。同时由于丘脑皮层环路的存在,抑制丘脑部分核团的兴奋性可以显著降低丘脑皮层环路的自发电活动,从而降低大脑感觉皮层的兴奋性。
Objective:N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors which are widely expressed in the central nervous system. Many anesthetics are known as NMDA receptor antagonists, but the local effects of these drugs on NMDA receptors are not clear. The sensory processing in thalamocortical circuit remains an open issue. In this study, we investigated the changes of tactile sensory processing in primary somatosensory cortex (S1) of rats by locally blocking the NMDA receptors in ventral posteromedial nucleus (VPM).
Methods:The study included 24 rats. During experiment procedure, anaesthesia was induced and maintained by infusion propofol. After surgery an extracellular tungsten electrodes were inserted into S1 for recording spontaneous local field potentials (sLFPs) and Somatosensory evoked potentials (SEPs) and a micro glass electrode was inserted into VPM for infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP-5) 1μl(5μg/lμl), ketamine 1μl (25μg/1μμl or 12.5μg/lμl) and saline solution 1μl. An extracellular AC amplifier was used and the raw electric signals were collected via an CDE 1401 interface to a personal computer. Whisker stimuli were performed by deflections of the optimal whisker on the contralateral face. spontaneous sLFPs power spectrum and SEPs were analysed before and after administration of NMDA receptor antagonists.
Results:
1. After administration of AP-51μl(5μg/μl), the amplitude of SEPs was lower andδ(1-4Hz),θ(4-8Hz),β(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
2. After administration of ketamine 1μl (25μg/μl), the amplitude of SEPs was reduced andβ(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
3. After administration of ketamine 1μl(12.5μg/μl), the amplitude of SEPs was reduced andδ(1-4Hz), a(8-12Hz),β(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
4. After administration of saline solution 1μ1 there was no significant deviation on sLFPs and SEPs than befor infusion.
Conclusions:The findings indicate that locally blocking NMDA receptor in VPM can reduce the excitability of primary somatosensory cortex which may result in a loss of information capacity.
方法：采用丙泊酚(propofol)对大鼠进行全身麻醉后,手术建立大鼠胞外电神经生理记录模型。在大鼠初级体感皮层内植入胞外记录金属电极。并通过气动装置偏转大鼠胡须刺激产生所需记录的SEPs。实验中利用特制玻璃微电极在分别在各组大鼠VPM内注射NMDA受体阻断剂AP-51μl (5μg/μl)、氯胺酮1μl (25μg/μl或12.5μg/μl)及生理盐水1μl。采集注射前300秒、注射后0-300秒、300-600秒、600-900秒等各时段的SEPs与注射前600秒注射后600秒的sLFPs,并分析比较其在用药前后的变化与差异。
结果：
1.在丘脑VPM中微量注射AP-51μl(5μg/μl)后,S1区内的δ(1-4Hz)、θ(4-8Hz)、β(12-25Hz)及γ(25-60Hz)四个频段电活动较注射前显著降低。另外注射AP-5后各时段的SEPs的反应电压幅度较注射前也明显降低；
2.在丘脑VPM中微量注射氯胺酮1μl (25μg/μl)后,S1区内的β(12-25Hz)及γ(25-60Hz)两个频段电活动及SEPs的反应电压幅度均显著降低；
3.在丘脑VPM中微量注射氯胺酮1μl (12.5μg/μl)后,S1区内的δ(1-4Hz)、α(8-12Hz)、β(12-25Hz)及γ(25-60Hz)两个频段电活动及SEPs的反应电压幅度均显著降低；
4.在丘脑VPM中微量注射生理盐水(1μl),对S1区内记录到的sLFPs各频段电活动及SEPs的反应电压幅度均无显著影响；
结论：通过阻断丘脑VPM内的兴奋性NMDA受体,可使外周传入大脑皮层的感觉信息量减少。同时由于丘脑皮层环路的存在,抑制丘脑部分核团的兴奋性可以显著降低丘脑皮层环路的自发电活动,从而降低大脑感觉皮层的兴奋性。
Objective:N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors which are widely expressed in the central nervous system. Many anesthetics are known as NMDA receptor antagonists, but the local effects of these drugs on NMDA receptors are not clear. The sensory processing in thalamocortical circuit remains an open issue. In this study, we investigated the changes of tactile sensory processing in primary somatosensory cortex (S1) of rats by locally blocking the NMDA receptors in ventral posteromedial nucleus (VPM).
Methods:The study included 24 rats. During experiment procedure, anaesthesia was induced and maintained by infusion propofol. After surgery an extracellular tungsten electrodes were inserted into S1 for recording spontaneous local field potentials (sLFPs) and Somatosensory evoked potentials (SEPs) and a micro glass electrode was inserted into VPM for infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP-5) 1μl(5μg/lμl), ketamine 1μl (25μg/1μμl or 12.5μg/lμl) and saline solution 1μl. An extracellular AC amplifier was used and the raw electric signals were collected via an CDE 1401 interface to a personal computer. Whisker stimuli were performed by deflections of the optimal whisker on the contralateral face. spontaneous sLFPs power spectrum and SEPs were analysed before and after administration of NMDA receptor antagonists.
