Discover the SciOpen Platform and Achieve Your Research Goals with Ease.
The brain is one of the most complex organs in nature. In this organ, multiple neurons, neuron clusters, or multiple brain regions are interconnected to form a complex structural network where various brain functions are completed through interaction. In recent years, multiple tools and techniques have been developed to analyze the composition of different cell types in the brain and to construct the brain atlas on macroscopic, mesoscopic, and microscopic levels. Meanwhile, researchers have found that many neuropsychiatric diseases, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are closely related to abnormal changes of brain structure, which means the investigation in brain structure not only provides a new idea for understanding the pathological mechanism of the diseases, but also provides imaging markers for early diagnosis and potential treatment. This article pays attention to the research of human brain structure, reviews the research progress of human brain structure and the structural mechanism of neurodegenerative diseases, and discusses the problems and prospects in the field.
Aamodt EJ, Williams RC Jr (1984) Microtubule-associated proteins connect microtubules and neurofilaments in vitro. Biochemistry 23: 6023−6031
Abeliovich A, Gitler AD (2016) Defects in trafficking bridge Parkinson's disease pathology and genetics. Nature 539: 207−216
Al-Amoudi A, Norlen LP, Dubochet J (2004) Cryo-electron microscopy of vitreous sections of native biological cells and tissues. J Struct Biol 148: 131−135
Ando Y, Okada H, Takemura G, Suzuki K, Takada C, Tomita H, Zaikokuji R, Hotta Y, Miyazaki N, Yano H, Muraki I, Kuroda A, Fukuda H, Kawasaki Y, Okamoto H, Kawaguchi T, Watanabe T, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Ogura S (2018) Brain-specific ultrastructure of capillary endothelial glycocalyx and its possible contribution for blood brain barrier. Sci Rep 8: 17523. https://doi.org/10.1038/s41598-018-35976-2
Balestrino R, Schapira AHV (2020) Parkinson disease. Eur J Neurol 27: 27−42
Bäuerlein FJB, Saha I, Mishra A, Kalemanov M, Martínez-Sánchez A, Klein R, Dudanova I, Hipp MS, Hartl FU, Baumeister W, Fernández-Busnadiego R (2017) In situ architecture and cellular interactions of polyQ inclusions. Cell 171: 179−187
Bolós M, Pallas-Bazarra N, Terreros-Roncal J, Perea JR, Jurado-Arjona J, Ávila J, Llorens-Martín M (2017) Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons. Transl Psychiatry 7: 1267. https://doi.org/10.1038/s41398-017-0013-6
Briggman KL, Helmstaedter M, Denk W (2011) Wiring specificity in the direction-selectivity circuit of the retina. Nature 471: 183−188
Brunello CA, Merezhko M, Uronen RL, Huttunen HJ (2020) Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci 77: 1721−1744
Bullen A, Taylor RR, Kachar B, Moores C, Fleck RA, Forge A (2014) Inner ear tissue preservation by rapid freezing: improving fixation by high-pressure freezing and hybrid methods. Hear Res 315: 49−60
Burgunder J-M (2015) Huntington’s disease: a tutorial review. Chin J Nerv Ment Dis 41: 577−591
Canter RG, Penney J, Tsai LH (2016) The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature 539: 187−196
Chan SL, Tan EK (2017) Targeting LRRK2 in Parkinson's disease: an update on recent developments. Expert Opin Ther Targets 21: 601−610
Chandra A, Dervenoulas G, Politis M (2019) Magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment. J Neurol 266: 1293−1302
Chen J, Marks E, Lai B, Zhang Z, Duce JA, Lam LQ, Volitakis I, Bush AI, Hersch S, Fox JH (2013) Iron accumulates in Huntington's disease neurons: protection by deferoxamine. PLoS One 8: e77023. https://doi.org/10.1371/journal.pone.0077023
Chen L, Wu Z, Hu D, Wang Y, Zhao F, Zhong T, Lin W, Wang L, Li G (2022) A 4D infant brain volumetric atlas based on the UNC/UMN baby connectome project (BCP) cohort. Neuroimage 253: 119097. https://doi.org/10.1016/j.neuroimage.2022.119097
Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep 13: 3391−3396
Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7: a020412. https://doi.org/10.1101/cshperspect.a020412
Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Böhning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE (2020) Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. Nature 588: 344−349
El Hajj H, Savage JC, Bisht K, Parent M, Vallières L, Rivest S, Tremblay M (2019) Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology. J Neuroinflammation 16: 87. https://doi.org/10.1186/s12974-019-1473-9
Femminella GD, Thayanandan T, Calsolaro V, Komici K, Rengo G, Corbi G, Ferrara N (2018) Imaging and molecular mechanisms of Alzheimer's disease: a review. Int J Mol Sci 19: 3702. https://doi.org/10.3390/ijms19123702
Fernandez-Moran H (1953) A diamond knife for ultrathin sectioning. Exp Cell Res 5: 255−256
Finkbeiner S (2011) Huntington's disease. Cold Spring Harb Perspect Biol 3: a007476. https://doi.org/10.1101/cshperspect.a007476
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547: 185−190
Friedmann D, Pun A, Adams EL, Lui JH, Kebschull JM, Grutzner SM, Castagnola C, Tessier-Lavigne M, Luo L (2020) Mapping mesoscale axonal projections in the mouse brain using a 3D convolutional network. Proc Natl Acad Sci USA 117: 11068−11075
Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, Dewson G, Glukhova A, Komander D (2022) Activation mechanism of PINK1. Nature 602: 328−335
Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, Ugurbil K, Andersson J, Beckmann CF, Jenkinson M, Smith SM, Van Essen DC (2016) A multi-modal parcellation of human cerebral cortex. Nature 536: 171−178
Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9: 13−24
Goh AM, Wibawa P, Loi SM, Walterfang M, Velakoulis D, Looi JC (2018) Huntington's disease: neuropsychiatric manifestations of Huntington's disease. Australas Psychiatry 26: 366−375
Gómez-Benito M, Granado N, García-Sanz P, Michel A, Dumoulin M, Moratalla R (2020) Modeling Parkinson's disease with the alpha-synuclein protein. Front Pharmacol 11: 356. https://doi.org/10.3389/fphar.2020.00356
Gong H, Xu D, Yuan J, Li X, Guo C, Peng J, Li Y, Schwarz LA, Li A, Hu B, Xiong B, Sun Q, Zhang Y, Liu J, Zhong Q, Xu T, Zeng S, Luo Q (2016) High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level. Nat Commun 7: 12142. https://doi.org/10.1038/ncomms12142
Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli RBG, Tusche M, Lopez-Iglesias C, Hoyer W, Heise H, Willbold D, Schröder GF (2017) Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science 358: 116−119
Guo Q, Bin H, Cheng J, Seefelder M, Engler T, Pfeifer G, Oeckl P, Otto M, Moser F, Maurer M, Pautsch A, Baumeister W, Fernández-Busnadiego R, Kochanek S (2018) The cryo-electron microscopy structure of huntingtin. Nature 555: 117−120
Henderson MX, Trojanowski JQ, Lee VM (2019) α-Synuclein pathology in Parkinson's disease and related α-synucleinopathies. Neurosci Lett 709: 134316. https://doi.org/10.1016/j.neulet.2019.134316
Henmar S, Simonsen EB, Berg RW (2020) What are the gray and white matter volumes of the human spinal cord? J Neurophysiol 124: 1792−1797
Jarrell TA, Wang Y, Bloniarz AE, Brittin CA, Xu M, Thomson JN, Albertson DG, Hall DH, Emmons SW (2012) The connectome of a decision-making neural network. Science 337: 437−444
Jia L, Du Y, Chu L, Zhang Z, Li F, Lyu D, Li Y, Li Y, Zhu M, Jiao H, Song Y, Shi Y, Zhang H, Gong M, Wei C, Tang Y, Fang B, Guo D, Wang F, Zhou A, Chu C, Zuo X, Yu Y, Yuan Q, Wang W, Li F, Shi S, Yang H, Zhou C, Liao Z, Lv Y, Li Y, Kan M, Zhao H, Wang S, Yang S, Li H, Liu Z, Wang Q, Qin W, Jia J (2020) Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health 5: e661−e671
Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501: 45−51
Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386: 896−912
Ke PC, Zhou R, Serpell LC, Riek R, Knowles TPJ, Lashuel HA, Gazit E, Hamley IW, Davis TP, Fändrich M, Otzen DE, Chapman MR, Dobson CM, Eisenberg DS, Mezzenga R (2020) Half a century of amyloids: past, present and future. Chem Soc Rev 49: 5473−5509
Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D, Kim DK, Kim HJ, Choi H, Hyun DW, Lee JY, Choi EY, Lee DS, Bae JW, Mook-Jung I (2020) Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model. Gut 69: 283−294
