Humans exposed to the space radiation environment encounter a different type of radiation than that found on Earth. Highly energetic particles can traverse the body, including the brain, and leave a path of damage that is difficult to repair and disrupts function. One consequence of this exposure is the development of radiation-induced cognitive dysfunction. The focus of this application is to resolve the mechanisms leading to radiation-induced cognitive dysfunction, in order to improve risk estimates for early and late CNS (central nervous system) effects caused by exposure to the space radiation environment. We have found that radiation impacts excitatory and inhibitory circuitry in the brain differently, and leads to significant disruptions to the structural integrity of neurons while altering the levels and activity of the proteins that regulate neuronal function. The situation is further complicated by the fact that different regions of the brain exhibit differential sensitivity to charged particle irradiation. Based on the foregoing we propose a comprehensive series of mechanistic studies analyzing the biochemical, structural, and electrophysiologic changes induced by radiation exposure that alter function to impact cognition. Carefully selected cognitive tasks and a wide variety of approaches will be used to critically analyze microcircuits in the brain and how charged particle-induced changes are transmitted via unique signaling pathways between cells that can alter gene expression profiles within cells. Collectively these studies will span a radiation effects pathway from synapse to cognition, with an overarching goal of determining whether charged particle irradiation leads to alterations in the excitatory and inhibitory activity of the brain at a global and/or region specific level. Our studies will therefore elucidate the functional consequences of radiation-induced changes on cognition that impose risk on mission critical activities and long-term cognitive health.
The following aims will address these objectives:
Specific aim 1: Ascertain the extent that charged particle irradiation elicits acute (2 week) and chronic (1 and 3 month) decrements in cognition dependent on hippocampal, medial prefrontal cortical and neocortical regions of the rodent brain. Determine if/how pharmacologic interventions designed to deplete microglia or inhibit CB1 activity alter cognition following charged particle exposure.
Specific aim 2: Quantify the extent of structural, synaptic, epigenetic and electrophysiologic alterations in neurons from specific regions of the brain following charged particle irradiation with and without specific pharmacologic interventions designed to inhibit CB1 activation.
Specific aim 3: Elucidate the functional importance of microglia and microglia-derived exosome mediated paracrine interactions in the irradiated brain. Determine how depletion of microglia affects structural and synaptic plasticity following charged particle irradiation. In vitro organotypic and acute slice studies will complement in vivo studies in defining the effect of microglial depletion and how microglia-derived exosome mediated signaling modifies target cell physiology. Additional in vitro studies will define the kinetics of vesicle secretion following irradiation and characterize the functional cargo (mitochondria, protein, mRNA, miRNA).
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Based on substantial preliminary data, we propose a comprehensive series of rodent studies to elucidate the neurobiological mechanisms of HZE ion-induced cognitive impairment. These studies will specifically bridge the continuum between early decrements and longer-term adverse outcomes. Biochemical studies will be coupled with immunohistochemical, morphometric, epigenetic and electrophysiologic analyses to define dose- and ion-specific effects in distinct brain regions that are discretely interrogated using carefully selected cognitive tasks. Cognitive tasks will focus on cortical function, with an emphasis on the medial prefrontal cortex (mPFC) that links the activities of cortical and hippocampal regions. We have now found that in response to HZE irradiation, mPFC and hippocampal neurons exhibit marked and persistent reductions in dendritic complexity, spine density and synaptic integrity along with marked alterations in pre- and postsynaptic protein levels. Changes in neuronal structure and synaptic integrity will be directly correlated with individual behavioral performance to establish quantitative criteria for establishing risks of developing acute and/or longerterm behavioral deficits. Recent findings from our laboratories have determined that irradiation leads to a differential effect on inhibitory and excitatory synapses, with corresponding changes to the inhibitory and excitatory tone in specific regions of the irradiated brain. Exposure to multiple radiation types (gamma rays, protons, heavy ions) leads to persistent upregulation of cannabinoid (CB1) receptors, an effect that promotes excitatory tone through the inhibition of inhibitory neurotransmitter release. Pharmacologic intervention inhibiting CB1 activation will be coupled with behavioral, 2-photon imaging, electrophysiologic and molecular studies to elucidate the functional consequences of HZE ion irradiation on specific excitatory and/or inhibitory circuits.
This experiment is currently in progress. Results will be available at the conclusion of the study.
Parihar VK, Angulo MC, Allen BD, Syage A, Usmani MT, Passerat de la Chapelle E, Amin AN, Flores L, Lin X, Giedzinski E, Limoli CL. Sex-specific cognitive deficits following space radiation exposure. Front Behav Neurosci. 2020 Sep 16;14:535885. [DOI]
Keiser AA, Kramár EA, Dong T, Shanur S, Pirodan M, Ru N, Acharya MM, Baulch JE, Limoli CL, Wood MA. Systemic HDAC3 inhibition ameliorates impairments in synaptic plasticity caused by simulated galactic cosmic radiation exposure in male mice. Neurobiol Learn Mem. 2020 Dec 23. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33359392 [DOI]
Klein PM, Parihar VK, Szabo GG, Zöldi M, Angulo MC, Allen BD, Amin AN, Nguyen QA, Katona I, Baulch JE, Limoli CL, Soltesz I. Detrimental impacts of mixed-ion radiation on nervous system function.
Neurobiol Dis. 2021 Jan 5. [DOI]
Crew health and performance is critical to successful human exploration beyond low Earth orbit.
The Human Research Program (HRP) investigates and mitigates the highest risks to human health
and performance, providing essential countermeasures and technologies for human space exploration.
Risks include physiological and performance effects from hazards such as radiation, altered gravity,
and hostile environments, as well as unique challenges in medical support, human factors,
and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify
the approach and research activities planned to address these risks, which are assigned to specific
Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.
The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/
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