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Protection of Neurogenesis as a Neuroprotectant Strategy for Low-Dose Space Radiation Exposure (First Award Fellowship)

Principal Investigator:
Linnea Vose, Ph.D.

Organization:
New York Medical College

Transcranial exposure to simulated galactic cosmic radiation (GCR) is known to impact learning and memory, synaptic plasticity, neuronal physiology, and neurogenesis. The brain is particularly susceptible to GCR-induced damage, likely due to the highly specialized cells, complex functions and plasticity required for cognition. Neurogenesis persists throughout adulthood in the hippocampus, a specialized structure in the temporal lobe required for memory formation. Since neural progenitor cells are very susceptible to damage from radiation, GCR could cause both subtle alterations in the function of mature neurons, and impair the ability of the brain to replace these cells. It is important to determine the dose-dependent effects of GCR, as well as identify potential therapeutics to minimize these effects. In considering the prospect of humans spending increasing amounts of time in space, a deeper understanding of the risks of long-duration GCR exposure, and search for effective countermeasures, are absolutely essential to mission success.

NASA Taskbook Entry

Technical Summary

Understanding the interactions between GCR and neurogenesis, and the effects of these on cognition, mood, and executive function, is critical for rational assessment of long-term CNS risk and efficient development of effective countermeasures for in-mission risks from GCR in long-duration space travel.

Our long-term goal is to protect the human brain from damage caused by GCR, thus minimizing cognitive deficits for astronauts performing long duration deep space missions. Since impaired neurogenesis is correlated with impaired cognition, we expect that preservation of neurogenesis will rescue cognitive impairments associated with GCR exposure. Repeated exposure to neural insults (such as ischemia or medical radiation) can result in activation of compensatory mechanisms over a period of days or weeks and reduce damage upon subsequent exposure. Thyroid hormone (TH) is required for normal neurogenesis, and hypothyroid humans and rodents exhibit decreased cognitive function and depression-like behavior which can be rescued by TH supplementation. The central hypotheses of this proposal are 1) the brain can become resistant to damage from repeated GCR exposures, and 2) TH supplementation may be a novel and effective therapeutic strategy to protect neurogenesis from GCR with an FDA approved compound (thyroxine).

Objectives and approaches:

1. Characterize the effects of repeated exposure to GCR on neurogenesis, synaptic plasticity, and behavior in mice. We hypothesize that there are long-term compensatory changes in hippocampal neurogenesis after a single GCR exposure, so that repeated low dose radiation may be less harmful than a single longer dose due to activation of neuroprotective pathways through hormesis, or “preconditioning.”

  1. 1A. Determine the effect of single versus repeated exposure to GCR on neurogenesis. We will perform semi-quantitative comparison of BrdU+ neurons labeled 2 weeks post-GCR versus doublecortin immunostaining of newborn neurons 3 or 6 months after single or repeated GCR exposure in the same mice.
  1.  1B. Determine the effect of repeated GCR on learning, memory, anxiety, and depression-like behavior. We will use Barnes maze, elevated plus maze, and Porsolt forced swim test to assess overall cognitive ability and emotional state of single, double, and sham irradiated mice.
  1.  1C. Determine the effect of repeated GCR on activity-dependent long-term synaptic plasticity and the functionality of newly born neurons. Using electrophysiological methods, we will look at the effects of GCR on magnitude, threshold and ceiling of long term potentiation (LTP), and neurophysiological synaptic and intrinsic function of single newborn neurons.

2. Rescue the effects of GCR on neurogenesis, behavior, and synaptic plasticity by concurrent treatment with thyroxine (TH). We predict that TH supplementation during GCR exposure will at least partially rescue neurogenesis, normalize performance in learning tasks, anxiety, depression-like behaviors, and synaptic function.

  1. 2A. Characterize the effect of TH treatment during GCR exposure on neurogenesis. Semi-quantitative comparison of BrdU+ neurons labeled 2 weeks post-GCR versus doublecortin immunostaining of newborn neurons 3 or 6 months after GCR with TH or vehicle treatment in the same mice.
  1. 2B. Characterize the effect of TH treatment during GCR on learning, anxiety, and depression-like behavior. We will use Barnes maze, elevated plus maze, and the Porsolt forced swim test to assess overall cognitive ability and emotional state of TH vs. vehicle treated mice exposed to GCR.

    2.  

  1. 2C. Characterize the effect of TH treatment on activity-dependent long-term synaptic plasticity and the functionality of newly born neurons.
    Using electrophysiological methods, we will look at the effects of GCR on magnitude, threshold and ceiling of LTP, and functionality of single newborn neurons

This proposal will test the effects of a dual, temporally spaced exposure to GCR, which has the potential to activate compensatory neurogenic mechanisms and be a closer approximation to long-term space exploration than single GCR exposure protocols. We believe that after a brief, low dose GCR-exposure the surviving neurons will be altered at the cellular level to be more resistant to future insults. The outcome of these studies will significantly advance our understanding of the effects of GCR on neural and cognitive processes necessary for safe and productive long duration deep space missions. These studies are designed to determine if GCR produces long-term impairments in synaptic plasticity necessary for learning and memory, if loss of neurogenesis contributes to impaired cognition, and test whether thyroxine, an FDA approved compound, is neuroprotective.

Earth Applications

A better understanding of the brain’s natural mechanisms to prevent radiation induced impairment is applicable to patients undergoing cancer treatment. Although the type of radiation is not identical, it is likely the brain would employ similar mechanisms and our findings may help prevent cognitive impairment in patients undergoing radiation therapy, either by exposing patients to a very small dose of radiation prior to high dose treatments, or by concurrent treatment with thyroxine.