Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

The mechanobiology of brain function

Nature Reviews Neuroscience volume 13, pages 867–878 (2012)Cite this article

Subjects

Abstract

All cells are influenced by mechanical forces. In the brain, force-generating and load-bearing proteins twist, turn, ratchet, flex, compress, expand and bend to mediate neuronal signalling and plasticity. Although the functions of mechanosensitive proteins have been thoroughly described in classical sensory systems, the effects of endogenous mechanical energy on cellular function in the brain have received less attention, and many working models in neuroscience do not currently integrate principles of cellular mechanics. An understanding of cellular-mechanical concepts is essential to allow the integration of mechanobiology into ongoing studies of brain structure and function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanical forces are generated and transduced in neurons.
Figure 2: Ion channel activity is sensitive to membrane mechanics.
Figure 3: Functional implications of mechanical force transduction between synaptic compartments.
Figure 4: Experimental approaches useful to the study of mechanobiology in neuroscience.

Similar content being viewed by others

References

  1. Hamill, O. P. & Martinac, B. Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81, 685–740 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Kim, D. H., Wong, P. K., Park, J., Levchenko, A. & Sun, Y. Microengineered platforms for cell mechanobiology. Annu. Rev. Biomed. Eng. 11, 203–233 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Eyckmans, J., Boudou, T., Yu, X. & Chen, C. S. A hitchhiker's guide to mechanobiology. Dev. Cell 21, 35–47 (2011). This paper provides a comprehensive review of the field of mechanobiology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hill, D. K. The volume change resulting from stimulation of a giant nerve fibre. J. Physiol. 111, 304–327 (1950).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tasaki, I., Kusano, K. & Byrne, P. M. Rapid mechanical and thermal changes in the garfish olfactory nerve associated with a propagated impulse. Biophys. J. 55, 1033–1040 (1989). This study describes the propagation of a mechanical wave along axons during action potential firing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim, G. H., Kosterin, P., Obaid, A. L. & Salzberg, B. M. A mechanical spike accompanies the action potential in Mammalian nerve terminals. Biophys. J. 92, 3122–3129 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Crick, F. Do dendritic spines twitch? Trends Neurosci. 5, 44–46 (1982).

    Article  Google Scholar 

  8. Star, E. N., Kwiatkowski, D. J. & Murthy, V. N. Rapid turnover of actin in dendritic spines and its regulation by activity. Nature Neurosci. 5, 239–246 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Elkin, B. S., Azeloglu, E. U., Costa, K. D. & Morrison, B. Mechanical heterogeneity of the rat hippocampus measured by atomic force microscope indentation. J. Neurotrauma 24, 812–822 (2007).

    Article  PubMed  Google Scholar 

  10. Gefen, A., Gefen, N., Zhu, Q., Raghupathi, R. & Margulies, S. S. Age-dependent changes in material properties of the brain and braincase of the rat. J. Neurotrauma 20, 1163–1177 (2003).

    Article  PubMed  Google Scholar 

  11. Kruse, S. A. et al. Magnetic resonance elastography of the brain. Neuroimage 39, 231–237 (2008).

    Article  PubMed  Google Scholar 

  12. Moore, S. W. & Sheetz, M. P. Biophysics of substrate interaction: influence on neural motility, differentiation, and repair. Dev. Neurobiol. 71, 1090–1101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moore, S. W., Roca-Cusachs, P. & Sheetz, M. P. Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. Dev. Cell 19, 194–206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McCracken, P. J., Manduca, A., Felmlee, J. & Ehman, R. L. Mechanical transient-based magnetic resonance elastography. Magn. Reson. Med. 53, 628–639 (2005).

    Article  PubMed  Google Scholar 

  15. Zhang, J., Green, M. A., Sinkus, R. & Bilston, L. E. Viscoelastic properties of human cerebellum using magnetic resonance elastography. J. Biomech. 44, 1909–1913 (2011).