Results:
1. After administration of AP-51μl(5μg/μl), the amplitude of SEPs was lower andδ(1-4Hz),θ(4-8Hz),β(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
2. After administration of ketamine 1μl (25μg/μl), the amplitude of SEPs was reduced andβ(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
3. After administration of ketamine 1μl(12.5μg/μl), the amplitude of SEPs was reduced andδ(1-4Hz), a(8-12Hz),β(12-25Hz) and y (25-60Hz) powers of sLFPs decreased significantly.
4. After administration of saline solution 1μ1 there was no significant deviation on sLFPs and SEPs than befor infusion.
Conclusions:The findings indicate that locally blocking NMDA receptor in VPM can reduce the excitability of primary somatosensory cortex which may result in a loss of information capacity.
引文
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[2]Miller, L.J., D.M. Nielsen, S.A. Schoen, et al., Perspectives on sensory processing disorder:a call for translational research. Front Integr Neurosci,2009.3:p.22.
[3]Varela, F., J.P. Lachaux, E. Rodriguez, et al., The brainweb:phase synchronization and large-scale integration. Nat Rev Neurosci,2001.2(4):p.229-39.
[4]Mashour, G.A., Integrating the science of consciousness and anesthesia. Anesth Analg, 2006.103(4):p.975-82.
[5]Sheeba, J.H., A. Stefanovska, and P.V. McClintock, Neuronal synchrony during anesthesia:a thalamocortical model. Biophys J,2008.95(6):p.2722-7.
[6]Vahle-Hinz, C., O. Detsch, M. Siemers, et al., Contributions of GABAergic and glutamatergic mechanisms to isoflurane-induced suppression of thalamic somatosensory information transfer. Exp Brain Res,2007.176(1):p.159-72.
[7]Judge, O., S. Hill, and J.F. Antognini, Modeling the effects of midazolam on cortical and thalamic neurons. Neurosci Lett,2009.464(2):p.135-9.
[8]Huguenard, J.R. and D.A. McCormick, Thalamic synchrony and dynamic regulation of global forebrain oscillations. Trends Neurosci,2007.30(7):p.350-6.
[9]Zhang, Z.W. and M. Deschenes, Intracortical axonal projections of lamina VI cells of the primary somatosensory cortex in the rat:a single-cell labeling study. J Neurosci, 1997.17(16):p.6365-79.
[10]Paoletti, P. and J. Neyton, NMDA receptor subunits:function and pharmacology. Curr Opin Pharmacol,2007.7(1):p.39-47.
[11]Schubert, D., R. Kotter, and J.F. Staiger, Mapping functional connectivity in barrel-related columns reveals layer-and cell type-specific microcircuits. Brain Struct Funct,2007.212(2):p.107-19.
[12]Brecht, M., Barrel cortex and whisker-mediated behaviors. Curr Opin Neurobiol, 2007.17(4):p.408-16.
[13]Petersen, C.C., The functional organization of the barrel cortex. Neuron,2007.56(2): p.339-55.
[14]Boisseau, N., M. Madany, P. Staccini, et al., Comparison of the effects of sevoflurane and propofol on cortical somatosensory evoked potentials. Br J Anaesth,2002.88(6): p.785-9.
[15]Liu, E.H., H.K. Wong, C.P. Chia, et al., Effects of isoflurane and propofol on cortical somatosensory evoked potentials during comparable depth of anaesthesia as guided by bispectral index. Br J Anaesth,2005.94(2):p.193-7.
[16]Vanlersberghe, C. and F. Camu, Propofol. Handb Exp Pharmacol,2008(182):p. 227-52.
[17]Famous, K.R., H.D. Schmidt, and R.C. Pierce, When administered into the nucleus accumbens core or shell, the NMDA receptor antagonist AP-5 reinstates cocaine-seeking behavior in the rat. Neurosci Lett,2007.420(2):p.169-73.
[18]Brown, E.N., R. Lydic, and N.D. Schiff, General anesthesia, sleep, and coma. N Engl J Med,2010.363(27):p.2638-50.
[19]Tsai, Y.T., H.L. Chan, S.T. Lee, et al., Significant thalamocortical coherence of sleep spindle, theta, delta, and slow oscillations in NREM sleep:recordings from the human thalamus. Neurosci Lett,2010.485(3):p.173-7.
[20]Campbell, I.G., EEG recording and analysis for sleep research. Curr Protoc Neurosci, 2009. Chapter 10:p. UnitlO 2.
[21]Mann, E.O. and I. Mody, Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons. Nat Neurosci,2010.13(2):p.205-12.
[22]Hudetz, A.G., Feedback suppression in anesthesia. Is it reversible? Conscious Cogn, 2009.18(4):p.1079-81.
[23]Scholpp, S. and A. Lumsden, Building a bridal chamber:development of the thalamus. Trends Neurosci,2010.33(8):p.373-80.
[24]Pinault, D., The thalamic reticular nucleus:structure, function and concept. Brain Res Brain Res Rev,2004.46(1):p.1-31.
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