CTW: Axonal Transport and Neuronal Mechanics

(November 3,2014 - November 7,2014 )

Organizers


Paul Bressloff
Department of Mathematics, University of Utah
Kristian Franze
Department of Physiology, Development and Neuroscience, University of Cambridge
Kyle Miller
Dept. of Zoology, Michigan State University
Jay Newby
Mathematical Biosciences Institute, The Ohio State University
Daniel Suter
Biological Sciences, Purdue University

A fundamental question in neurobiology is how do axons, the thin cellular cables that transmit information in the nervous system, grow? Since ~95% of total protein found in the axon is made in the cell body, it is widely recognized that axonal transport is essential for this process. In parallel, there is a deep interest in developing a better understanding of how growth cone mechanics, at the tip of the axon, modulate the rate and control the direction of axonal elongation. While these topics lend themselves well to mathematical modeling there has been limited direct interaction between experimentalists and theoreticians. Answering these questions is important for understanding the development of the nervous system, the pathological progression of neurodegenerative diseases such as Alzheimer's, and for designing novel approaches to promote neuronal regeneration following disease, stroke, or trauma. Recent progress in the field, facilitated by the development of novel experimental and theoretical approaches, has led to new insights and interest in interdisciplinary studies of axonal transport and neuromechanics. The goal of this workshop is to bring together leading cell biologists, engineers, physicists, and mathematicians to openly discuss exciting new findings, long-standing questions, and the future of our field. The timeliness of this meeting and its relevance to the mission of the MBI is most evident from three recent reviews by the organizers (Bressloff and Newby, 2013; Franze et al., 2013; Suter and Miller, 2011). In brief these reviews discuss the emerging role of forces in axonal elongation, mathematical models that have been developed to study the contribution of axonal transport to elongation, and the importance of developing mathematical models to study neuromechanics.

Accepted Speakers

Ahmad Athamneh
Biological Sciences, Purdue University
Roberto Bernal
Physics Department, Universidad de Santiago de Chile (USACH)
Anthony Brown
Neuroscience, The Ohio State University
Catherine Collins
Molecular, Cellular, and Developmental Biology, University of Michigan
Corina Drapaca
Engineering Science and Mechanics, Pennsylvania State University
Bonnie Firestein
Cell Biology and Neuroscience, Rutgers University
Paul Forscher
Molecular, Cellular and Developmental Biology, Yale University
Gianluca Gallo
Anatomy and Cell Biology, Temple University
Fernanda Garate
Physics, universidad de santiago de chile
Julian Garcia Grajales
Mathematical Institute, Mathematical Institute
Timothy Gomez
Neuroscience, University of Wisconsin
Alain Goriely
Mathematical Institute, University of Oxford
Bruce Graham
Computing Science and Mathematics, University of Stirling
Stephanie Gupton
Cell Biology & Physiology, University of North Carolina, Chapel Hill
Mary Halloran
Zoology, University of Wisconsin
David Holcman
Applied mathematics and Computational Biology, Ecole Normale Superieure
Paul Janmey
Physiology, University of Pennsylvania
Christopher Johnson
Physics & Astronomy, Ohio University
Peter Jung
Quantitative Biology Institute, Ohio University
Ellen Kuhl
Mechanical Engineering and Bioengineering, Stanford University
Michelle LaPlaca
Scott McKinley
Mathematics, University of Florida
Jay Newby
Mathematical Biosciences Institute, The Ohio State University
Matthew O'Toole
Mathematics, Kettering University
Bryan Pfister
Biomedical Engineering, New Jersey Institute of Technology
Sathya Puthanveettil
Neuroscience, The Scripps Research Institute
Jürgen Reingruber
Biology, Ecole Normale Superieure
Taher Saif
Mechanical Science and Engineering, University of Illinois at Urbana-Champaign
Esther Stoeckli
Joy Thompson
Physiology, Development and Neuroscience, University of Cambridge
Jeff Urbach
Physics, Georgetown University
Chuan Xue
Department of Mathematics, The Ohio State University
Monday, November 3, 2014
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:15 AM

Greetings and info from MBI - Marty Golubitsky

09:15 AM
09:30 AM

Welcome By Organizers

09:30 AM
10:10 AM
Anthony Brown - TBD

Abstract Not Submitted

10:10 AM
10:50 AM
Peter Jung - Slow Axonal Transport and Neuronal Morphology

Abstract Not Submitted

10:50 AM
11:20 AM

Break

11:20 AM
12:00 PM
Chuan Xue - Modeling the segregation of microtubules and neurofilaments in diseases

Abstract not submitted.

12:00 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Sathya Puthanveettil - Long-term memory storage: Kinesins and its cargos

Abstract to come.

