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Degeneracy in Hippocampal Physiology and Plasticity bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted October 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Degeneracy in hippocampal physiology and plasticity * Rahul Kumar Rathour and Rishikesh Narayanan Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India. * Corresponding Author Rishikesh Narayanan, Ph.D. Molecular Biophysics Unit Indian Institute of Science Bangalore 560 012, India. e-mail: [email protected] Phone: +91-80-22933372 Fax: +91-80-23600535 Abbreviated title: Degeneracy in the hippocampus Keywords: hippocampus; degeneracy; learning; memory; encoding; homeostasis; plasticity; physiology; causality; reductionism; holism; structure-function relationships; variability; compensation; intrinsic excitability 1 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted October 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis, that demonstrate the expression of degeneracy in hippocampal physiology and plasticity. We assess the potential of degeneracy as a framework to achieve encoding and homeostasis without cross-interferences, and postulate that multiscale parametric and interactional complexity could establish disparate routes towards accomplishing these conjoint goals. These disparate routes then provide several degrees of freedom to the encoding- homeostasis system in accomplishing its tasks in an input- and state-dependent manner. Finally, the expression of degeneracy spanning multiple scales offers an ideal reconciliation to several outstanding controversies, through the recognition that the seemingly contradictory disparate observations are merely alternate routes that the system might recruit towards accomplishment of its goals. Juxtaposed against the ubiquitous prevalence of degeneracy and its strong links to evolution, it is perhaps apt to add a corollary to Theodosius Dobzhansky’s famous quote and state “nothing in physiology makes sense except in the light of degeneracy”. 2 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted October 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TABLE OF CONTENTS 1. Introduction ...................................................................................................................................................... 4 2. Degeneracy: Foundations from the perspective of an encoding system ...................................... 7 2.1. Degeneracy vs. compensation ....................................................................................................................................... 9 2.2. Dissociation between different forms of homeostasis ..................................................................................... 14 2.3. Baseline vs. plasticity profile homeostasis ............................................................................................................ 16 2.4. Encoding and homeostasis within the degeneracy framework .................................................................. 19 2.5. Curse-of-dimensionality or evolutionary robustness ....................................................................................... 21 2.6. Error correction mechanisms .................................................................................................................................... 23 3. Degeneracy at multiple scales in the hippocampus .......................................................................... 26 3.1. Degeneracy in the properties of channels and receptors ............................................................................... 28 3.2. Degeneracy in neuronal physiological properties ............................................................................................ 31 3.3. Degeneracy in calcium regulation and in the induction of synaptic plasticity .................................... 36 3.4. Degeneracy in signaling cascades that regulate synaptic plasticity ........................................................ 41 3.5. Degeneracy in the expression of synaptic plasticity ......................................................................................... 43 3.6. Degeneracy in the induction and expression of non-synaptic plasticity ................................................. 46 3.7. Degeneracy in metaplasticity and in maintaining stability of learning ................................................. 50 3.8. Degeneracy in the generation and regulation of local field potentials ................................................... 53 3.9. Degeneracy in neural coding ...................................................................................................................................... 55 3.10. Degeneracy in learning and memory ................................................................................................................... 59 4. The causality conundrum .......................................................................................................................... 62 4.1. Inevitable flaws in an experimental plan to establish causality that leaps across multiple scales .. 63 4.2. Degeneracy: The way forward ................................................................................................................................... 66 5. Conclusions ..................................................................................................................................................... 69 ACKNOWLEDGMENTS ...................................................................................................................................... 71 REFERENCES ....................................................................................................................................................... 72 3 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted October 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1. Introduction The pervasive question on the relationship between structure and function spans every aspect of life, science and philosophy: from building architectures to the mind-body problem, from connectomics to genomics to proteomics, from subatomic structures to cosmic bodies and from biomechanics to climate science. Even within a limited perspective spanning only neuroscience, the question has been posed at every scale of brain organization spanning the genetic to behavioral ends of the spectrum. Efforts to address this question have resulted in extensive studies that have yielded insights about the critical roles of protein structure and localization, synaptic ultrastructure, dendritic morphology, microcircuit organization and large-scale synaptic connectivity in several neural and behavioral functions. The question on the relationship between structure and function has spawned wide- ranging debates, with disparate approaches towards potential answers. At one extreme is the suggestion that structure defines function (Buzsaki, 2006): “The safest way to start speculating about the functions of a structure is to inspect its anatomical organization carefully. The dictum “structure defines function” never fails, although the architecture in itself is hardly ever sufficient to provide all the necessary clues.” Within this framework, the following is considered as a route for understanding neural systems and behavior (Buzsaki, 2006): “First, we need to know the basic “design” of its circuitry at both microscopic and macroscopic levels. Second, we must decipher the rules governing interactions among neurons and neuronal systems that give rise to overt and covert behaviors.” The other extreme is the assertion that “form follows function”, elucidated by Bert Sakmann (Sakmann, 2017), quoting Louis Sullivan: bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted October 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. “Whether it be the sweeping eagle in his flight, or the open apple-blossom, the toiling work-horse, the blithe swan, the branching oak, the winding stream at its base, the drifting clouds, over all the coursing sun, form ever follows function, and this is the law. Where function does not change, form does
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