    Article  PubMed  Google Scholar 

  16. Sack, I., Streitberger, K. J., Krefting, D., Paul, F. & Braun, J. The influence of physiological aging and atrophy on brain viscoelastic properties in humans. PLoS ONE 6, e23451 (2011). This paper uses MRE to characterize changes in the rigidity of the human brain as a function of age.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wuerfel, J. et al. MR-elastography reveals degradation of tissue integrity in multiple sclerosis. Neuroimage 49, 2520–2525 (2010).

    Article  PubMed  Google Scholar 

  18. Murphy, M. C. et al. Decreased brain stiffness in Alzheimer's disease determined by magnetic resonance elastography. J. Magn. Reson. Imaging 34, 494–498 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Crawford, G. E. & Earnshaw, J. C. Viscoelastic relaxation of bilayer lipid membranes. Frequency-dependent tension and membrane viscosity. Biophys. J. 52, 87–94 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pastor, R. W. & Feller, S. E. Time scales of lipid dynamics and molecular dynamics. Biol. Membr. 1, 4–29 (1996).

    Google Scholar 

  21. Almeida, P. F. F. & Vaz, W. L. C. in Structure and Dynamics of Membranes: From Cells to Vesicles Vol. 1 (eds Lipowsky, R. & Sackmann, E.) 305–357 (Elsevier, 1995).

    Book  Google Scholar 

  22. Evans, E. A. & Hochmuth, R. M. in Current Topics in Membranes and Transport Vol. 10 (eds Bronner, F. & Kleinzeller, A.) 1–64 (Academic Press, 1978).

    Google Scholar 

  23. Seifriz, W. An elastic value of protoplasm, with further observations on the viscosity of protoplasm. J. Exp. Biol. 2, 1–11 (1924).

    Google Scholar 

  24. Kueh, H. Y. & Mitchison, T. J. Structural plasticity in actin and tubulin polymer dynamics. Science 325, 960–963 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Galkin, V. E., Orlova, A. & Egelman, E. H. Actin filaments as tension sensors. Curr. Biol. 22, R96–R101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hill, T. L. & Kirschner, M. W. Bioenergetics and kinetics of microtubule and actin filament assembly-disassembly. Int. Rev. Cytol. 78, 1–125 (1982).

    Article  CAS  PubMed  Google Scholar 

  27. Theriot, J. A. The polymerization motor. Traffic 1, 19–28 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Feynman, R. P., Leighton, R. B. & Sands, M. in The Feynman Lectures on Physics Vol. 1, Ch. 46, 46–49 (Addison-Wessley, 1963).

    Google Scholar 

  29. Peskin, C. S., Odell, G. M. & Oster, G. F. Cellular motions and thermal fluctuations: the Brownian ratchet. Biophys. J. 65, 316–324 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hill, T. L. & Kirschner, M. W. Subunit treadmilling of microtubules or actin in the presence of cellular barriers: possible conversion of chemical free energy into mechanical work. Proc. Natl Acad. Sci. USA 79, 490–494 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Footer, M. J., Kerssemakers, J. W., Theriot, J. A. & Dogterom, M. Direct measurement of force generation by actin filament polymerization using an optical trap. Proc. Natl Acad. Sci. USA 104, 2181–2186 (2007). Using optical trapping methods, this paper quantifies the force generated by small bundles of F-actin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Parekh, S. H., Chaudhuri, O., Theriot, J. A. & Fletcher, D. A. Loading history determines the velocity of actin-network growth. Nature Cell Biol. 7, 1219–1223 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Kosztin, I., Bruinsma, R., O'Lague, P. & Schulten, K. Mechanical force generation by G proteins. Proc. Natl Acad. Sci. USA 99, 3575–3580 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schliwa, M. & Woehlke, G. Molecular motors. Nature 422, 759–765 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Smith, S. J. Neuronal cytomechanics: the actin-based motility of growth cones. Science 242, 708–715 (1988).

    Article  CAS  PubMed  Google Scholar 

  36. Betz, T., Koch, D., Lu, Y. B., Franze, K. & Kas, J. A. Growth cones as soft and weak force generators. Proc. Natl Acad. Sci. USA 108, 13420–13425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chan, C. E. & Odde, D. J. Traction dynamics of filopodia on compliant substrates. Science 322, 1687–1691 (2008). This paper provides a quantitative description of a 'motor-clutch' model in which retrograde F-actin flow can differentially generate traction forces in growth cones of neurons.