02:40 PM
03:20 PM
Scott McKinley - TBD

Abstract Not Submitted

03:20 PM
03:50 PM

Break

03:50 PM
04:30 PM
Jay Newby - Microtubule transport of mRNA in dendrites

A key component in the cellular mechanisms underlying learning and memory involves the distribution and delivery of mRNA to synaptic sites in dendrites. A minimal three-state random intermittent search model of motor-driven mRNA transport is developed to explore the question of why motor-driven mRNA are observed moving bidirectionally. The model is analyzed by computing the probability an mRNA is delivered to a synaptic target and the average delivery time (MFPT). It is found that if the branched geometry of the dendrite is ignored, a purely unidirectional transport strategy will result in the smallest MFPT at any given delivery probability. The branched geometry of the dendrite is then incorporated into the model, and it is shown that a phase transition exists for a critical delivery probability where bidirectional strategies improve the corresponding MFPT. To further explore the impact of motor-driven transport behavior on mRNAdelivery, the three-state model is extended to include a detailed, biophysical model of a multimotor complex coordinated through a tug-of-war. The model is analyzed to explore how various measurable, physical quantities, such as adenosine triphosphate, can be tuned to optimize cargo delivery.

04:30 PM
05:00 PM

General Discussion

05:00 PM
07:00 PM

Reception and Poster Session

07:00 PM

Shuttle pick-up from MBI

Tuesday, November 4, 2014
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:40 AM
Mary Halloran - The kinesin adaptor Calsyntenin-1 regulates axon branching, axonal transport and microtubule dynamics

Abstract not submitted.

09:40 AM
10:20 AM
Esther Stoeckli - Trafficking of specific guidance receptors regulates axonal behavior at choice points

During neural circuit formation, axons have to find their target cells to make appropriate synaptic contacts. Along their trajectory, axons contact one or several intermediate targets. At each of them, axons need to switch their behavior from attraction to repulsion in order to move on. Axon guidance at intermediate targets, or choice points, depends on the precise regulation of guidance receptors on the growth cone surface. Dorsal commissural (dI1) axons crossing the ventral midline of the spinal cord in the floor plate represent a convenient model for the analysis of the molecular mechanism underlying the switch in axonal behavior.

We identified a role of Calsyntenin1 in the regulation of vesicular trafficking of guidance receptors in dI1 axons. In cooperation with RabGDI, Calsyntenin1 shuttles Rab11-positive vesicles containing Robo1 to the growth cone surface. In contrast, Calsyntenin1-mediated trafficking of Frizzled3, a guidance receptor in the Wnt pathway is independent of RabGDI. Thus, tightly regulated insertion of guidance receptors, which is required for midline crossing and the subsequent turn into the longitudinal axis, is achieved by their specific trafficking along axons.

10:20 AM
10:50 AM

Break

10:50 AM
11:30 AM
David Holcman - Modeling neurite outgrowth based on vesicular trafficking and microtubule dynamics

Abstract to come.

11:30 AM
12:10 PM
Matthew O'Toole - TBD

Abstract Not Submitted

12:10 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Stephanie Gupton - TRIM9 coordinates cytoskeletal dynamics and vesicle trafficking during Netrin-dependent axon guidance and branching

Abstract to come.

02:40 PM
03:20 PM
Gianluca Gallo - Cytoskeletal basis of axon collateral branching: Insights from Monte Carlo simulations

The formation of a functional nervous system requires the establishment of proper patterns of synaptic connectivity between neurons. Each neuron generates a single axon, but often makes synapses on 100s-1000s of other neurons in disparate parts of the nervous system. The ability of a single axon to generate such complex patterns of connectivity is due to the branching of the axon. Neuronal morphogenesis is dependent on the interactions between the two major components of the cytoskeleton; actin filaments and microtubules. Branches are initiated as actin filament based filopodial protrusions from the main axon shaft, which subsequently mature into branches containing actin filaments and microtubules. This presentation will detail a Monte Carlo simulation of the basic cytoskeletal events underlying the formation of axon branches. The simulation receives empirically derived input values related to aspects of the dynamics of the actin and microtubule cytoskeleton, and returns outputs in the same metric as empirically determined measurement of branch formation. The simulation thus allows direct analysis between empirically derived variables and the final output of the system (i.e., branch formation). The simulation faithfully reproduces the effects of branch inducing factors (e.g., NGF) and suggests new venues of empirical investigation.

03:20 PM
03:50 PM

Break

03:50 PM
04:30 PM
Bruce Graham - Mathematical models of intracellular transport-limited neurite elongation and branching

Abstract not submitted.

04:30 PM
05:00 PM

General Discussion

05:00 PM

Shuttle pick-up from MBI

Wednesday, November 5, 2014
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:40 AM
Jeff Urbach - Biomechanics and dynamics of growth cones in engineered environments

Abstract not submitted.

09:40 AM
10:20 AM
Roberto Bernal - TBD

Abstract Not Submitted

10:20 AM
10:50 AM

Break

10:50 AM
11:30 AM
Taher Saif - Axonal transport is modulated by axonal tension

Abstract not submitted.

11:30 AM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Paul Forscher - Treadmilling Actin Filament Arrays and Chemotropic Axon Growth

I will discuss the respective roles adhesion and actin dynamics play in axon growth acceleration in response to a soluble chemotropic factor.

02:40 PM
03:20 PM
Timothy Gomez - Mechanochemical signals that guide axon development.

Abstract not submitted.

