User login

You are here

Journal Club Theme of December 2014: Neuromechanics

ashutosh.agrawal's picture

Descartes said: `I think, therefore I am’. Darwin wrote, ‘I think’. Unarguably, the brain is the most complex and mysterious part of our body that has intrigued both scientists and philosophers alike for centuries. It is the seat of our sensory perception, emotions, learning, memory, and consciousness. While the role of electrochemistry in the working of the brain and these processes have been investigated extensively in the last century, the role of mechanics or mechanical stimuli in controlling the structure and function of the brain has remained essentially elusive. This is so despite the fact that the building blocks of the brain at the cellular scale are known to be responsive to mechanical environment in other biological structures and contexts. The goal of this article is to present a brief overview of some of the recent developments in the area of physical neuroscience that have explored and advanced this paradigm and suggest three specific papers on this subject for the Journal Club (listed in the end).

Our brain is made up of two main cell types- interconnected neurons that transmit the electrical waves (called action potential or spike) and the support cells called glia. The interneuronal communication is established via influx and efflux of neurotransmitters at neuronal interfaces called junctions or synapses. With around 86 billion neurons in our body, the efficacy with which signals are seamlessly transduced across various length and time scales is simply mindboggling. It was the pioneering work of Alan Lloyd Hodkin and Andrew Huxley in early 1950s that led to a fundamental understanding of signaling in the brain and catapulted the field of neuroscience [1-5]. In a series of seminal studies, they unraveled the mechanism of initiation and propagation of action potentials in squid giant axons. They proposed an electrochemical model in which the axonal membrane served as a capacitor and the ion channels as conductors allowing ionic flow under the influence of electrochemical gradient. Since then the main focus in neuroscience has been on elucidating the electrochemistry of the brain!   

However, several studies adopted the less-traveled path and provided promising evidence of the coupling between the mechanics and electrochemistry. Seminal work by Bray in 70s and 80s revealed that tension is a key player in the growth of neurons [6, 7]. His study revealed that growth cones, driving neuronal growth, apply tension and that their directionality is dictated by tension. He also applied external tension and showed a direct impact on neuronal growth. That this growth is modulated by tension-dependent microtubule assembly was recently shown in [8].  Mechanics-oriented studies got a further boost by the discovery of Saif and co-workers that live neurons maintain a resting tension of about 1-13 nN in the axonal domains [9]. In addition, they found that theaxonal tension impacts transport and aggregation dynamics of vesicles that bears direct relevance to not only growth but also memory and learning, as vesicle-dependent neurotransmitter and calcium release regulates synaptic plasticity [10, 11] (see Taher’s blog article: http://imechanica.org/node/6635).

Another set of studies has shown a direct connection between mechanical forces and signaling. Studies on voltage-gated ion channels, traditionally known to respond to ionic concentrations only, unambiguously revealed their `mechanosensitive’ response [12-14]. When subjected to applied tension, these channels opened much sooner at a transmembrane potential much closer to the resting potential of the axonal membrane (around -80 mV). Brownell and co-workers discovered the role of electromechanical coupling in the hearing mechanism [15, 16]. Since then various theoretical and experimental works have investigated the piezoelectric response and its consequences in the cochlear outer hair cells [17, 18]. The two-way coupling between the electrochemistry and mechanics was further established in an ingenious study. When neuronal cells from rat were subjected to an applied voltage, cells inflated due to voltage-induced tension changes that resulted in the deflection of piezoelectric nanoribbons [19].

With regards to modeling of ion channels and action potential, Heimburg challenged the existing notion of action potential and proposed a model that goes beyond electro-chemistry and incorporates theromodynamics [20, 21]. He modeled nerve impulses as solitons propagating in axonal membranes residing close to the melting transition. Using his model, he was able to explain thermal effects and working of anaesthesia which are not explained by the Hodgkin-Huxley model. In our lab, we have developed a model to explain mechanosensitivity at the scale of a single channel. With a simple electromechanical model for simulating membrane-protein interactions, we are able to explain tension-induced changes in channel gating. Further enrichment and scaling-up of the model in the future would, hopefully, allow us to predict the impact of mechanical stimuli on action potential.