    Article  CAS  PubMed  Google Scholar 

  38. Matus, A. Actin-based plasticity in dendritic spines. Science 290, 754–758 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Gao, Y. et al. β-III spectrin is critical for development of Purkinje cell dendritic tree and spine morphogenesis. J. Neurosci. 31, 16581–16590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nestor, M. W., Cai, X., Stone, M. R., Bloch, R. J. & Thompson, S. M. The actin binding domain of βI-spectrin regulates the morphological and functional dynamics of dendritic spines. PLoS ONE 6, e16197 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Komada, M. & Soriano, P. βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J. Cell Biol. 156, 337–348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Devaux, J. J. The C-terminal domain of ssIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. J. Physiol. 588, 4719–4730 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Desai, A. & Mitchison, T. J. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Odde, D. J., Ma, L., Briggs, A. H., DeMarco, A. & Kirschner, M. W. Microtubule bending and breaking in living fibroblast cells. J. Cell Sci. 112, 3283–3288 (1999). This paper describes the elastic energy stored in microtubules as they are bent.

    CAS  PubMed  Google Scholar 

  45. Dogterom, M. & Yurke, B. Measurement of the force-velocity relation for growing microtubules. Science 278, 856–860 (1997). This article provides a quantitative description of the mechanical forces generated by growing microtubules.

    Article  CAS  PubMed  Google Scholar 

  46. Svoboda, K. & Block, S. M. Force and velocity measured for single kinesin molecules. Cell 77, 773–784 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Visscher, K., Schnitzer, M. J. & Block, S. M. Single kinesin molecules studied with a molecular force clamp. Nature 400, 184–189 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Brangwynne, C. P. et al. Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement. J. Cell Biol. 173, 733–741 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hu, X., Viesselmann, C., Nam, S., Merriam, E. & Dent, E. W. Activity-dependent dynamic microtubule invasion of dendritic spines. J. Neurosci. 28, 13094–13105 (2008). This article provides evidence that microtubules can affect hippocampal and cortical dendritic spines in an activity-dependent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jaworski, J. et al. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61, 85–100 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Lee, M. K. & Cleveland, D. W. Neuronal intermediate filaments. Annu. Rev. Neurosci. 19, 187–217 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Mukhopadhyay, R., Kumar, S. & Hoh, J. H. Molecular mechanisms for organizing the neuronal cytoskeleton. Bioessays 26, 1017–1025 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Geisler, N. & Weber, K. Self-assembly in vitro of the 68,000 molecular weight component of the mammalian neurofilament triplet proteins into intermediate-sized filaments. J. Mol. Biol. 151, 565–571 (1981).

    Article  CAS  PubMed  Google Scholar 

  54. Brown, H. G. & Hoh, J. H. Entropic exclusion by neurofilament sidearms: a mechanism for maintaining interfilament spacing. Biochemistry 36, 15035–15040 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Pekny, M. & Lane, E. B. Intermediate filaments and stress. Exp. Cell Res. 313, 2244–2254 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Cleveland, D. W. et al. Involvement of neurofilaments in the radial growth of axons. J. Cell Sci. Suppl. 15, 85–95 (1991).

    Article  CAS  PubMed  Google Scholar 

  57. Kumar, S., Yin, X., Trapp, B. D., Paulaitis, M. E. & Hoh, J. H. Role of long-range repulsive forces in organizing axonal neurofilament distributions: evidence from mice deficient in myelin-associated glycoprotein. J. Neurosci. Res. 68, 681–690 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Leterrier, J. F., Kas, J., Hartwig, J., Vegners, R. & Janmey, P. A. Mechanical effects of neurofilament cross-bridges. Modulation by phosphorylation, lipids, and interactions with F-actin. J. Biol. Chem. 271, 15687–15694 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Dityatev, A., Schachner, M. & Sonderegger, P. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nature Rev. Neurosci. 11, 735–746 (2010).

    Article  CAS  Google Scholar 

  60. Dityatev, A. & Fellin, T. Extracellular matrix in plasticity and epileptogenesis. Neuron Glia Biol. 4, 235–247 (2008).