03:20 PM
03:50 PM

Break

03:50 PM
04:30 PM
Alain Goriely - Aspects of brain mechanics such as swelling and damages

Abstract not submitted.

04:30 PM
05:10 PM
Laura Anne Lowery
05:10 PM
05:40 PM

General Discussion

05:40 PM

Shuttle pick-up from MBI

Thursday, November 6, 2014
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:20 AM
Dan Fenn - Short Talk: TBD

Abstract Not Submitted

09:20 AM
09:40 AM
Christopher Johnson - Short Talk: TBD

Abstract Not Submitted

09:40 AM
10:00 AM
Ahmad Athamneh - Short Talk: Traction force measurement in Aplysia Californica growth cones during adhesion-induced growth

Abstract Not Submitted.

10:00 AM
10:20 AM
Jürgen Reingruber - Short Talk: Modeling axonal targeting with synergetic interactions

Axonal transport and growth cone dynamics play a fundamental role for pathfinding and the formation of neuronal networks in the brain. During neuronal development, migrating axons wire the brain by generating long range connections between different brain regions. In the visual system, the retinotopic map connects the retina to the visual centers in the midbrain. When axons from retinal ganglion cells reach the optic tectum (superior colliculus in mammals) they form ordered connections with tectal neurons thereby establishing a topographic map. The map precision is important to correctly transmit the visual information projected onto the retina. Families of ephrin guidance molecule distributed in gradients in the retina and tectum play a crucial role in the map formation process. In addition, engrailed homeoprotein transcription factors are important for axonal guidance. Engrailed displays a graded expression in the chick optic tectum and participates in axonal guidance. Moreover, engrailed regulates the expression of ephrinA5 and increases the sensitivity of growth cones to ephrinA5 repellent activity. The molecular pathway for the engrailed-ephrinA5 interaction involves the internalization of engrailed into the growth cone, which stimulates the production and secretion of ATP, followed by hydrolysis of extracellular ATP into adenosine and the activation of membrane bound
adenosine A1 receptor that are present in higher concentrations in temporal than nasal GCs. Based on these findings, we propose a computational model that shows how the synergetic interaction between engrailed and ephrinA5 increases the precision of the map formation.

10:20 AM
10:50 AM

Break

10:50 AM
11:10 AM
Joy Thompson - Short Talk: Role of tissue stiffness in embryonic axon guidance.

Neuronal growth is essential for nervous system development and is also required for regeneration after nervous tissue injury. As axons and dendrites grow towards their targets, they are guided by environmental cues, including a well-characterised set of biochemical signals. Recent in vitro studies suggest that neuronal growth can also be regulated by mechanical properties of the substrate. However, the role of mechanical cues in axon pathfinding in vivo, and the spatiotemporal dynamics of tissue mechanics during early nervous system development, are still largely unknown. Here we investigate the role of tissue stiffness in axon guidance within the early embryo, using the Xenopus laevis optic tract as a model system. Retinal ganglion cell (RGC) axons form the optic tract by growing from the embryonic retina, along a stereotypical path on the brain surface, and terminating at their target, the tectum. We have developed in vivo atomic force microscopy (AFM) to map tissue stiffness along the optic tract at different developmental stages. We find that the embryonic brain is overall mechanically inhomogeneous, and that brain stiffness changes over time. Specifically, we find that the elastic stiffness of the tectum is consistently lower than the rest of the path taken by RGCs. Our results indicate that the path of RGCs is correlated with stiffness gradients in vivo, before axon growth stalls after reaching the softer region. These findings are consistent with a role for substrate mechanics in axon pathfinding, which might not only be crucial during development but also during regenerative processes in the nervous system.

11:10 AM
11:30 AM
Julian Garcia Grajales - Short Talk: Mechanical modeling of neurites

Computational Neuron Mechanics appears as a new multidisciplinary _eld potentially able to study medical challenges such as Alzheimer's disease, tumor growth/migration or traumatic brain injury at cell level. Although computational modeling has been widely used in di_erent Neuroscience applications, the tremendous importance of the interactions between the neuron and its surrounding media/stimulus have been rarely explored. Aimed at analyzing these inter- actions, this work proposes a new multiscale computational framework particularized for two representative scenarios: axonal growth and electrophysiological-mechanical coupling of neu- rites. In the former, the intertwined relation between a biochemical stimulus and the mechanical properties of axons is studied, whereas in the latter, the functional impairments of neurites as a consequence of mechanical constraints are explored. To accomplish these objectives, we de- vise a large scale parallel _nite di_erence program, called Neurite, with the necessary exibility and versatility to implement biological models. In the case of the axonal growth, the program was adapted to simulate microtubule polymerization providing axon mechanical properties as a function of its microtubule occupancy. For the electrophysiological-mechanical coupling case, Neurite was used to relate macroscopic mechanical loading to microscopic strains and strain rates, and to simulate electrical signal propagation along neurites under mechanical loading. For both cases, the models were calibrated against experimental results available in the litera- ture. The growth model showed dramatic variations in the mechanical properties at the tip of the axon, whereas the electrophysiological-mechanical model represents a novelty for predicting the alteration of neuronal electrophysiological function under mechanical loading, thus linking mechanical traumas to subsequent acute functional de_cits.

