小鼠海马CA1亚区不同类型神经元对空间编码的倾向性研究

空间导航和空间记忆对动物生存至关重要。动物通过海马脑区来编码和存储空间位置信息并进行空间导航。海马细胞在特定空间位置放电形成位置场，被称为位置细胞。在不同环境中，海马细胞表现出各自的空间编码倾向。例如，在特定环境中，某些细胞只有一个位置场，某些细胞可能有多个位置场，而其他细胞在该环境中可能不活动或不存在位置场。在其他环境或实验范式中，这些神经元的放电活动或位置场性质可能发生变化。

海马结构分为齿状回、CA3、CA2和CA1四个亚区，每个亚区均存在位置细胞。CA1亚区接收其他亚区的信息输入并作为海马的输出亚区。本研究通过在小鼠CA1细胞中标记携带钙指示剂的荧光蛋白，并使用钙成像技术记录CA1细胞的活动；通过虚拟现实环境模拟现实中难以实现的实验范式，研究了CA1神经元在多种实验条件下的编码特征，探索了它们在不同实验范式下的空间编码倾向。

我们采用了多个实验范式得到以下结果：1）新环境：小鼠从熟悉环境中到新环境，一部分位置细胞，其位置场会改变位置或者消失；原本不存在位置场的细胞可能会出现新的位置场。2）大环境：CA1细胞的位置场个数呈伽马-泊松分布、负二项分布或泊松分布。随着环境的扩大，相应的位置场大小在环境中所占比例减小。3）增益（gain）改变：正常情况下gain等于1，即虚拟世界移动的距离等于动物跑过的实际路程。当gain大于1时，即虚拟世界移动的距离大于动物跑过的实际路程，位置场向运动的方向偏移；相反，当gain小于1时，即虚拟世界移动的距离小于动物跑过的实际路程，位置场向运动的反方向偏移。4）环境瞬移：小鼠在跑动时突然被传送到虚拟世界的另一个位置，在传送区附近的位置场会向传送区域偏移，在传送区后的位置场会消失。经过一段距离的矫正后，空间编码恢复正常。

这项研究探讨了小鼠海马CA1亚区细胞在虚拟现实环境中的不同实验范式下的空间编码倾向。通过模拟各种实验条件，我们深入了解了小鼠海马CA1亚区神经元在不同环境和实验条件下的空间信息处理能力。这些发现可能为理解人类和其他动物的空间认知提供思路。

[1] SCOVILLE W B, MILNER B. Loss of recent memory after bilateral hippocampal lesions[J/OL]. Journal of Neurology, Neurosurgery, and Psychiatry, 1957, 20(1): 11-21. DOI:10.1136/jnnp.20.1.11.
[2] O’KEEFE J, NADEL L. The hippocampus as a cognitive map[M]. Oxford : New York: Clarendon Press ; Oxford University Press, 1978.
[3] HENZE D A, BORHEGYI Z, CSICSVARI J, et al. Intracellular features predicted by extracellular recordings in the hippocampus in vivo[J/OL]. Journal of Neurophysiology, 2000, 84(1): 390-400. DOI:10.1152/jn.2000.84.1.390.
[4] O’KEEFE J. Place units in the hippocampus of the freely moving rat[J/OL]. Experimental Neurology, 1976, 51(1): 78-109. DOI:10.1016/0014-4886(76)90055-8.
[5] MULLER R U, KUBIE J L. The firing of hippocampal place cells predicts the future position of freely moving rats[J/OL]. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 1989, 9(12): 4101-4110. DOI:10.1523/JNEUROSCI.09-12-04101.1989.
[6] MOSER E I, KROPFF E, MOSER M B. Place cells, grid cells, and the brain’s spatial representation system[J/OL]. Annual Review of Neuroscience, 2008, 31: 69-89. DOI:10.1146/annurev.neuro.31.061307.090723.
[7] MUELLER S G, CHAO L L, BERMAN B, et al. Evidence for functional specialization of hippocampal subfields detected by MR subfield volumetry on high resolution images at 4 T[J/OL]. NeuroImage, 2011, 56(3): 851-857. DOI:10.1016/j.neuroimage.2011.03.028.
[8] AMARAL D G, WITTER M P. The three-dimensional organization of the hippocampal formation: a review of anatomical data[J/OL]. Neuroscience, 1989, 31(3): 571-591. DOI:10.1016/0306-4522(89)90424-7.