If we look at the subject from the point of view of health sciences, we see the urgency to elucidate the physical underpinnings of various neuronal and neurological disorders such as multiple sclerosis, Alzheimer, schizophrenia, Parkinson’s disease, traumatic brain injury (TBI) etc. In this regard, several advancements have been made in understanding TBI experienced by soldiers, sports players and others who experience a whip-lash kind of event. These disorders are caused by rapid acceleration or deceleration of the brain tissue and its internal collision with the skull leading to various symptoms such as blurred vision, loss of coordination, convulsions, among many others. In a recent study, Ramesh and co-workers established a link between TBI and axonal injury using a multi-scale continuum mechanics framework sensitive to the microstructural anisotropy arising from axonal orientation [22]. In another study, impact-induced axonal swelling arising from loss of protein-mediated contact between neurons and the surrounding matrix was found to be a cause of mild TBI [23]. On a different note, Castanzo and co-workers modeled fluid-structure interaction within the brain to gain physical insights into hydrocephalus, a disease characterized by abnormal accumulation of cerebrospinal fluid in the brain [24].

Finally, I conclude with a subject most abstract and enigmatic, that has been at the core of human quest for ages- the consciousness. Do physical laws govern our consciousness? Koch and Crick (co-discover of the DNA structure) proposed the idea of `neuronal correlates of consciousness’- the minimal set of neuronal events that enables a conscious perception [25]. In his book [26], Koch asks the question `What is the relation between the conscious mind and its physical basis in the electro-chemical interactions in the body?’ Aligned with the theme of this article, we can take the liberty of extending this idea further and ask if there are any mechanical signatures associated with subjective state of our brain (including dreams, hallucination, meditation) at the molecular and cellular scales. According to one proposed theory, elementary states of consciousness are manifestations of gravitation-induced reduction of quantum states in polymeric structures called microtubules in neurons [27]. Since the framework of quantum-gravity is yet to be established, it’s validity remains an open question.

To summarize, the field of neuromechanics is in its embryonic stage with a myriad of exciting problems awaiting scientific inquiry that can shed light on how we sense, think, act and learn. Together with sister sciences, mechanics can help solve the mysteries of the brain at the molecular, cellular, system and behavioral scales. To what extent the conscious mind can identify itself, time will tell…

With elementary knowledge in this area,I have dared to put forth a brief summary sprinkled with my views, with the hope that those who know more will pardon my naiveté and chime-in and those who find this topic fascinating will join the exciting voyage. For a more in-depth review on the topic, I recommend [28]. In particular, the following papers would make an excellent initial read for the purpose of the Journal club: 

  • Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of physiology, 117(4), 500.
  • Brownell, W. E., Spector, A. A., Raphael, R. M., & Popel, A. S. (2001). Micro-and nanomechanics of the cochlear outer hair cell. Annual review of biomedical engineering, 3(1), 169-194.
  • Heimburg, T., & Jackson, A. D. (2005). On soliton propagation in biomembranes and nerves. Proceedings of the National Academy of Sciences of the United States of America, 102(28), 9790-9795.

 

Happy Holidays!

 

References:

[1] Hodgkin, A. L., Huxley, A. F., & Katz, B. (1952). Measurement of current-voltage relations in the membrane of the giant axon of Loligo. The Journal of physiology, 116(4), 424.

[2] Hodgkin, A. L., & Huxley, A. F. (1952). Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. The Journal of physiology, 116(4), 449.

[3] Hodgkin, A. L., & Huxley, A. F. (1952). The components of membrane conductance in the giant axon of Loligo. The Journal of physiology, 116(4), 473-496.

[4] Hodgkin, A. L., & Huxley, A. F. (1952). The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. The Journal of physiology,116(4), 497-506.

[5] Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of physiology, 117(4), 500.

[6] Bray, D. (1979). Mechanical tension produced by nerve cells in tissue culture. Journal of cell science, 37(1), 391-410.

[7] Bray, D. (1984). Axonal growth in response to experimentally applied mechanical tension. Developmental biology, 102(2), 379-389.

[8] Nguyen, T. D., Hogue, I. B., Cung, K., Purohit, P. K., & McAlpine, M. C. (2013). Tension-induced neurite growth in microfluidic channels. Lab Chip, 13(18), 3735-3740.