11:30 AM
11:50 AM
Fernanda Garate - Short Talk: TBD

Abstract Not Submitted

11:50 AM
12:10 PM

General Discussion

12:10 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Bonnie Firestein - Assessing Effects on Dendritic Arborization: Novel Sholl Analyses and Imaging of Microtubule Dynamics.

The precise patterning of dendrites is important for determining how information is processed by a neuron. The neuron cannot receive appropriate information when there is an abnormal decrease in dendrite branching. Thus, disruption of proper signaling networks results. We and others have made significant progress on characterizing extracellular and intrinsic factors that regulate dendrite number or branching by altering cytoskeletal dynamics. Generally, changes to the dendritic arbor are assessed by Sholl analysis or simple dendrite counting. However, we have found that this general method often overlooks local changes to the arbor. We have developed a program (titled "Bonfire") to facilitate digitization of neurite morphology and subsequent Sholl analysis and to assess changes to root, intermediate, and terminal neurites. More recently, we have studied how microtubule dynamics are altered when changes occur to the dendritic arbor. Our future goal is to combine Sholl analysis and microtubule dynamic studies to understand how dendrites assume specific morphologies.

02:40 PM
03:20 PM
Ellen Kuhl - On The Role Of Neuromechanics In Human Brain Development

Convolutions are a classical hallmark of most mammalian brains. Brain surface morphology is often associated with intelligence and closely correlated to neurological dysfunction. Yet, we know surprisingly little about the underlying mechanisms that drive cortical folding. To explore the evolution of brain surface morphology, we establish a neuromechanical model using the nonlinear field theories of mechanics supplemented by the continuum theory of finite growth. Continuum modeling allows us to seamlessly integrate information across the scales and correlate organ-level phenomena such as cortical folding to molecular-level processes such as axonal elongation. We show that our model can predict the formation of complex surface morphologies including symmetry breaking and secondary folding. Computational modeling naturally explains why larger mammalian brains tend to be more convoluted than smaller brains and provides a mechanistic interpretation of pathological malformations of lissencephaly and polymicrogyria. Understanding the role of physical forces during the development of the nervous system may have direct implications on the diagnostics and treatment of neurological disorders including severe retardation, epilepsy, schizophrenia, and autism.

03:20 PM
03:50 PM

Break

03:50 PM
04:30 PM
Paul Janmey - How soft is the brain? Compression stiffening and mechanosensing by glial cells

Abstract Not Submitted.

04:30 PM
05:00 PM

General Discussion

05:00 PM

Shuttle pick-up from MBI

Friday, November 7, 2014
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:40 AM
Corina Drapaca - Mathematical Modeling of Brain Neuro-Mechanics

It is well known that mechanical loading and biochemical imbalances can alter brain’s functions and/or structure and lead to neurological diseases. Mathematical models of brain neuro-mechanics can play an important role in highlighting the mechanisms that govern healthy and diseased processes and thus help develop better diagnostic and therapeutic tools. We propose to model the brain as a triphasic composite made of solid, fluid and ionic phases and show some numerical simulations that suggest that normal pressure hydrocephalus could be caused by an imbalance in the salt concentration in the absence of an elevated intracranial pressure. We will also show some numerical simulations of the coupling between the proposed triphasic model and the Hodgkin-Huxley model that permit the investigation of possible linkages between brain’s functionality and mechanical behavior.

09:40 AM
10:20 AM
Bryan Pfister - Extreme Axon Stretch Growth

Axons span the body over great distances; up to a meter in humans and much longer in large mammals. The study of axon growth has mainly focused on the extension and migration of growth cones during development. Once axons integrate with their targets, however, axonal fibers continue to grow in synchrony with body growth. The likely regulatory mechanism that accommodates for such symbiotic interaction is the biomechanical stretching of axons, a formidable stimulus of neuronal growth. Our lab has engineered bioreactors to uniaxially stretch grow axons in culture that can be microscopically visualized in real time. Nerves can quickly adapt to increasing rates of stretch-growth. Below 25% applied strain axons grow in absence of occlusion of axon transport and long-term disconnection. Neurons from stretch grown axons do not show evidence of chromatolysis and can produce normal electrical activity. Under these conditions, persistent axon stretch upregulates developmental and regenerative associated genes. Bioinformatics analysis using Ingenuity pathway analysis software revealed significant changes in lipid metabolism, molecular transport, and small molecule biochemistry. Further, stress-response and regenerative associated genes such as SPRR1a and ATF3 were found to be upregulated, implicating a novel role in development in addition to their transient expression following injury. These results suggest that axon stretch growth is a process whereby neuronal expansion is regulated by developmental stress, which leads to a unique transcriptional profile that accommodates axon growth.