    Article  PubMed  Google Scholar 

  61. Pantazopoulos, H., Woo, T. U., Lim, M. P., Lange, N. & Berretta, S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch. Gen. Psychiatry 67, 155–166 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Thoumine, O., Kocian, P., Kottelat, A. & Meister, J. J. Short-term binding of fibroblasts to fibronectin: optical tweezers experiments and probabilistic analysis. Eur. Biophys. J. 29, 398–408 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Chavis, P. & Westbrook, G. Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411, 317–321 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Baumgartner, W., Golenhofen, N., Grundhofer, N., Wiegand, J. & Drenckhahn, D. Ca2+ dependency of N-cadherin function probed by laser tweezer and atomic force microscopy. J. Neurosci. 23, 11008–11014 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mendez, P., De Roo, M., Poglia, L., Klauser, P. & Muller, D. N-cadherin mediates plasticity-induced long-term spine stabilization. J. Cell Biol. 189, 589–600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Arikkath, J. & Reichardt, L. F. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 31, 487–494 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Arnadottir, J. & Chalfie, M. Eukaryotic mechanosensitive channels. Annu. Rev. Biophys. 39, 111–137 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Reeves, D., Ursell, T., Sens, P., Kondev, J. & Phillips, R. Membrane mechanics as a probe of ion-channel gating mechanisms. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 78, 041901 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sukharev, S. & Corey, D. P. Mechanosensitive channels: multiplicity of families and gating paradigms. Sci. STKE 2004, re4 (2004).

    PubMed  Google Scholar 

  70. Morris, C. E. Voltage-gated channel mechanosensitivity: fact or friction? Front. Physiol. 2, 25 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Cantor, R. S. The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry 36, 2339–2344 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Jerabek, H., Pabst, G., Rappolt, M. & Stockner, T. Membrane-mediated effect on ion channels induced by the anesthetic drug ketamine. J. Am. Chem. Soc. 132, 7990–7997 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Schikorski, T. & Stevens, C. F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J. Neurosci. 17, 5858–5867 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Murthy, V. N., Schikorski, T., Stevens, C. F. & Zhu, Y. Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32, 673–682 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Siechen, S., Yang, S., Chiba, A. & Saif, T. Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals. Proc. Natl Acad. Sci. USA 106, 12611–12616 (2009). This elegant study shows that mechanical tension at neuromuscular junction synapses can accelerate synaptic vesicle clustering in presynaptic terminals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Umeda, T., Ebihara, T. & Okabe, S. Simultaneous observation of stably associated presynaptic varicosities and postsynaptic spines: morphological alterations of CA3-CA1 synapses in hippocampal slice cultures. Mol. Cell. Neurosci. 28, 264–274 (2005). This article provides evidence that hippocampal synapses are tightly mechanically coupled.

    Article  CAS  PubMed  Google Scholar 

  77. Chen, B. M. & Grinnell, A. D. Integrins and modulation of transmitter release from motor nerve terminals by stretch. Science 269, 1578–1580 (1995). This paper shows that presynaptic membrane stretch can increase synaptic vesicle exocytosis in an integrin-mediated fashion at neuromuscular junctions.