[9] HARVEY C D, COLLMAN F, DOMBECK D A, et al. Intracellular dynamics of hippocampal place cells during virtual navigation[J/OL]. Nature, 2009, 461(7266): 941-946. DOI:10.1038/nature08499.
[10] CHEN G, LU Y, KING J A, et al. Differential influences of environment and self-motion on place and grid cell firing[J/OL]. Nature Communications, 2019, 10(1): 630. DOI:10.1038/s41467-019-08550-1.
[11] YUSTE R, KATZ L C. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters[J/OL]. Neuron, 1991, 6(3): 333-344. DOI:10.1016/0896-6273(91)90243-s.
[12] OHKI K, CHUNG S, CH’NG Y H, et al. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex[J/OL]. Nature, 2005, 433(7026): 597-603. DOI:10.1038/nature03274.
[13] EICHENBAUM H. A cortical–hippocampal system for declarative memory[J/OL]. Nature Reviews Neuroscience, 2000, 1(1): 41-50. DOI:10.1038/35036213.
[14] NICOLL R A, SCHMITZ D. Synaptic plasticity at hippocampal mossy fibre synapses[J/OL]. Nature Reviews Neuroscience, 2005, 6(11): 863-876. DOI:10.1038/nrn1786.
[15] KANDEL E R, SCHWARTZ J H, JESSELL T M, et al. Principles of Neural Science, chapter 6[M]. McGraw-Hill Professional, 2012.
[16] PURVES D, AUGUSTINE G J, FITZPATRICK D, et al. Neurosciences[M]. De Boeck Supérieur, 2019.
[17] STRANGE B A, WITTER M P, LEIN E S, et al. Functional organization of the hippocampal longitudinal axis[J/OL]. Nature Reviews Neuroscience, 2014, 15(10): 655-669. DOI:10.1038/nrn3785.
[18] MOSER M B, MOSER E I. Distributed encoding and retrieval of spatial memory in the hippocampus[J/OL]. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 1998, 18(18): 7535-7542. DOI:10.1523/JNEUROSCI.18-18-07535.1998.
[19] LEE I, KESNER R P. Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory[J/OL]. Nature Neuroscience, 2002, 5(2): 162-168. DOI:10.1038/nn790.
[20] KNIERIM J J, NEUNUEBEL J P. Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics[J/OL]. Neurobiology of Learning and Memory, 2016, 129: 38-49. DOI:10.1016/j.nlm.2015.10.008.
[21] ROGERS L. Homing tendencies of large mammals: a review[J]. 1988.
[22] BLODGETT H C. The effect of the introduction of reward upon the maze performance of rats[J]. University of California Publications in Psychology, 1929, 4: 113-134.
[23] TOLMAN E C. Cognitive maps in rats and men[J/OL]. Psychological Review, 1948, 55: 189-208. DOI:10.1037/h0061626.
[24] SPENCE K W, BERGMANN G, LIPPITT R. A study of simple learning under irrelevant motivational-reward conditions[J/OL]. Journal of Experimental Psychology, 1950, 40: 539-551. DOI:10.1037/h0060543.
[25] A R R. A theory of Pavlovian conditioning : Variations in the effectiveness of reinforcement and non-reinforcement[J]. Classical conditioning, Current research and theory, 1972, 2: 64-69.
[26] MORRIS R G M, GARRUD P, RAWLINS J N P, et al. Place navigation impaired in rats with hippocampal lesions[J/OL]. Nature, 1982, 297(5868): 681-683. DOI:10.1038/297681a0.
[27] HØYDAL Ø A, SKYTØEN E R, ANDERSSON S O, et al. Object-vector coding in the medial entorhinal cortex[J/OL]. Nature, 2019, 568(7752): 400-404. DOI:10.1038/s41586-019-1077-7.
[28] LATUSKE P, KORNIENKO O, KOHLER L, et al. Hippocampal Remapping and Its Entorhinal Origin[J/OL]. Frontiers in Behavioral Neuroscience, 2018, 11
[2023-03-07]. https://www.frontiersin.org/articles/10.3389/fnbeh.2017.00253.
[29] MULLER R U, KUBIE J L. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells[J/OL]. Journal of Neuroscience, 1987, 7(7): 1951-1968. DOI:10.1523/JNEUROSCI.07-07-01951.1987.
[30] MULLER R, BOSTOCK E, TAUBE J, et al. On the directional firing properties of hippocampal place cells[J/OL]. The Journal of Neuroscience, 1994, 14(12): 7235-7251. DOI:10.1523/JNEUROSCI.14-12-07235.1994.