10:20 AM
10:50 AM

Break

10:50 AM
11:30 AM
Michelle LaPlaca - Neural mechanobiology and neuronal vulnerability to traumatic loading

Abstract Not Submitted

11:30 AM
12:10 PM
Catherine Collins - using Drosophila as a model to study axonal injury signaling, axonal degeneration and mitochondrial trafficking

Abstract Not Submitted

12:10 PM
01:00 PM

General Discussion and Closing Remarks

01:00 PM

Shuttle pick-up from MBI (One back to hotel and one to airport)

Name Email Affiliation
Athamneh, Ahmad aathamne@purdue.edu Biological Sciences, Purdue University
Bates, Dan bates@math.colostate.edu Department of Mathematics, Colorado State University
Bernal, Roberto roberto.bernal@usach.cl Physics Department, Universidad de Santiago de Chile (USACH)
Bray, Dennis db10009@cam.ac.uk Physiology, Develoment, Neuroscience, University of Cambridge
Bressloff, Paul bressloff@math.utah.edu Department of Mathematics, University of Utah
Brown, Anthony brown.2302@osu.edu Neuroscience, The Ohio State University
Cebulla, Colleen colleen.cebulla@osumc.edu Ophthalmology and Visual Science, The Ohio State University
Collins, Catherine collinca@umich.edu Molecular, Cellular, and Developmental Biology, University of Michigan
Drapaca, Corina csd12@psu.edu Engineering Science and Mechanics, Pennsylvania State University
Firestein, Bonnie firestein@biology.rutgers.edu Cell Biology and Neuroscience, Rutgers University
Forscher, Paul paul.forscher@yale.edu Molecular, Cellular and Developmental Biology, Yale University
Franze, Kristian kf284@cam.ac.uk Department of Physiology, Development and Neuroscience, University of Cambridge
Gallo, Gianluca gianluca.gallo@temple.edu Anatomy and Cell Biology, Temple University
Garate, Fernanda fernanda.garate@usach.cl Physics, universidad de santiago de chile
Garcia Grajales, Julian Julian.GarciaGrajales@maths.ox.ac.uk Mathematical Institute, Mathematical Institute
Gomez, Timothy tmgomez@wisc.edu Neuroscience, University of Wisconsin
Goriely, Alain Alain.Goriely@maths.ox.ac.uk Mathematical Institute, University of Oxford
Graham, Bruce b.graham@cs.stir.ac.uk Computing Science and Mathematics, University of Stirling
Gupton, Stephanie stephanie_gupton@med.unc.edu Cell Biology & Physiology, University of North Carolina, Chapel Hill
Halloran, Mary mchalloran@wisc.edu Zoology, University of Wisconsin
Heidemann, Steven heideman@msu.edu Physiology, Michigan State University
Holcman, David holcman@biologie.ens.fr Applied mathematics and Computational Biology, Ecole Normale Superieure
Janmey, Paul janmey@mail.med.upenn.edu Physiology, University of Pennsylvania
Johnson, Christopher cj791502@ohio.edu Physics & Astronomy, Ohio University
Jung, Peter jung@phy.ohiou.edu Quantitative Biology Institute, Ohio University
Karamched, Bhargav bkaramched@gmail.com Mathematics, University of Utah
Kuhl, Ellen ekuhl@stanford.edu Mechanical Engineering and Bioengineering, Stanford University
LaPlaca, Michelle michelle.laplaca@bme.gatech.edu
Lowery, Laura Anne laura.lowery@bc.edu Biology, Boston College
Maia, Pedro pedro.doria.maia@gmail.com Applied Mathematics, University of Washington
McKinley, Scott scott.mckinley@ufl.edu Mathematics, University of Florida
Miller, Kyle kmiller@msu.edu Dept. of Zoology, Michigan State University
Mussel, Matan matanmus@gmail.com Department of Biomedical Engineering, Tel Aviv University
Newby, Jay newby.23@mbi.osu.edu Mathematical Biosciences Institute, The Ohio State University
O'Neill, Kate km.fitzgerald@rutgers.edu Biomedical Engineering, Rutgers University
O'Toole, Matthew motoole@kettering.edu Mathematics, Kettering University
Osan, Remus rosan@gsu.edu Mathematics and Statistics, Georgia State University
Pfister, Bryan bryan.j.pfister@njit.edu Biomedical Engineering, New Jersey Institute of Technology
Puthanveettil, Sathya sputhanv@scripps.edu Neuroscience, The Scripps Research Institute
Reingruber, Juergen reingrub@biologie.ens.fr Biology, Ecole Normale Superieure
Ronan, Lisa Lr344@cam.ac.uk Department of Psychiatry, University of Cambridge
Saif, Taher saif@illinois.edu Mechanical Science and Engineering, University of Illinois at Urbana-Champaign
Stoeckli, Esther esther.stoeckli@imls.uzh.ch
Suter, Daniel dsuter@purdue.edu Biological Sciences, Purdue University
Thompson, Amelia ajt88@cam.ac.uk Physiology, Development and Neuroscience, University of Cambridge
Urbach, Jeffrey urbach@physics.georgetown.edu Physics, Georgetown University
Xue, Chuan cxue@math.osu.edu Department of Mathematics, The Ohio State University
Short Talk: Traction force measurement in Aplysia Californica growth cones during adhesion-induced growth

Abstract Not Submitted.

