Element/Subdiscipline: NSBRI--Radiation Effects Team
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, learning, and memory. 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 alter the ability of the brain to replace these cells. 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.
Since impaired neurogenesis is correlated with impaired cognition, we expected that preservation of neurogenesis has the potential to rescue cognitive impairments associated with GCR 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. 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. The central hypotheses of this proposal were 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).
For each neuroprotective method, we proposed to expose mice to 56Fe in doses of 0, 5+45, 25+25, and 50 cGy, with dual irradiations spaced 4 days apart. One group of mice receiving 50 cGy also received daily treatment with thyroxine (TH) for one week before and after irradiation. Mice from each group were subjected to a battery of behavioral tests (learning, memory, anxiety, and depression-like behavior), analysis of synaptic plasticity and neuronal function, and quantification of newborn neurons. These experiments were performed at both 4 and 8 months after exposure to 56Fe, to determine the long-term consequences of each intervention. Behavioral and electrophysiological data has been collected for the 4 month time point. Interestingly, TH treatment rescued radiation-induced changes in anxiety, but increased depression-like behavior in male and female mice. Dual, spaced radiation exposure enhanced synaptic plasticity (in females) and learning acquisition, but not memory (in males and females). These findings suggest that our interventions were, in fact, altering hippocampal function.
Future experiments in progress include quantification of neurogenesis at the 4 month time point. Biochemical analysis of samples collected immediately after GCR exposure will quantify serum TH levels and activity levels of brain enzymes involved in TH metabolism. In addition, all behavior, synaptic plasticity, and neurogenesis experiments will also be performed on the cohorts of mice 8 months post-GCR exposure (Spring 2017).
Neuroscience 2016, San Diego, CA, November 12-16, 2016. , Nov-2016
2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016
Element/Subdiscipline: NSBRI--Radiation Effects Team
Exposure to galactic cosmic radiation (GCR), such as that experienced by astronauts, impacts learning and memory, synaptic plasticity, neuronal function, and neurogenesis in animals. Impairments in memory and emotional state could be detrimental to astronauts in-mission performance. Neurogenesis continues in adulthood in the hippocampus, and thyroid hormone is necessary for hippocampal neurogenesis. We hypothesize that low dose thyroid hormone treatment may be protective of neurogenesis in mice exposed to GCR. We further propose that one exposure to low dose radiation will make newborn neurons resistant to damage and death from a second GCR exposure.
We will test these hypotheses by treating mice with one longer or two shorter bouts of GCR. Mice will recover for 3-6 months and be tested in four ways: 1) quantifying number of newborn neurons in each group to assess neurogenesis immediately after GCR exposure and months later; 2) behavioral tests to quantify learning, memory, depression-like behaviors, and anxiety; 3) measuring the strength of long-term activity-dependent synaptic plasticity that underlies learning and memory; and 4) patch-clamp recording to assess synaptic function of newborn neurons. Additionally, we will treat mice with thyroid hormone during GCR exposure to determine if supplementation can prevent radiation-induced impairments of neurogenesis, learning, memory, depression-like, and anxiety behaviors.
These studies will advance our understanding of mechanisms underlying the effects of GCR on cognitive processes necessary for safe and productive long-range space missions. They are designed to determine if GCR produces long-term impairments in synaptic plasticity necessary for learning, memory, and mood stability, and if loss of neurogenesis contributes to impaired cognition. Understanding the interactions between GCR and neurogenesis, and their effects on cognition, mood, and executive function, is critical for rational assessment of long-term central nervous system risk and development of effective countermeasures for in-mission risks from GCR in long-duration human space travel.