Operant responding following exposure to HZE particles and its relationship to particle energy and linear energy transfer

https://doi.org/10.1016/j.asr.2011.03.008Get rights and content

Abstract

On exploratory class missions astronauts will be exposed to a variety of heavy particles (HZE particles) which differ in terms of particle energy and particle linear energy transfer. The present experiments were designed to evaluate how these physical characteristics of different particles affect cognitive performance, specifically operant responding. Following exposure to 28Si, 48Ti, 12C and 16O particles at the NASA Space Radiation Laboratory rats were tested for their ability to respond appropriately to changes in reinforcement schedules using an operant task. The results showed that the effectiveness of different particles in disrupting cognitive performance, defined as the lowest dose that produced a performance decrement, varied as a function of the energy of the specific particle: for comparisons between different energies of the same particle (e.g., 56Fe) the effectiveness of the particle was directly proportional to particle linear energy transfer, whereas for comparisons between different particles (e.g., 56Fe and 16O) effectiveness was inversely proportional to particle linear energy transfer. The results are discussed in terms of the mechanisms that influence the effectiveness of different particles and energies and in terms of their implications for analyzing the possible risks to astronauts of decrements in cognitive performance following exposure to HZE particles on long-duration exploratory class missions.

Introduction

On exploratory class missions, astronauts will be exposed to particles of high energy and charge (HZE particles), which are not typically experienced in low earth orbit (Cucinotta et al., 2001, Edwards, 2001, Schimmerling et al., 2003). Analyses of the potential risks faced by astronauts on these missions outside the protection provided by the magnetic field of the earth have, for the most part, focused on HZE particle-induced carcinogenesis (Schimmerling et al., 2003, Hellweg and Baumstark-Khan, 2007, Cucinotta and Durante, 2006, Dziegielewski et al., 2010, Trani et al., 2010). In general, research shows that the probability of HZE particle-induced mutagenesis is related to the absorbed dose multiplied by a quality factor which is related to particle LET (e.g., Fry, 1986, Hellweg and Baumstark-Khan, 2007, Cucinotta and Durante, 2006); such that there is an increase in the frequency of chromosomal aberrations and tumor development as the LET of the particles increases within the range of 100–200 keV/μm (Ainsworth, 1986, Blakely and Kronenberg, 1998, Brooks et al., 2001, Shuryak and Brenner, 2010, Keszenman and Sutherland, 2010). These observations have generally provided the basis for analyzing potential risks to astronauts from exposure to HZE particles on long-duration missions outside the magnetic field of the earth.

However, in addition to its mutagenic effects, exposure to HZE particles also affects behavioral endpoints. Concordant with the results on the relationship between LET and carcinogenesis cited above, behavioral endpoints that are mediated by the peripheral nervous system, such as taste aversion learning in rats and emesis in ferrets, show a similar relationship to LET (Rabin et al., 1989, Rabin et al., 1991, Rabin et al., 1992), such that lower doses are needed to affect behavior as LET increases.

Exposure to HZE particles also disrupts performance on a variety of cognitive tasks which depend upon the integrity of the central nervous system (CNS), including spatial learning and memory, measured using the Morris water maze (Shukitt-Hale et al., 2000); recognition memory, measured using the novel object recognition task (Rabin et al., 2009); responsiveness to environmental stimuli, measured using operant responding on an ascending fixed-ratio reinforcement schedule (Rabin et al., 2002); apomorphine modulated prepulse inhibition of the acoustic startle response (Haerich et al., 2005); and contextual fear conditioning (Villasana et al., 2010). Performance on these tasks is mediated by specific structures in the CNS, specifically the striatum for operant responding (Lindner et al., 1997); the hippocampus for spatial learning (Shukitt-Hale et al., 2000) and contextual fear conditioning (Villasana et al., 2010); the perirhinal cortex for object recognition memory (Duva et al., 1997, Ennaceur and Aggleton, 1997); and the prefrontal cortex for prepulse inhibition (Geyer et al., 2001, Swerdlow et al., 2001). Exposure to HZE particles leads to inflammation (Rola et al., 2005) and oxidative stress (Denisova et al., 2002, Limoli et al., 2007) which may affect performance of these tasks by disrupting the functioning of the dopaminergic system (Joseph et al., 1992, Joseph et al., 1993). In addition to generalized effects on neuronal function, exposure to HZE particles can disrupt hipoocampal neurogenesis (Casadesus et al., 2005, Raber et al., 2004) and lead to structural alterations in dendritic spines in the hippocampus and cortex (Quasem et al., 2007). The deficits in cognitive performance are an apparent consequence of the effects of exposure to HZE particles on CNS function.

In contrast to the effects of exposure to HZE particles on chromosomal aberrations and behaviors dependent upon the peripheral nervous system, cognitive endpoints which depend upon the integrity of the CNS, as indicated above, apparently show a more complex relationship between particle LET and effectiveness. Preliminary research using several energies of 56Fe, 48Ti and 28Si particles (Rabin et al., 2007) indicated that both the particle energy and particle LET influence the effectiveness of these particles in disrupting cognitive performance, measured as the lowest dose needed to produce a performance decrement. These results indicated that exposure to the lower LET 56Fe or 28Si particles (1000 MeV/n; LET  150 and 44 keV/μm, respectively) required a higher dose to disrupt cognitive performance compared to higher LET 56Fe or 28Si (600 MeV/n; LET  189 and 55 keV/μm, respectively) particles which disrupted performance at a lower dose. In contrast, the lower LET 600 MeV/n 28Si particles (LET  55 keV/μm) disrupted performance at a lower dose than the higher LET 600 MeV/n 56Fe particles (LET  189 keV/μm).