TBD

Abstract Not Submitted

TBD

Abstract Not Submitted

using Drosophila as a model to study axonal injury signaling, axonal degeneration and mitochondrial trafficking

Abstract Not Submitted

using Drosophila as a model to study axonal injury signaling, axonal degeneration and mitochondrial trafficking

Abstract not submitted.

Mathematical Modeling of Brain Neuro-Mechanics

It is well known that mechanical loading and biochemical imbalances can alter brain’s functions and/or structure and lead to neurological diseases. Mathematical models of brain neuro-mechanics can play an important role in highlighting the mechanisms that govern healthy and diseased processes and thus help develop better diagnostic and therapeutic tools. We propose to model the brain as a triphasic composite made of solid, fluid and ionic phases and show some numerical simulations that suggest that normal pressure hydrocephalus could be caused by an imbalance in the salt concentration in the absence of an elevated intracranial pressure. We will also show some numerical simulations of the coupling between the proposed triphasic model and the Hodgkin-Huxley model that permit the investigation of possible linkages between brain’s functionality and mechanical behavior.

Short Talk: TBD

Abstract Not Submitted

Assessing Effects on Dendritic Arborization: Novel Sholl Analyses and Imaging of Microtubule Dynamics.

The precise patterning of dendrites is important for determining how information is processed by a neuron. The neuron cannot receive appropriate information when there is an abnormal decrease in dendrite branching. Thus, disruption of proper signaling networks results. We and others have made significant progress on characterizing extracellular and intrinsic factors that regulate dendrite number or branching by altering cytoskeletal dynamics. Generally, changes to the dendritic arbor are assessed by Sholl analysis or simple dendrite counting. However, we have found that this general method often overlooks local changes to the arbor. We have developed a program (titled "Bonfire") to facilitate digitization of neurite morphology and subsequent Sholl analysis and to assess changes to root, intermediate, and terminal neurites. More recently, we have studied how microtubule dynamics are altered when changes occur to the dendritic arbor. Our future goal is to combine Sholl analysis and microtubule dynamic studies to understand how dendrites assume specific morphologies.

Treadmilling Actin Filament Arrays and Chemotropic Axon Growth

I will discuss the respective roles adhesion and actin dynamics play in axon growth acceleration in response to a soluble chemotropic factor.

Cytoskeletal basis of axon collateral branching: Insights from Monte Carlo simulations

The formation of a functional nervous system requires the establishment of proper patterns of synaptic connectivity between neurons. Each neuron generates a single axon, but often makes synapses on 100s-1000s of other neurons in disparate parts of the nervous system. The ability of a single axon to generate such complex patterns of connectivity is due to the branching of the axon. Neuronal morphogenesis is dependent on the interactions between the two major components of the cytoskeleton; actin filaments and microtubules. Branches are initiated as actin filament based filopodial protrusions from the main axon shaft, which subsequently mature into branches containing actin filaments and microtubules. This presentation will detail a Monte Carlo simulation of the basic cytoskeletal events underlying the formation of axon branches. The simulation receives empirically derived input values related to aspects of the dynamics of the actin and microtubule cytoskeleton, and returns outputs in the same metric as empirically determined measurement of branch formation. The simulation thus allows direct analysis between empirically derived variables and the final output of the system (i.e., branch formation). The simulation faithfully reproduces the effects of branch inducing factors (e.g., NGF) and suggests new venues of empirical investigation.

Short Talk: TBD

Abstract Not Submitted

Short Talk: Mechanical modeling of neurites

Computational Neuron Mechanics appears as a new multidisciplinary _eld potentially able to study medical challenges such as Alzheimer's disease, tumor growth/migration or traumatic brain injury at cell level. Although computational modeling has been widely used in di_erent Neuroscience applications, the tremendous importance of the interactions between the neuron and its surrounding media/stimulus have been rarely explored. Aimed at analyzing these inter- actions, this work proposes a new multiscale computational framework particularized for two representative scenarios: axonal growth and electrophysiological-mechanical coupling of neu- rites. In the former, the intertwined relation between a biochemical stimulus and the mechanical properties of axons is studied, whereas in the latter, the functional impairments of neurites as a consequence of mechanical constraints are explored. To accomplish these objectives, we de- vise a large scale parallel _nite di_erence program, called Neurite, with the necessary exibility and versatility to implement biological models. In the case of the axonal growth, the program was adapted to simulate microtubule polymerization providing axon mechanical properties as a function of its microtubule occupancy. For the electrophysiological-mechanical coupling case, Neurite was used to relate macroscopic mechanical loading to microscopic strains and strain rates, and to simulate electrical signal propagation along neurites under mechanical loading. For both cases, the models were calibrated against experimental results available in the litera- ture. The growth model showed dramatic variations in the mechanical properties at the tip of the axon, whereas the electrophysiological-mechanical model represents a novelty for predicting the alteration of neuronal electrophysiological function under mechanical loading, thus linking mechanical traumas to subsequent acute functional de_cits.

Mechanochemical signals that guide axon development.

Abstract not submitted.