[9] Rajagopalan, J., Tofangchi, A., & A Saif, M. T. (2010). Drosophila Neurons Actively Regulate Axonal Tension In Vivo. Biophysical journal, 99(10), 3208-3215.

[10] Siechen, S., Yang, S., Chiba, A., & Saif, T. (2009). Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals. Proceedings of the National Academy of Sciences, 106(31), 12611-12616.

[11] Ahmed, W. W., Williams, B. J., Silver, A. M., & Saif, T. A. (2013). Measuring nonequilibrium vesicle dynamics in neurons under tension. Lab on a Chip,13(4), 570-578.

[12] Gu, C. X., Juranka, P. F., & Morris, C. E. (2001). Stretch-Activation and Stretch-Inactivation of Shaker-IR, a Voltage-Gated K+ Channel. Biophysical Journal, 80(6), 2678-2693.

[13] Beyder, A., Rae, J. L., Bernard, C., Strege, P. R., Sachs, F., & Farrugia, G. (2010). Mechanosensitivity of Nav1. 5, a voltage-sensitive sodium channel. The Journal of physiology, 588(24), 4969-4985.

[14] Schmidt, D., del Mármol, J., & MacKinnon, R. (2012). Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K+ channels. Proceedings of the National Academy of Sciences, 109(26), 10352-10357.

[15] Brownell, W. E., Bader, C. R., Bertrand, D., & de Ribaupierre, Y. (1985). Evoked mechanical responses of isolated cochlear outer hair cells. Science, 227(4683), 194-196. 

[16] Kachar, B., Brownell, W. E., Altschuler, R., & Fex, J. (1986). Electrokinetic shape changes of cochlear outer hair cells. 

[17] Brownell, W. E., Spector, A. A., Raphael, R. M., & Popel, A. S. (2001). Micro-and nanomechanics of the cochlear outer hair cell. Annual review of biomedical engineering, 3(1), 169-194.

[18] Powers, R. J., Kulason, S., Atilgan, E., Brownell, W. E., Sun, S. X., Barr-Gillespie, P. G., & Spector, A. A. (2014). The Local Forces Acting on the Mechanotransduction Channel in Hair Cell Stereocilia. Biophysical Journal, 106(11), 2519-2528.

[19] Nguyen, T. D., Deshmukh, N., Nagarah, J. M., Kramer, T., Purohit, P. K., Berry, M. J., & McAlpine, M. C. (2012). Piezoelectric nanoribbons for monitoring cellular deformations. Nature nanotechnology, 7(9), 587-593.

[20] Heimburg, T., & Jackson, A. D. (2005). On soliton propagation in biomembranes and nerves. Proceedings of the National Academy of Sciences of the United States of America, 102(28), 9790-9795.

[21] Appali, R., van Rienen, U., & Heimburg, T. (2012). A comparison of the Hodgkin-Huxley model and the soliton theory for the action potential in nerves. Advances in Planar Lipid Bilayers and Liposomas, 16, 271-279.

[22] Wright, R. M., & Ramesh, K. T. (2012). An axonal strain injury criterion for traumatic brain injury. Biomechanics and modeling in mechanobiology, 11(1-2), 245-260.

[23] Hemphill, M. A., Dabiri, B. E., Gabriele, S., Kerscher, L., Franck, C., Goss, J. A., Alford, P. W., & Parker, K. K. (2011). A possible role for integrin signaling in diffuse axonal injury. PloS one, 6(7), e22899.

[24] Roy, S., Heltai, L., Drapaca, C. S., & Costanzo, F. (2012). An immersed finite element method approach for brain biomechanics, Mechanics of Biological Systems and Materials, Volume 5, Springer.

[25] Crick, F., & Koch, C. (2003). A framework for consciousness. Nature Neuroscience, 6, 119-126, Roberts & Company Publishers.

[26] Koch, C. (2004). The quest for consciousness: A neurobiological approach.   

[27] Hameroff, S., & Penrose, R. (2014). Consciousness in the universe: A review of the ‘Orch OR’theory. Physics of life reviews, 11(1), 39-78.

[28] Tyler, W. J. (2012). The mechanobiology of brain function. Nature Reviews Neuroscience, 13(12), 867-878.

Subscribe to Comments for "Journal Club Theme of December 2014: Neuromechanics"

Recent comments

More comments

Syndicate

Subscribe to Syndicate