[31] FENTON A A, KAO H Y, NEYMOTIN S A, et al. Unmasking the CA1 Ensemble Place Code by Exposures to Small and Large Environments: More Place Cells and Multiple, Irregularly Arranged, and Expanded Place Fields in the Larger Space[J/OL]. Journal of Neuroscience, 2008, 28(44): 11250-11262. DOI:10.1523/JNEUROSCI.2862-08.2008.
[32] LEVER C, BURTON S, JEEWAJEE A, et al. Boundary vector cells in the subiculum of the hippocampal formation. \ud[J/OL]. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 2009, 29(31): 9771-9777. DOI:10.1523/JNEUROSCI.1319-09.2009.
[33] HAFTING T, FYHN M, MOLDEN S, et al. Microstructure of a spatial map in the entorhinal cortex[J/OL]. Nature, 2005, 436(7052): 801-806. DOI:10.1038/nature03721.
[34] DERDIKMAN D, WHITLOCK J R, TSAO A, et al. Fragmentation of grid cell maps in a multicompartment environment[J/OL]. Nature Neuroscience, 2009, 12(10): 1325-1332. DOI:10.1038/nn.2396.
[35] BARRY C, HAYMAN R, BURGESS N, et al. Experience-dependent rescaling of entorhinal grids[J/OL]. Nature Neuroscience, 2007, 10(6): 682-684. DOI:10.3410/f.1084758.537805.
[36] BURGESS N, O’KEEFE J. Models of place and grid cell firing and theta rhythmicity[J/OL]. Current Opinion in Neurobiology, 2011, 21(5): 734-744. DOI:10.1016/j.conb.2011.07.002.
[37] ROWLAND D C, ROUDI Y, MOSER M B, et al. Ten Years of Grid Cells[J/OL]. Annual Review of Neuroscience, 2016, 39(1): 19-40. DOI:10.1146/annurev-neuro-070815-013824.
[38] EVANS T, BICANSKI A, BUSH D, et al. How environment and self-motion combine in neural representations of space[J/OL]. The Journal of Physiology, 2016, 594(22): 6535-6546. DOI:10.1113/JP270666.
[39] MCNAUGHTON B L, BATTAGLIA F P, JENSEN O, et al. Path integration and the neural basis of the “cognitive map”[J/OL]. Nature Reviews Neuroscience, 2006, 7(8): 663-678. DOI:10.1038/nrn1932.
[40] TAUBE J S. The Head Direction Signal: Origins and Sensory-Motor Integration[J/OL]. Annual Review of Neuroscience, 2007, 30(1): 181-207. DOI:10.1146/annurev.neuro.29.051605.112854.
[41] FINKELSTEIN A, DERDIKMAN D, RUBIN A, et al. Three-dimensional head-direction coding in the bat brain[J/OL]. Nature, 2015, 517(7533): 159-164. DOI:10.1038/nature14031.
[42] WINTER S S, CLARK B J, TAUBE J S. Disruption of the head direction cell network impairs the parahippocampal grid cell signal[J/OL]. Science, 2015, 347(6224): 870-874. DOI:10.1126/science.1259591.
[43] KIM M, JEFFERY K J, MAGUIRE E A. Multivoxel Pattern Analysis Reveals 3D Place Information in the Human Hippocampus[J/OL]. Journal of Neuroscience, 2017, 37(16): 4270-4279. DOI:10.1523/JNEUROSCI.2703-16.2017.
[44] KROPFF E, CARMICHAEL J E, MOSER M B, et al. Speed cells in the medial entorhinal cortex[J/OL]. Nature, 2015, 523(7561): 419-424. DOI:10.1038/nature14622.
[45] WANG C, CHEN X, KNIERIM J J. Egocentric and allocentric representations of space in the rodent brain[J/OL]. Current Opinion in Neurobiology, 2020, 60: 12-20. DOI:10.1016/j.conb.2019.11.005.
[46] ANDERSSON S O, MOSER E I, MOSER M B. Visual stimulus features that elicit activity in object-vector cells[J/OL]. Communications Biology, 2021, 4(1): 1-13. DOI:10.1038/s42003-021-02727-5.
[47] COLGIN L L, MOSER E I, MOSER M B. Understanding memory through hippocampal remapping[J/OL]. Trends in Neurosciences, 2008, 31(9): 469-477. DOI:10.1016/j.tins.2008.06.008.
[48] MCHUGH T J, JONES M W, QUINN J J, et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network[J/OL]. Science (New York, N.Y.), 2007, 317(5834): 94-99. DOI:10.1126/science.1140263.