Aspects of brain mechanics such as swelling and damages

Abstract not submitted.

Mathematical models of intracellular transport-limited neurite elongation and branching

Abstract not submitted.

TRIM9 coordinates cytoskeletal dynamics and vesicle trafficking during Netrin-dependent axon guidance and branching

Abstract to come.

The kinesin adaptor Calsyntenin-1 regulates axon branching, axonal transport and microtubule dynamics

Abstract not submitted.

Modeling neurite outgrowth based on vesicular trafficking and microtubule dynamics

Abstract to come.

How soft is the brain? Compression stiffening and mechanosensing by glial cells

Abstract Not Submitted.

Short Talk: TBD

Abstract Not Submitted

Slow Axonal Transport and Neuronal Morphology

Abstract Not Submitted

On The Role Of Neuromechanics In Human Brain Development

Convolutions are a classical hallmark of most mammalian brains. Brain surface morphology is often associated with intelligence and closely correlated to neurological dysfunction. Yet, we know surprisingly little about the underlying mechanisms that drive cortical folding. To explore the evolution of brain surface morphology, we establish a neuromechanical model using the nonlinear field theories of mechanics supplemented by the continuum theory of finite growth. Continuum modeling allows us to seamlessly integrate information across the scales and correlate organ-level phenomena such as cortical folding to molecular-level processes such as axonal elongation. We show that our model can predict the formation of complex surface morphologies including symmetry breaking and secondary folding. Computational modeling naturally explains why larger mammalian brains tend to be more convoluted than smaller brains and provides a mechanistic interpretation of pathological malformations of lissencephaly and polymicrogyria. Understanding the role of physical forces during the development of the nervous system may have direct implications on the diagnostics and treatment of neurological disorders including severe retardation, epilepsy, schizophrenia, and autism.

Neural mechanobiology and neuronal vulnerability to traumatic loading

Abstract Not Submitted

TBD

Abstract Not Submitted

Microtubule transport of mRNA in dendrites

A key component in the cellular mechanisms underlying learning and memory involves the distribution and delivery of mRNA to synaptic sites in dendrites. A minimal three-state random intermittent search model of motor-driven mRNA transport is developed to explore the question of why motor-driven mRNA are observed moving bidirectionally. The model is analyzed by computing the probability an mRNA is delivered to a synaptic target and the average delivery time (MFPT). It is found that if the branched geometry of the dendrite is ignored, a purely unidirectional transport strategy will result in the smallest MFPT at any given delivery probability. The branched geometry of the dendrite is then incorporated into the model, and it is shown that a phase transition exists for a critical delivery probability where bidirectional strategies improve the corresponding MFPT. To further explore the impact of motor-driven transport behavior on mRNAdelivery, the three-state model is extended to include a detailed, biophysical model of a multimotor complex coordinated through a tug-of-war. The model is analyzed to explore how various measurable, physical quantities, such as adenosine triphosphate, can be tuned to optimize cargo delivery.

TBD

Abstract Not Submitted

Extreme Axon Stretch Growth

Axons span the body over great distances; up to a meter in humans and much longer in large mammals. The study of axon growth has mainly focused on the extension and migration of growth cones during development. Once axons integrate with their targets, however, axonal fibers continue to grow in synchrony with body growth. The likely regulatory mechanism that accommodates for such symbiotic interaction is the biomechanical stretching of axons, a formidable stimulus of neuronal growth. Our lab has engineered bioreactors to uniaxially stretch grow axons in culture that can be microscopically visualized in real time. Nerves can quickly adapt to increasing rates of stretch-growth. Below 25% applied strain axons grow in absence of occlusion of axon transport and long-term disconnection. Neurons from stretch grown axons do not show evidence of chromatolysis and can produce normal electrical activity. Under these conditions, persistent axon stretch upregulates developmental and regenerative associated genes. Bioinformatics analysis using Ingenuity® pathway analysis software revealed significant changes in lipid metabolism, molecular transport, and small molecule biochemistry. Further, stress-response and regenerative associated genes such as SPRR1a and ATF3 were found to be upregulated, implicating a novel role in development in addition to their transient expression following injury. These results suggest that axon stretch growth is a process whereby neuronal expansion is regulated by developmental stress, which leads to a unique transcriptional profile that accommodates axon growth.

Long-term memory storage: Kinesins and its cargos

Abstract to come.

Short Talk: Modeling axonal targeting with synergetic interactions

Axonal transport and growth cone dynamics play a fundamental role for pathfinding and the formation of neuronal networks in the brain. During neuronal development, migrating axons wire the brain by generating long range connections between different brain regions. In the visual system, the retinotopic map connects the retina to the visual centers in the midbrain. When axons from retinal ganglion cells reach the optic tectum (superior colliculus in mammals) they form ordered connections with tectal neurons thereby establishing a topographic map. The map precision is important to correctly transmit the visual information projected onto the retina. Families of ephrin guidance molecule distributed in gradients in the retina and tectum play a crucial role in the map formation process. In addition, engrailed homeoprotein transcription factors are important for axonal guidance. Engrailed displays a graded expression in the chick optic tectum and participates in axonal guidance. Moreover, engrailed regulates the expression of ephrinA5 and increases the sensitivity of growth cones to ephrinA5 repellent activity. The molecular pathway for the engrailed-ephrinA5 interaction involves the internalization of engrailed into the growth cone, which stimulates the production and secretion of ATP, followed by hydrolysis of extracellular ATP into adenosine and the activation of membrane bound
adenosine A1 receptor that are present in higher concentrations in temporal than nasal GCs. Based on these findings, we propose a computational model that shows how the synergetic interaction between engrailed and ephrinA5 increases the precision of the map formation.

