NIH Research Festival
Neuronal death is a common outcome of neural injury and neurodegenerative diseases. Apart from the physical damage to the neural structure, e.g., axonal injury in the cases of spinal cord injury or optic nerve injury, it is becoming increasingly clear that glial cells and the neuro-inflammatory local microenvironment are critical determinants for neuronal death vs. survival. Mammalian hibernators such as the ground squirrel (GS) survive cold winters by suppressing their metabolism and reducing their body temperature to near-freezing without any cellular impairment. The molecular mechanisms underlying such an extreme form of adaptation may be harnessed for various medical applications. Specifically, investigation of global changes in the retina of hibernating GSs revealed immune suppression during hibernation. We thus speculated that hibernating animals might naturally respond differently to neural injury; Furthermore, the mechanisms of this differential response might be used to develop therapeutic strategies that promote neuronal survival following injury or during neurodegeneration. To investigate differential immune responses in hibernating vs. active GS, we assessed retinal ganglion cell (RGC) and optic nerve responses to optic nerve crush (ONC). Using immunohistochemistry and an automated image processing algorithm, we counted surviving RGCs across the entire GS retina following ONC. We found that in active GSs, ONC led to massive RGC loss (85% loss by 14d post-injury), whereas in hibernating GSs, more than 80% of RGCs survived 14d after ONC. Further investigation at the injury site and in the retina revealed that the local immune responses that were mounted by microglia in active GSs were instead largely absent in hibernating GSs. To investigate whether this lack of microglia activation contributes to RGC survival, we transiently eliminated microglia in active GSs using pharmacology, thus mimicking the local immune suppression seen in hibernating GSs. This manipulation indeed protected RGCs in non-hibernating GSs following ONC. Further experiments are being performed to determine the molecular mechanisms of microglial suppression during hibernation, which may help us discover the secrets of the neural protection “superpower” possessed by hibernating GS.
Scientific Focus Area: Neuroscience
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