Protracted brain development in a rodent model of extreme longevity.

Orsolya K Penz,John Larson,Janos Fuzik,Tibor Harkany,Thomas J Park,Roman Romanov,Erik Keimpema,Aleksandra B Kurek

doi:10.1038/srep11592

Abstract

Extreme longevity requires the continuous and large-scale adaptation of organ systems to delay senescence. Naked mole rats are the longest-living rodents, whose nervous system likely undergoes life-long adaptive reorganization. Nevertheless, neither the cellular organization of their cerebral cortex nor indices of structural neuronal plasticity along extreme time-scales have been established. We find that adult neurogenesis and neuronal migration are not unusual in naked mole rat brains. Instead, we show the prolonged expression of structural plasticity markers, many recognized as being developmentally controlled, and multi-year-long postnatal neuromorphogenesis and spatial synapse refinement in hippocampal and olfactory structures of the naked mole rat brain. Neurophysiological studies on identified hippocampal neurons demonstrated that morphological differentiation is disconnected from the control of excitability in all neuronal contingents regardless of their ability to self-renew. Overall, we conclude that naked mole rats show an extremely protracted period of brain maturation that may permit plasticity and resilience to neurodegenerative processes over their decades-long life span. This conclusion is consistent with the hypothesis that naked mole rats are neotenous, with retention of juvenile characteristics to permit survival in a hypoxic environment, with extreme longevity a consequence of greatly retarded development.

Highlights

Extreme longevity requires the continuous and large-scale adaptation of organ systems to delay senescence
This is supported by i) the presence of axonal pathways, fetal-like guide scaffolds and neurochemical arrangements known to dominate in mouse fetuses[16], ii) continued morphogenesis of hippocampal neurons and iii) incomplete synapse segregation in the hippocampus, including mixed subcellular targeting of glutamatergic and GABAergic terminals along the somatodendritic axis of principal neurons
To the best of our knowledge, there is no clear consensus definition for “juvenile”, “adult” or “aged” naked mole rats, whose spontaneous and forced behaviors significantly differ from standard laboratory rodents[18], and since any such classification in rodents relates to reaching full reproductive capacity

Summary

Introduction

Extreme longevity requires the continuous and large-scale adaptation of organ systems to delay senescence. Longevity generally correlates with body size and covariates such as basal metabolic rate and brain volume[1] Exceptions to this rule may indicate species adaptations specific for long life or environmental conditions that, secondarily, can result in extreme longevity. We demonstrate the continued and slowed acquisition of mature neuronal morphology, lasting up to at least 10 years postnatally, to build brain volume and neuronal circuits This is supported by i) the presence of axonal pathways, fetal-like guide scaffolds and neurochemical arrangements known to dominate in mouse fetuses[16], ii) continued morphogenesis of hippocampal neurons and iii) incomplete synapse segregation in the hippocampus, including mixed subcellular targeting of glutamatergic and GABAergic terminals along the somatodendritic axis of principal neurons. Our data identify that developmental processes occurring at the hour-to-day scale in mouse are prolonged along months-to-years time scales in naked mole rats, highlighting that neoteny is a successful evolutionary strategy to enhance the capacity of the central nervous system for successful environmental adaptation to extreme longevity

Methods

Results

Conclusion