Kim S, Sakaie K, Blümcke I, Jones S, Lowe MJ (2021) Whole-brain, ultra-high spatial resolution ex vivo MRI with off-the-shelf components. Magn Reson Imaging 76: 39−48
Knudsen EI (2020) Evolution of neural processing for visual perception in vertebrates. J Comp Neurol 528: 2888−2901
Korogod N, Petersen CC, Knott GW (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife 4: e05793. https://doi.org/10.7554/eLife.05793
Krueger M, Härtig W, Reichenbach A, Bechmann I, Michalski D (2013) Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One 8: e56419. https://doi.org/10.1371/journal.pone.0056419
Latta H, Hartmann JF (1950) Use of a glass edge in thin sectioning for electron microscopy. Proc Soc Exp Biol Med 74: 436−439
Lehrer J (2009) Neuroscience: making connections. Nature 457: 524−527
Li A, Gong H, Zhang B, Wang Q, Yan C, Wu J, Liu Q, Zeng S, Luo Q (2010) Micro-optical sectioning tomography to obtain a high-resolution atlas of the mouse brain. Science 330: 1404−1408
Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J Neurosci 21: 8473−8481
Li Q, Weiland A, Chen X, Lan X, Han X, Durham F, Liu X, Wan J, Ziai WC, Hanley DF, Wang J (2018a) Ultrastructural characteristics of neuronal death and white matter injury in mouse brain tissues after intracerebral hemorrhage: coexistence of ferroptosis, autophagy, and necrosis. Front Neurol 9: 581. https://doi.org/10.3389/fneur.2018.00581
Li X, Yu B, Sun Q, Zhang Y, Ren M, Zhang X, Li A, Yuan J, Madisen L, Luo Q, Zeng H, Gong H, Qiu Z (2018b) Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons. Proc Natl Acad Sci USA 115: 415−420
Liu YT, Tao CL, Zhang X, Xia W, Shi DQ, Qi L, Xu C, Sun R, Li XW, Lau PM, Zhou ZH, Bi GQ (2020) Mesophasic organization of GABA(A) receptors in hippocampal inhibitory synapses. Nat Neurosci 23: 1589−1596
Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N (2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396: 413−446
Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453: 869−878
Michalski D, Grosche J, Pelz J, Schneider D, Weise C, Bauer U, Kacza J, Gärtner U, Hobohm C, Härtig W (2010) A novel quantification of blood-brain barrier damage and histochemical typing after embolic stroke in rats. Brain Res 1359: 186−200
Mikula S, Denk W (2015) High-resolution whole-brain staining for electron microscopic circuit reconstruction. Nat Methods 12: 541−546
Milanesi L, Sheynis T, Xue WF, Orlova EV, Hellewell AL, Jelinek R, Hewitt EW, Radford SE, Saibil HR (2012) Direct three-dimensional visualization of membrane disruption by amyloid fibrils. Proc Natl Acad Sci USA 109: 20455−20460
Monfrini E, Di Fonzo A (2017) Leucine-rich repeat kinase (LRRK2) genetics and Parkinson's disease. Adv Neurobiol 14: 3−30
Muller HR (1957) Freeze-drying as a fixation technic for plant cells. J Ultrastruct Res 1: 109−137
Nakamura S (1993) Huntington's disease-advances in gene mapping. Nihon Rinsho 51: 2481−2487
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64: 113−122
Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, Wang Q, Lau C, Kuan L, Henry AM, Mortrud MT, Ouellette B, Nguyen TN, Sorensen SA, Slaughterbeck CR, Wakeman W, Li Y, Feng D, Ho A, Nicholas E, Hirokawa KE, Bohn P, Joines KM, Peng H, Hawrylycz MJ, Phillips JW, Hohmann JG, Wohnoutka P, Gerfen CR, Koch C, Bernard A, Dang C, Jones AR, Zeng H (2014) A mesoscale connectome of the mouse brain. Nature 508: 207−214
Pieri L, Madiona K, Bousset L, Melki R (2012) Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys J 102: 2894−2905
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045−2047
Porter KR, Blum J (1953) A study in microtomy for electron microscopy. Anat Rec 117: 685−710
Rastogi S, Sharma V, Bharti PS, Rani K, Modi GP, Nikolajeff F, Kumar S (2021) The evolving landscape of exosomes in neurodegenerative diseases: exosomes characteristics and a promising role in early diagnosis. Int J Mol Sci 22(1): 440. https://doi.org/10.3390/ijms22010440
Rodríguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, Avershina E, Rudi K, Narbad A, Jenmalm MC, Marchesi JR, Collado MC (2015) The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis 26: 26050. https://doi.org/10.3402/mehd.v26.26050