Axonal transport is modulated by axonal tension

Abstract not submitted.

Trafficking of specific guidance receptors regulates axonal behavior at choice points

During neural circuit formation, axons have to find their target cells to make appropriate synaptic contacts. Along their trajectory, axons contact one or several intermediate targets. At each of them, axons need to switch their behavior from attraction to repulsion in order to move on. Axon guidance at intermediate targets, or choice points, depends on the precise regulation of guidance receptors on the growth cone surface. Dorsal commissural (dI1) axons crossing the ventral midline of the spinal cord in the floor plate represent a convenient model for the analysis of the molecular mechanism underlying the switch in axonal behavior.

We identified a role of Calsyntenin1 in the regulation of vesicular trafficking of guidance receptors in dI1 axons. In cooperation with RabGDI, Calsyntenin1 shuttles Rab11-positive vesicles containing Robo1 to the growth cone surface. In contrast, Calsyntenin1-mediated trafficking of Frizzled3, a guidance receptor in the Wnt pathway is independent of RabGDI. Thus, tightly regulated insertion of guidance receptors, which is required for midline crossing and the subsequent turn into the longitudinal axis, is achieved by their specific trafficking along axons.

Short Talk: Role of tissue stiffness in embryonic axon guidance.

Neuronal growth is essential for nervous system development and is also required for regeneration after nervous tissue injury. As axons and dendrites grow towards their targets, they are guided by environmental cues, including a well-characterised set of biochemical signals. Recent in vitro studies suggest that neuronal growth can also be regulated by mechanical properties of the substrate. However, the role of mechanical cues in axon pathfinding in vivo, and the spatiotemporal dynamics of tissue mechanics during early nervous system development, are still largely unknown. Here we investigate the role of tissue stiffness in axon guidance within the early embryo, using the Xenopus laevis optic tract as a model system. Retinal ganglion cell (RGC) axons form the optic tract by growing from the embryonic retina, along a stereotypical path on the brain surface, and terminating at their target, the tectum. We have developed in vivo atomic force microscopy (AFM) to map tissue stiffness along the optic tract at different developmental stages. We find that the embryonic brain is overall mechanically inhomogeneous, and that brain stiffness changes over time. Specifically, we find that the elastic stiffness of the tectum is consistently lower than the rest of the path taken by RGCs. Our results indicate that the path of RGCs is correlated with stiffness gradients in vivo, before axon growth stalls after reaching the softer region. These findings are consistent with a role for substrate mechanics in axon pathfinding, which might not only be crucial during development but also during regenerative processes in the nervous system.

Biomechanics and dynamics of growth cones in engineered environments

Abstract not submitted.

Modeling the segregation of microtubules and neurofilaments in diseases

Abstract not submitted.

Posters

Integrate-and-Fire Model of Axonal Length Control

A fundamental question in cell biology is how the sizes of cellular and subcellular structures are determined in order to scale with physiological requirements. Here, we develop a mathematical model of a recently hypothesized bidirectional motor transport mechanism for cellular length control in axons, which is distinct from standard proposed mechanisms for cellular size regulation. An anterograde signal is transported by kinesin motors from the cell body to the tip of the growing axon, where it activates the dynein-mediated transport of a retrograde signal back to the cell body. The retrograde signal then represses the anterograde signal via negative feedback, resulting in an oscillation whose frequency decreases with axonal length. If this frequency is correlated with axonal length, then frequency-dependent activation of transcription factors could regulate axonal growth. The proposed mechanism predicts that reducing either of the signals should increase axonal length. We describe this model mathematically using an Integrate-and-Fire model.

Drag of the cytosol as a transport mechanism in neurons

Axonal transport is typically divided into two components, distinguished by their mean velocity The fast component includes steady trafficking of different organelles and vesicles, actively transported by motor proteins. The slow component comprises non-membranous materials, undergoing infrequent bidirectional motion. The underlying mechanism of the slow axonal transport has been under debate during the past three decades. We propose a simple displacement mechanism that may be central for the distribution of soluble molecules not carried by vesicles. It relies on the cytoplasmic drag induced by organelle movement and readily accounts for the key experimental observations pertaining to the slow component transport. The induced cytoplasmic drag is predicted to depend mainly on the distribution of microtubules in the axon, the organelle transport rate, and the physical properties of the axon's external layer.

Matan Mussel1*, Keren Zeevy1*, Haim Diamant2and Uri Nevo1

1Department of Biomedical Engineering,

2School of Chemistry, Tel Aviv University

*These authors contributed equally to the work