    Article  CAS  PubMed  Google Scholar 

  78. Fatt, P. & Katz, B. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. 117, 109–128 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Balice-Gordon, R. J. & Lichtman, J. W. In vivo visualization of the growth of pre- and postsynaptic elements of neuromuscular junctions in the mouse. J. Neurosci. 10, 894–908 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yasuda, R. & Murakoshi, H. The mechanisms underlying the spatial spreading of signaling activity. Curr. Opin. Neurobiol. 21, 313–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Murakoshi, H., Wang, H. & Yasuda, R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kostic, A., Sap, J. & Sheetz, M. P. RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons. J. Cell Sci. 120, 3895–3904 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Flanagan, L. A., Ju, Y. E., Marg, B., Osterfield, M. & Janmey, P. A. Neurite branching on deformable substrates. Neuroreport 13, 2411–2415 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Pfister, B. J., Iwata, A., Meaney, D. F. & Smith, D. H. Extreme stretch growth of integrated axons. J. Neurosci. 24, 7978–7983 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fass, J. N. & Odde, D. J. Tensile force-dependent neurite elicitation via anti-β1 integrin antibody-coated magnetic beads. Biophys. J. 85, 623–636 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zheng, J. et al. Tensile regulation of axonal elongation and initiation. J. Neurosci. 11, 1117–1125 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Koch, D., Rosoff, W. J., Jiang, J., Geller, H. M. & Urbach, J. S. Strength in the periphery: growth cone biomechanics and substrate rigidity response in peripheral and central nervous system neurons. Biophys. J. 102, 452–460 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bridgman, P. C., Dave, S., Asnes, C. F., Tullio, A. N. & Adelstein, R. S. Myosin IIB is required for growth cone motility. J. Neurosci. 21, 6159–6169 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bray, D. Axonal growth in response to experimentally applied mechanical tension. Dev. Biol. 102, 379–389 (1984).

    Article  CAS  PubMed  Google Scholar 

  90. Hoge, C. W. et al. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N. Engl. J. Med. 358, 453–463 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Meaney, D. F. & Smith, D. H. Biomechanics of concussion. Clin. Sports Med. 30, 19–31 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Farkas, O. & Povlishock, J. T. Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. Prog. Brain Res. 161, 43–59 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Wolf, J. A., Stys, P. K., Lusardi, T., Meaney, D. & Smith, D. H. Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J. Neurosci. 21, 1923–1930 (2001). This study provides evidence that traumatic injuries to the CNS can involve the mechanical activation of voltage-gated sodium channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hemphill, M. A. et al. A possible role for integrin signaling in diffuse axonal injury. PLoS ONE 6, e22899 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Farkas, O., Lifshitz, J. & Povlishock, J. T. Mechanoporation induced by diffuse traumatic brain injury: an irreversible or reversible response to injury? J. Neurosci. 26, 3130–3140 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kilinc, D., Gallo, G. & Barbee, K. A. Mechanically-induced membrane poration causes axonal beading and localized cytoskeletal damage. Exp. Neurol. 212, 422–430 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Lo, E. H., Wang, X. & Cuzner, M. L. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J. Neurosci. Res. 69, 1–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Rajagopalan, J. & Saif, M. T. MEMS sensors and microsystems for cell mechanobiology. J. Micromech. Microeng. 21, 54002–54012 (2011).

    Article  PubMed  Google Scholar 

  99. McBride, D. W. Jr & Hamill, O. P. Pressure-clamp technique for measurement of the relaxation kinetics of mechanosensitive channels. Trends Neurosci. 16, 341–345 (1993).

    Article  PubMed  Google Scholar 

  100. Gullapalli, R. R., Tabouillot, T., Mathura, R., Dangaria, J. H. & Butler, P. J. Integrated multimodal microscopy, time-resolved fluorescence, and optical-trap rheometry: toward single molecule mechanobiology. J. Biomed. Opt. 12, 014012 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, Y. & Wang, N. FRET and mechanobiology. Integr. Biol. 1, 565–573 (2009).

    Article  CAS  Google Scholar 

  102. Meng, F., Suchyna, T. M., Lazakovitch, E., Gronostajski, R. M. & Sachs, F. Real time FRET based detection of mechanical stress in cytoskeletal and extracellular matrix proteins. Cell. Mol. Bioeng. 4, 148–159 (2011).

    Article  PubMed  Google Scholar 

  103. Azeloglu, E. U. & Costa, K. D. Atomic force microscopy in mechanobiology: measuring microelastic heterogeneity of living cells. Methods Mol. Biol. 736, 303–329 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Yang, M. T., Fu, J., Wang, Y. K., Desai, R. A. & Chen, C. S. Assaying stem cell mechanobiology on microfabricated elastomeric substrates with geometrically modulated rigidity. Nature Protoc. 6, 187–213 (2011).

