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Degeneracy in Hippocampal Physiology and Plasticity bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted July 30, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 July 30, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 the conjoint goals of encoding and homeostasis without cross-interferences. We postulate that biological complexity, involving interactions among the numerous parameters spanning different scales of analysis, 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. Against the backdrop of 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 July 30, 2018. 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. Highlights • Degeneracy is the ability of structurally distinct elements to yield similar function • We postulate a critical role for degeneracy in the emergence of stable encoding systems • We catalog lines of evidence for the expression of degeneracy in the hippocampus • We suggest avenues for research to explore degeneracy in stable encoding systems • Dobzhansky wrote: “nothing in biology makes sense except in the light of evolution” • A corollary: “nothing in physiology makes sense except in the light of degeneracy” 3 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted July 30, 2018. 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 ...................................................................................................................................................... 5 2. Degeneracy: Foundations from the perspective of an encoding system ...................................... 8 2.1. Degeneracy vs. compensation .................................................................................................................................... 10 2.2. Dissociation between different forms of homeostasis ..................................................................................... 15 2.3. Baseline vs. plasticity profile homeostasis ............................................................................................................ 17 2.4. Encoding and homeostasis within the degeneracy framework .................................................................. 20 2.5. Curse-of-dimensionality or evolutionary robustness ....................................................................................... 22 2.6. Error correction mechanisms .................................................................................................................................... 24 3. Degeneracy at multiple scales in the hippocampus .......................................................................... 27 3.1. Degeneracy in the properties of channels and receptors ............................................................................... 29 3.2. Degeneracy in neuronal physiological properties ............................................................................................ 32 3.3. Degeneracy in calcium regulation and in the induction of synaptic plasticity .................................... 38 3.4. Degeneracy in signaling cascades that regulate synaptic plasticity ........................................................ 42 3.5. Degeneracy in the expression of synaptic plasticity ......................................................................................... 44 3.6. Degeneracy in the induction and expression of non-synaptic plasticity ................................................. 46 3.7. Degeneracy in metaplasticity and in maintaining stability of learning ................................................. 51 3.8. Degeneracy in the generation and regulation of local field potentials ................................................... 54 3.9. Degeneracy in neural coding ...................................................................................................................................... 56 3.10. Degeneracy in learning and memory ................................................................................................................... 60 4. The causality conundrum .......................................................................................................................... 63 4.1. Inevitable flaws in an experimental plan to establish causality that leaps across multiple scales .. 63 4.2. Degeneracy: The way forward ................................................................................................................................... 67 5. Conclusions ..................................................................................................................................................... 70 ACKNOWLEDGMENTS ...................................................................................................................................... 72 REFERENCES ....................................................................................................................................................... 73 4 bioRxiv preprint doi: https://doi.org/10.1101/203943; this version posted July 30, 2018. 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 1. Introduction 2 The pervasive question on the relationship between structure and function spans every aspect of 3 life, science and philosophy: from building architectures to the mind-body problem, from 4 connectomics to genomics to proteomics, from subatomic structures to cosmic bodies and from 5 biomechanics to climate science. Even within a limited perspective spanning only neuroscience, 6 the question has been posed at every scale of brain organization spanning the genetic to 7 behavioral ends of the spectrum. Efforts to address this question have resulted in extensive 8 studies that have yielded insights about the critical roles of protein structure and localization, 9 synaptic ultrastructure, dendritic morphology, microcircuit organization and large-scale synaptic 10 connectivity in several neural and behavioral functions. 11 The question on the relationship between structure and function has spawned wide- 12 ranging debates, with disparate approaches towards potential answers. At one extreme is the 13 suggestion that structure defines function (Buzsaki, 2006): 14 “The safest way to start speculating about the functions of a structure is to inspect 15 its anatomical organization carefully. The dictum “structure defines function” never 16 fails, although the architecture in itself is hardly ever sufficient to provide all the 17 necessary clues.” 18 19 Within this framework, the following is considered as a route for understanding neural systems 20 and behavior (Buzsaki, 2006): 21 “First, we need to know the
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