The Interplay between Branching and Pruning on Neuronal Target Search during Developmental Growth: Functional Role and Implications

PLOS ONE, Oct 2011

Regenerative strategies that facilitate the regrowth and reconnection of neurons are some of the most promising methods in spinal cord injury research. An essential part of these strategies is an increased understanding of the mechanisms by which growing neurites seek out and synapse with viable targets. In this paper, we use computational and theoretical tools to examine the targeting efficiency of growing neurites subject to limited resources, such as maximum total neural tree length. We find that in order to efficiently reach a particular target, growing neurites must achieve balance between pruning and branching: rapidly growing neurites that do not prune will exhaust their resources, and frequently pruning neurites will fail to explore space effectively. We also find that the optimal branching/pruning balance must shift as the target distance changes: different strategies are called for to reach nearby vs. distant targets. This suggests the existence of a currently unidentified higher-level regulatory factor to control arborization dynamics. We propose that these findings may be useful in future therapies seeking to improve targeting rates through manipulation of arborization behaviors.

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The Interplay between Branching and Pruning on Neuronal Target Search during Developmental Growth: Functional Role and Implications

Shinbrot T (2011) The Interplay between Branching and Pruning on Neuronal Target Search during Developmental Growth: Functional Role and Implications. PLoS ONE 6(10): e25135. doi:10.1371/journal.pone.0025135 The Interplay between Branching and Pruning on Neuronal Target Search during Developmental Growth: Functional Role and Implications Remus Os an 0 Emily Su 0 Troy Shinbrot 0 Jialin Charles Zheng, University of Nebraska Medical Center, United States of America 0 1 Department of Mathematics and Statistics, Georgia State University , Atlanta , Georgia , United States of America, 2 Department of Mathematics and Statistics, Boston University , Boston , Massachusetts, United States of America, 3 Department of Biomedical Engineering, Rutgers University , Piscataway, New Jersey , United States of America Regenerative strategies that facilitate the regrowth and reconnection of neurons are some of the most promising methods in spinal cord injury research. An essential part of these strategies is an increased understanding of the mechanisms by which growing neurites seek out and synapse with viable targets. In this paper, we use computational and theoretical tools to examine the targeting efficiency of growing neurites subject to limited resources, such as maximum total neural tree length. We find that in order to efficiently reach a particular target, growing neurites must achieve balance between pruning and branching: rapidly growing neurites that do not prune will exhaust their resources, and frequently pruning neurites will fail to explore space effectively. We also find that the optimal branching/pruning balance must shift as the target distance changes: different strategies are called for to reach nearby vs. distant targets. This suggests the existence of a currently unidentified higher-level regulatory factor to control arborization dynamics. We propose that these findings may be useful in future therapies seeking to improve targeting rates through manipulation of arborization behaviors. - Funding: R.O. has received funding from the Center for Neuroscience, Boston University (internal grant). E.S. and T.S. have received funding from the New Jersey Commission on Spinal Cord Research (06-3055-SCR-E-0 and 07-2932-SCR-E-0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Search and pursuit problems have been studied extensively, leading to optimal strategies, for example search for food in an unpatterned landscape [1], pursuit of a duck in a circular pond [2] or search along persistent random walks [3]. In this paper, we study the search by neurons of viable targets during regeneration. As we will show, this problem presents particular issues that distinguish it from other historical search exercises for instance, a single axon can branch to produce multiple search avenues, and an axon probing a fruitless avenue can die back, recovering cellular resources. During normal development, controlled growth and elaboration of neuronal extensions (axons, dendrites, and synaptic connections) are central to establishing a functional nervous system [45]. Accordingly, deficits and alterations in the programmed neural architecture caused by trauma lead to impaired function. After spinal cord injury, for example, injury to both the central nervous system (CNS) and peripheral nervous system (PNS) lead to loss of motor and sensory capabilities. Consequently, re-establishing functional connections is essential to successful post-traumatic repair of the nervous system. Axonal connectivity between neurons is complex and varied, involving morphologies that facilitate connections to very different types of targets [67]. For many neurons, this means that exuberant axonal projections generated during development must be differentially regulated so that beneficial branches are elongated while aberrant branches are eliminated [89]. For other neurons, direct, unwavering axonal trajectories are abruptly and purposefully eliminated after their collaterals have reached an appropriate target. This large scale axon degeneration has been documented and studied in a variety of developmental systems, for example in retinotopic mapping in chick and the superior colliculus of mice [10]. The relationship between neuronal morphology and synaptic connectivity is exemplified by the heterogeneous population of neurons found in the dorsal root ganglion (DRG), where complexity and variability in geometric shapes of sensory neurons are observed, thus reflecting the diverse range of modalities served by DRG neurons [11]. In the present work, we focus on one piece of this puzzle: the interplay between branching and branchelimination processes in establishing appropriate synaptic partnerships. Mathematical and computational studies within t (...truncated)


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Remus Oşan, Emily Su, Troy Shinbrot. The Interplay between Branching and Pruning on Neuronal Target Search during Developmental Growth: Functional Role and Implications, PLOS ONE, 2011, Volume 6, Issue 10, DOI: 10.1371/journal.pone.0025135