These preliminary results suggest that analyses of the risk for HZE particle-induced cognitive deficits on exploratory class missions may require a different set of assumptions than are utilized for the analysis of the risk of carcinogenesis. However, this conclusion must be considered tentative because only a few particles and energies were utilized. A more reliable evaluation of this hypothesis requires the use of a greater variety of particles and energies. The experiments described below were designed to evaluate the effects on cognitive performance of a more representative sample of HZE particles, such as might be encountered on an extended duration exploratory class mission. The task that was utilized was operant responding on an ascending fixed-ratio reinforcement schedule. This task measures the activational and effort-related components of motivated behaviors; the motivation of an organism to work for a reward (Salamone, 1994, Salamone and Correa, 2002) and indicates the responsiveness of the organism to changes in environmental contingencies, including changes in reinforcement schedules and is dependent upon the integrity of the striatum (Lindner et al., 1997).

Section snippets

Subjects

The subjects for all experiments were male Sprague-Dawley rats obtained from Taconic Farms and weighing 200–225 g (6–8 wks of age) at the time of irradiation. The sample size for all particles (experiments) was 10 rats/dose. The rats were maintained at AAALAC-accredited facilities at Brookhaven National Laboratory (BNL) for 1 week prior to exposure. One day following irradiation, they were shipped to the University of Maryland, Baltimore County (UMBC) for behavioral testing. The facilities at UMBC

Results

Exposing rats to a specific dose of HZE particles disrupts the performance of operant responding on an ascending FR schedule at the higher reinforcement schedules. The response pattern for determining the threshold for the disruption of operant responding following exposure to specific HZE particles is shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4. Fig. 1 presents the results for 290 MeV/n 12C, which was the only energy of 12C tested. Fig. 2, Fig. 3, Fig. 4 present the results for the two energies

Discussion

The results show that exposure to all types and energies of HZE particles disrupt the ability of rats to respond appropriately on an ascending FR reinforcement schedule. Compared to the non-irradiated controls, at some dose of HZE particles the irradiated rats failed to increase responding despite further increases in the reinforcement ratio. However, the dose of radiation needed to disrupt performance varied as a function of both the energy and LET of the particle. When comparing the doses

Acknowledgments

This research was supported by NASA Grant NNX08AM66G. In memory of James A. Joseph who passed away while the paper was being written. He was a valued colleague and friend.

References (44)

  • W. Schimmerling et al.

    Radiation risk and human space exploration

    Adv. Space Res.

    (2003)
  • J.W. Wilson et al.

    Approach and issues related to shield material design to protect astronauts from space radiation

    Mater. Des.

    (2001)
  • F. Ballarini et al.

    Heavy-ion effects: from track structure to DNA and chromosome damage

    New J. Phys.

    (2008)
  • E.A. Blakely et al.

    Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness

    Radiat. Res.

    (1998)
  • A.L. Brooks et al.

    Relative effectiveness of HZE iron-56 particles for the induction of cytogenetic damage in vivo

    Radiat. Res.

    (2001)
  • F.A. Cucinotta et al.

    The effects of delta rays on the number of particle-track traversals per cell in laboratory and space exposures

    Radiat. Res.

    (1998)
  • F.A. Cucinotta et al.

    Space radiation cancer risks and uncertainties for Mars missions

    Radiat. Res.

    (2001)
  • N. Denisova et al.

    Brain signaling and behavioral responses induced by exposure to 56Fe radiation

    Radiat. Res.

    (2002)
  • M. Durante et al.

    Cytogenetic effects of high energy iron ions: dependence on shielding thickness and material

    Radiat. Res.

    (2005)
  • J. Dziegielewski et al.

    Heavy ions, radioprotectors and genomic instability: implications for human space exploration

    Radiat. Environ. Biophys.

    (2010)
  • C.A. Duva et al.

    Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats

    Behav. Neurosci.

    (1997)
  • A.A. Edwards

    RBE of radiations in space and the implications for space travel

    Phys. Med.

    (2001)
  • Cited by (40)

    • Progressive increase in the complexity and translatability of rodent testing to assess space-radiation induced cognitive impairment

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      The underlying cause of the high failure rate of SR exposed rats in the FF stage remains speculative, but the majority of the rats did start digging for the food reward indicating they understood the nature of the task. Moreover, the non-habituating rats showed no obvious signs of anhedonia (sucrose preference test, or general appearance and activity in the cage), suggesting that SR-irradiated rats may have an inability to maintain attention on the task or reduced motivation/ reward valuation (as suggested by the Operant response data (Poulose et al., 2011, 2017; Rabin et al., 1994, 2003, 2005a,b,c, 2011, 2014, 2015a,b, 2018, 2019a,b)). The SD stage interrogates the rats’ decision making abilities.

    • Detrimental impacts of mixed-ion radiation on nervous system function

      2021, Neurobiology of Disease
      Citation Excerpt :

      While less abundant, the increasingly energetic HZE components of GCR produce higher multiplicities of ionization through triggering additional particle emission along their primary track and generating secondary delta ray emissions that spread laterally along sparsely ionizing tracks that significantly increase the cross section of impacted tissue (Cucinotta and Durante 2006; Autsavapromporn et al. 2013). Like proton and α-particle radiation, exposure to individual HZE ion species such as oxygen (Rabin et al. 2011; Carr et al. 2018), silicon (Rabin et al. 2011; Whoolery et al. 2017) and iron (Britten et al. 2012; Cherry et al. 2012; Haley et al. 2013) all can produce persistent behavioral and cognitive deficits. Over the course of deep space voyages to the Moon or Mars, astronauts will be chronically exposed to elevated levels of GCR, calculated to be approximately 1.5 cGy/month (Zeitlin et al. 2013; Cucinotta et al. 2014).

    View all citing articles on Scopus
    View full text