[49] KENTROS C G, AGNIHOTRI N T, STREATER S, et al. Increased attention to spatial context increases both place field stability and spatial memory[J/OL]. Neuron, 2004, 42(2): 283-295. DOI:10.1016/s0896-6273(04)00192-8.
[50] LEE I, YOGANARASIMHA D, RAO G, et al. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3[J/OL]. Nature, 2004, 430(6998): 456-459. DOI:10.1038/nature02739.
[51] FRANK L M, STANLEY G B, BROWN E N. Hippocampal plasticity across multiple days of exposure to novel environments[J/OL]. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 2004, 24(35): 7681-7689. DOI:10.1523/JNEUROSCI.1958-04.2004.
[52] COHEN J D, BOLSTAD M, LEE A K. Experience-dependent shaping of hippocampal CA1 intracellular activity in novel and familiar environments[J/OL]. eLife, 2017, 6: e23040. DOI:10.7554/eLife.23040.
[53] KJELSTRUP K B, SOLSTAD T, BRUN V H, et al. Finite Scale of Spatial Representation in the Hippocampus[J/OL]. Science, 2008
[2021-10-23]. https://www.science.org/doi/abs/10.1126/science.1157086. DOI:10.1126/science.1157086.
[54] RICH P D, LIAW H P, LEE A K. Large environments reveal the statistical structure governing hippocampal representations[J/OL]. Science, 2014, 345(6198): 814-817. DOI:10.1126/science.1255635.
[55] LEE D, LIN B J, LEE A K. Hippocampal Place Fields Emerge upon Single-Cell Manipulation of Excitability During Behavior[J/OL]. Science, 2012, 337(6096): 849-853. DOI:10.1126/science.1221489.
[56] ELIAV T, MAIMON S R, ALJADEFF J, et al. Multiscale representation of very large environments in the hippocampus of flying bats[J/OL]. Science, 2021, 372(6545): eabg4020. DOI:10.1126/science.abg4020.
[57] BURGESS N. Grid cells and theta as oscillatory interference: Theory and predictions[J/OL]. Hippocampus, 2008, 18(12): 1157-1174. DOI:10.1002/hipo.20518.
[58] CHEN G, MANSON D, CACUCCI F, et al. Absence of Visual Input Results in the Disruption of Grid Cell Firing in the Mouse[J/OL]. Current Biology, 2016, 26(17): 2335-2342. DOI:10.1016/j.cub.2016.06.043.
[59] MÜLLER R, SCHNITZLER H U. Acoustic flow perception in cf-bats: Extraction of parameters[J/OL]. The Journal of the Acoustical Society of America, 2000, 108(3): 1298-1307. DOI:10.1121/1.1287842.
[60] AHARON G, SADOT M, YOVEL Y. Bats Use Path Integration Rather Than Acoustic Flow to Assess Flight Distance along Flyways[J/OL]. Current Biology, 2017, 27(23): 3650-3657.e3. DOI:10.1016/j.cub.2017.10.012.
[61] LOOMIS J M, KLATZKY R L, GOLLEDGE R G, et al. Nonvisual navigation by blind and sighted: Assessment of path integration ability[J/OL]. Journal of Experimental Psychology: General, 1993, 122: 73-91. DOI:10.1037/0096-3445.122.1.73.
[62] CHEN G, KING J A, BURGESS N, et al. How vision and movement combine in the hippocampal place code[J/OL]. Proceedings of the National Academy of Sciences, 2013, 110(1): 378-383. DOI:10.1073/pnas.1215834110.
[63] ADRIAN E D, ZOTTERMAN Y. The impulses produced by sensory nerve-endings[J]. The Journal of Physiology, 1926, 61(2): 151-171.
[64] MOISESCU D G, ASHLEY C C, CAMPBELL A K. Comparative aspects of the calcium-sensitive photoproteins aequorin and obelin[J/OL]. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1975, 396(1): 133-140. DOI:10.1016/0005-2728(75)90196-6.
[65] BLINKS, PRENDERGAST F G, ALLEN D G. Photoproteins as biological calcium indicators[J]. Pharmacological Reviews, 1976, 28(1): 1-93.
[66] TSIEN R Y. New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures[J/OL]. Biochemistry, 1980, 19(11): 2396-2404. DOI:10.1021/bi00552a018.
[67] OHKURA M, MATSUZAKI M, KASAI H, et al. Genetically Encoded Bright Ca2+ Probe Applicable for Dynamic Ca2+ Imaging of Dendritic Spines[J/OL]. Analytical Chemistry, 2005, 77(18): 5861-5869. DOI:10.1021/ac0506837.
[68] MIYAWAKI A, LLOPIS J, HEIM R, et al. Fluorescent indicators for Ca2+based on green fluorescent proteins and calmodulin[J/OL]. Nature, 1997, 388(6645): 882-887. DOI:10.1038/42264.
[69] HUISKEN J, SWOGER J, DEL BENE F, et al. Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy[J/OL]. Science, 2004, 305(5686): 1007-1009. DOI:10.1126/science.1100035.
[70] DENK W, STRICKLER J H, WEBB W W. Two-Photon Laser Scanning Fluorescence Microscopy[J/OL]. Science, 1990, 248(4951): 73-76. DOI:10.1126/science.2321027.
[71] ZIV Y, BURNS L D, COCKER E D, et al. Long-term dynamics of CA1 hippocampal place codes[J/OL]. Nature Neuroscience, 2013, 16(3): 264-266. DOI:10.1038/nn.3329.
[72] GAFFAN D. Idiothetic input into object-place configuration as the contribution to memory of the monkey and human hippocampus: a review[J/OL]. Experimental Brain Research, 1998, 123(1-2): 201-209. DOI:10.1007/s002210050562.
[73] HÖLSCHER C, SCHNEE A, DAHMEN H, et al. Rats are able to navigate in virtual environments[J/OL]. Journal of Experimental Biology, 2005, 208(3): 561-569. DOI:10.1242/jeb.01371.
[74] LEE H Y, KUO M D, CHANG T C, et al. Development of virtual reality environment for tracking rat behavior[J]. Chinese Journal of Medical and Biological Engineering, 2007, 27(2): 71-78.
[75] KERR J N D, GREENBERG D, HELMCHEN F. Imaging input and output of neocortical networks in vivo[J/OL]. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(39): 14063-14068. DOI:10.1073/pnas.0506029102.
[76] ZHOU P, RESENDEZ S L, RODRIGUEZ-ROMAGUERA J, et al. Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data[J/OL]. eLife, 2018, 7: e28728. DOI:10.7554/eLife.28728.
[77] PNEVMATIKAKIS E A, SOUDRY D, GAO Y, et al. Simultaneous Denoising, Deconvolution, and Demixing of Calcium Imaging Data[J/OL]. Neuron, 2016, 89(2): 285-299. DOI:10.1016/j.neuron.2015.11.037.
[78] SHEINTUCH L, RUBIN A, BRANDE-EILAT N, et al. Tracking the Same Neurons across Multiple Days in Ca2+ Imaging Data[J/OL]. Cell Reports, 2017, 21(4): 1102-1115. DOI:10.1016/j.celrep.2017.10.013.
[79] SKAGGS W, MCNAUGHTON B, GOTHARD K. An Information-Theoretic Approach to Deciphering the Hippocampal Code[C/OL]//Advances in Neural Information Processing Systems: 卷 5. Morgan-Kaufmann, 1992
[2023-03-02]. https://proceedings.neurips.cc/paper/1992/hash/5dd9db5e033da9c6fb5ba83c7a7ebea9-Abstract.html.
[80] LEE J S, BRIGUGLIO J J, COHEN J D, et al. The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value[J/OL]. Cell, 2020, 183(3): 620-635.e22. DOI:10.1016/j.cell.2020.09.024.
[81] LEUTGEB S, LEUTGEB J K, BARNES C A, et al. Independent Codes for Spatial and Episodic Memory in Hippocampal Neuronal Ensembles[J/OL]. Science, 2005, 309(5734): 619-623. DOI:10.1126/science.1114037.
[82] SMITH P F, DARLINGTON C L, ZHENG Y. Move it or lose it--is stimulation of the vestibular system necessary for normal spatial memory?[J/OL]. Hippocampus, 2010, 20(1): 36-43. DOI:10.1002/hipo.20588.
[83] STACKMAN R W, CLARK A S, TAUBE J S. Hippocampal spatial representations require vestibular input[J/OL]. Hippocampus, 2002, 12(3): 291-303. DOI:10.1002/hipo.1112.
[84] GOTHARD K M, SKAGGS W E, MCNAUGHTON B L. Dynamics of Mismatch Correction in the Hippocampal Ensemble Code for Space: Interaction between Path Integration and Environmental Cues[J/OL]. The Journal of Neuroscience, 1996, 16(24): 8027-8040. DOI:10.1523/JNEUROSCI.16-24-08027.1996.