    Article  CAS  Google Scholar 

  105. Simmons, C. S. et al. Integrated strain array for cellular mechanobiology studies. J. Micromech. Microeng. 21, 54016–54025 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Taylor, A. M., Dieterich, D. C., Ito, H. T., Kim, S. A. & Schuman, E. M. Microfluidic local perfusion chambers for the visualization and manipulation of synapses. Neuron 66, 57–68 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Taylor, A. M. et al. A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nature Methods 2, 599–605 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cheng, C. M. et al. Probing localized neural mechanotransduction through surface-modified elastomeric matrices and electrophysiology. Nature Protoc. 5, 714–724 (2010).

    Article  CAS  Google Scholar 

  109. Dalecki, D. Mechanical bioeffects of ultrasound. Annu. Rev. Biomed. Eng. 6, 229–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Tufail, Y., Yoshihiro, A., Pati, S., Tauchmann, M. L. & Tyler, W. J. Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound. Nature Protoc. 6, 1453–1470 (2011).

    Article  CAS  Google Scholar 

  111. Kucewicz, J. C. et al. Functional tissue pulsatility imaging of the brain during visual stimulation. Ultrasound Med. Biol. 33, 681–690 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Berg, D. Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease. J. Neural Transm. 118, 453–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Mariappan, Y. K., Glaser, K. J. & Ehman, R. L. Magnetic resonance elastography: a review. Clin. Anat. 23, 497–511 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Boulet, T., Kelso, M. L. & Othman, S. F. Microscopic magnetic resonance elastography of traumatic brain injury model. J. Neurosci. Methods 201, 296–306 (2011).

    Article  PubMed  Google Scholar 

  115. Engelhardt, H., Gaub, H. & Sackmann, E. Viscoelastic properties of erythrocyte membranes in high-frequency electric fields. Nature 307, 378–380 (1984).

    Article  CAS  PubMed  Google Scholar 

  116. Katnik, C. & Waugh, R. Electric fields induce reversible changes in the surface to volume ratio of micropipette-aspirated erythrocytes. Biophys. J. 57, 865–875 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. MacQueen, L. A., Buschmann, M. D. & Wertheimer, M. R. Mechanical properties of mammalian cells in suspension measured by electro-deformation. J. Micromech. Microeng. 20, 065007 (2010).

    Article  CAS  Google Scholar 

  118. Tabarean, I. V. & Morris, C. E. Membrane stretch accelerates activation and slow inactivation in Shaker channels with S3-S4 linker deletions. Biophys. J. 82, 2982–2994 (2002). This paper describes the effects of membrane tension on the activation and inactivation of a prototypical voltage-gated channel, the Shaker potassium channel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Maingret, F., Fosset, M., Lesage, F., Lazdunski, M. & Honore, E. TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem. 274, 1381–1387 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Brohawn, S. G., del Marmol, J. & MacKinnon, R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335, 436–441 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Maingret, F., Patel, A. J., Lesage, F., Lazdunski, M. & Honore, E. Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J. Biol. Chem. 274, 26691–26696 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Lin, W., Laitko, U., Juranka, P. F. & Morris, C. E. Dual stretch responses of mHCN2 pacemaker channels: accelerated activation, accelerated deactivation. Biophys. J. 92, 1559–1572 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Niu, X., Qian, X. & Magleby, K. L. Linker-gating ring complex as passive spring and Ca2+-dependent machine for a voltage- and Ca2+-activated potassium channel. Neuron 42, 745–756 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Morris, C. E. & Juranka, P. F. Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch. Biophys. J. 93, 822–833 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Beyder, A. et al. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J. Physiol. 588, 4969–4985 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Calabrese, B., Tabarean, I. V., Juranka, P. & Morris, C. E. Mechanosensitivity of N-type calcium channel currents. Biophys. J. 83, 2560–2574 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Etzion, Y. & Grossman, Y. Pressure-induced depression of synaptic transmission in the cerebellar parallel fibre synapse involves suppression of presynaptic N-type Ca2+ channels. Eur. J. Neurosci. 12, 4007–4016 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Paoletti, P. & Ascher, P. Mechanosensitivity of NMDA receptors in cultured mouse central neurons. Neuron 13, 645–655 (1994). The modulation of NMDA receptor activity by mechanical pressure applied to neuronal membranes is described in this article.