Roostaei T, Nazeri A, Sahraian MA, Minagar A (2014) The human cerebellum: a review of physiologic neuroanatomy. Neurol Clin 32: 859−869
Rosas HD, Chen YI, Doros G, Salat DH, Chen NK, Kwong KK, Bush A, Fox J, Hersch SM (2012) Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol 69: 887−893
Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl): S10−S17
Sanchez-Varo R, Trujillo-Estrada L, Sanchez-Mejias E, Torres M, Baglietto-Vargas D, Moreno-Gonzalez I, De Castro V, Jimenez S, Ruano D, Vizuete M, Davila JC, Garcia-Verdugo JM, Jimenez AJ, Vitorica J, Gutierrez A (2012) Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer's mice hippocampus. Acta Neuropathol 123: 53−70
Santos Armentia E, Martín Noguerol T, Suárez Vega V (2019) Advanced magnetic resonance imaging techniques for tumors of the head and neck. Radiologia (Engl Ed) 61: 191−203
Saudou F, Humbert S (2016) The Biology of Huntingtin. Neuron 89: 910−926
Saygin AP, Sereno MI (2008) Retinotopy and attention in human occipital, temporal, parietal, and frontal cortex. Cereb Cortex 18: 2158−2168
Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1: 1269
Schellenberg GD, Montine TJ (2012) The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol 124: 305−323
Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, Steyaert J, Maslen SL, Komander D (2017) Structure of PINK1 in complex with its substrate ubiquitin. Nature 552: 51−56
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8: 595−608
Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE, Navarro PP, Castaño-Díez D, Schweighauser G, Graff-Meyer A, Goldie KN, Sütterlin R, Huisman E, Ingrassia A, Gier Y, Rozemuller AJM, Wang J, Paepe A, Erny J, Staempfli A, Hoernschemeyer J, Großerüschkamp F, Niedieker D, El-Mashtoly SF, Quadri M, Van IWFJ, Bonifati V, Gerwert K, Bohrmann B, Frank S, Britschgi M, Stahlberg H, Van de Berg WDJ, Lauer ME (2019) Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes. Nat Neurosci 22: 1099−1109
Shampo MA, Kyle RA (1997) Ernst Ruska-inventor of the electron microscope. Mayo Clin Proc 72: 148. https://doi.org/10.4065/72.2.148
Sjostrand FS (1953) The ultrastructure of the innersegments of the retinal rods of the guinea pig eye as revealed by electron microscopy. J Cell Comp Physiol 42: 45−70
Sporns O, Tononi G, Kötter R (2005) The human connectome: a structural description of the human brain. PLoS Comput Biol 1: e42. https://doi.org/10.1371/journal.pcbi.0010042
Taylor JP, Brown RH, Jr., Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539: 197−206
Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY, Ménade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K (2013) Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340: 1451−1455
Trinkaus VA, Riera-Tur I, Martínez-Sánchez A, Bäuerlein FJB, Guo Q, Arzberger T, Baumeister W, Dudanova I, Hipp MS, Hartl FU, Fernández-Busnadiego R (2021) In situ architecture of neuronal α-Synuclein inclusions. Nat Commun 12: 2110. https://doi.org/10.1038/s41467-021-22108-0
Van Essen DC, Ugurbil K (2012) The future of the human connectome. Neuroimage 62: 1299−1310
Volpe JJ (2009) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 8: 110−124
Watanabe R, Buschauer R, Böhning J, Audagnotto M, Lasker K, Lu TW, Boassa D, Taylor S, Villa E (2020) The in situ structure of parkinson's disease-linked LRRK2. Cell 182: 1508−1518
Wohlgemuth MJ, Moss CF (2016) Midbrain auditory selectivity to natural sounds. Proc Natl Acad Sci USA 113: 2508−2513
Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539: 180−186
Xiaoyan Xue XG, Min Li, Minhuan Luo (2015) Research progress on the pathogenesis of neurodegenerative diseases. Chin J Gerontol 35: 3149−3152
Yousaf T, Dervenoulas G, Politis M (2018) Advances in MRI methodology. Int Rev Neurobiol 141: 31−76
Zhang B, Wu L-L, Wu Y-Y, Pan LJ, Lou SS, Kong (2016) The Application of highpressure freezing-freeze substitution technique in ultrastructure of nervous tissue. J Chin ElectrMicrosc Soc 36: 45−50
Zhong Q, Li A, Jin R, Zhang D, Li X, Jia X, Ding Z, Luo P, Zhou C, Jiang C, Feng Z, Zhang Z, Gong H, Yuan J, Luo Q (2021) High-definition imaging using line-illumination modulation microscopy. Nat Methods 18: 309−315
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.