    Article  CAS  PubMed  Google Scholar 

  129. Singh, P. et al. N-methyl-d-aspartate receptor mechanosensitivity is governed by C terminus of NR2B subunit. J. Biol. Chem. 287, 4348–4359 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Maroto, R. et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nature Cell Biol. 7, 179–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Liedtke, W. Handbook of Experimental Pharmacology Vol. 179 (eds Flockerzi, V. & Nilius, B.) 473–487 (Springer, 2007).

    Google Scholar 

  132. Grimm, C., Kraft, R., Sauerbruch, S., Schultz, G. & Harteneck, C. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J. Biol. Chem. 278, 21493–21501 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Thomas, D., Plant, L. D., Wilkens, C. M., McCrossan, Z. A. & Goldstein, S. A. Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron 58, 859–870 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, W. K. et al. Mechanosensitive gating of CFTR. Nature Cell Biol. 12, 507–512 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

W.J.T is supported by funds from a US Department of Defense grant from the US Army Research, Development, and Engineering Command (RDECOM W911NF-09-0431), a Defense Advanced Research Projects Agency Young Faculty Award (DARPA N66001-10-1-4032) and a McKnight Technological Innovation in Neuroscience Award.

Author information

Authors and Affiliations

  1. William J. Tyler is at The Virginia Tech Carilion Research Institute, School of Biomedical Engineering and Sciences, Virginia Tech, Roanoke, Virginia 24016, USA. wtyler@vt.edu,

    William J. Tyler

Authors
  1. William J. Tyler
    View author publications

    You can also search for this author inPubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

William J. Tyler's homepage

Glossary

Axon blebbing

The appearance of pathologically swollen regions (blebs) along an axon, which are thought to result from the local breakdown of cytoskeleton proteins in response to mechanical or oxidative stress.

Brownian ratchet

A perpetual motion machine constructed of a paddle wheel, ratchet and pawl that is useful for describing how work (or lack thereof) can be generated by random thermal fluctuations.

Catastrophic depolymerization

This term refers to the dynamic instability of microtubules; catastrophic depolymerization occurs when they rapidly switch from a growing to a shrinking state.

Elastic modulus

A numerical value describing the stiffness of a material or the tendency of a material to be deformed in response to force. The stiffer a material is, the higher its elastic modulus will be.

Elastomeric micropost substrate

A microfabricated substrate consisting of an array of tiny posts made of soft polymers that bend or become deflected to report traction forces generated by cells growing on them.

Elastomers

Materials such as rubber (usually polymers) with elastic or viscoelastic properties that enable them to return to their original state after deformation.

Gibb's free energy

Usually denoted G, it is the amount of energy available for work in a closed system at equilibrium under a constant temperature and pressure.

Magnetic resonance elastography

(MRE). A medical imaging technique used to measure the stiffness of tissue by introducing shear waves in tissue and quantifying their wavelengths as they propagate through the tissue using MRI.

Maxwell material

A material with both viscous and elastic properties; see viscoelastic material.

Mitotic spindle

A subcellular structure observable during the metaphase of cell division, when microtubules attach to kinetochores and begin to generate the forces required to pull chromosomes apart for subsequent incorporation into daughter cells.

Poisson's ratio

The ratio of transverse strain to axial strain in the direction of the stretching force.

Traction force microscopy

An optical method used to estimate the traction forces generated by growing cells as reported by the displacement of fluorescent microbeads embedded in a polyacrylamide hydrogel substrate.

Trans-gauche isomerization

A process by which fatty acids (acyl chains) experience changes in their conformational state and develop kinks in their molecular structure.

Viscoelastic material

Often referred to as a non-Newtonian material, this is a material that has both viscous and elastic properties and that experiences strain as a nonlinear function of time when stress is applied to it.

Viscoelastic relaxation time

The nonlinear recovery time for a viscoelastic material to return to its original state after experiencing a deformation force or stress.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tyler, W. The mechanobiology of brain function. Nat Rev Neurosci 13, 867–878 (2012). https://doi.org/10.1038/nrn3383

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3383

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing