Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of 28Si Radiation

Britten, Richard A.; Duncan, Vania D.; Fesshaye, Arriyam; Rudobeck, Emil; Nelson, Gregory A.; Vlkolinský, Roman

doi:10.1667/rr15458.1

Cited by 31 publications

(25 citation statements)

References 59 publications

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“…While such SR-induced changes in ubiquitin-mediated cellular protein homeostasis will undoubtedly have profound effects on neuronal physiology and functionality, the ubiquitin-proteome system (UPS) plays a key role in regulating memory formation and consolidation [ 37 , 38 , 39 ]. Thus, differences in the UPS may serve to modulate the impact of SR-induced changes in neurotransmission on neurocognitive performance, and may explain the poor correlation between these parameters in our previous studies [ 18 , 21 ]. We thus established the composition of the hippocampal proteome in adult male rats exposed to 15 cGy 1 GeV/n 48 Ti ions and identified protein signatures that are biomarkers of (1) Ti exposure and (2) spatial memory performance, and whether these biomarker proteins are involved with the UPS.…”

Section: Introductionmentioning

confidence: 93%

“…This bifurcating response of neurocognitive processes to SR exposure has important consequences for risk assessments but also provides a unique opportunity to establish the impact of SR on neurophysiology, and the subsequent adaptive responses associated with the impairment or preservation of neurocognitive performance. SR exposure induces multiple changes in the functionality of hippocampal neurons: changes in the complexity of the dendritic tree in the hippocampus [ 15 , 16 , 17 , 18 ], long-term suppression of glutamatergic transmission and NR2A receptor levels in the hippocampus [ 19 ], homeostatic synaptic plasticity [ 18 , 19 , 20 , 21 , 22 , 23 ], as well as autophagy and persistent oxidative stress [ 24 ]. Recent studies also suggest that SR-induced neurocognitive decrements may be regulated by non-neuronal components, with the activation status of the microglia in the first few days after exposure being important [ 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System

Tidmore

Dutta

Fesshaye

et al. 2021

IJMS

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Exposure of rodents to <20 cGy Space Radiation (SR) impairs performance in several hippocampus-dependent cognitive tasks, including spatial memory. However, there is considerable inter-individual susceptibility to develop SR-induced spatial memory impairment. In this study, a robust label-free mass spectrometry (MS)-based unbiased proteomic profiling approach was used to characterize the composition of the hippocampal proteome in adult male Wistar rats exposed to 15 cGy of 1 GeV/n 48Ti and their sham counterparts. Unique protein signatures were identified in the hippocampal proteome of: (1) sham rats, (2) Ti-exposed rats, (3) Ti-exposed rats that had sham-like spatial memory performance, and (4) Ti-exposed rats that impaired spatial memory performance. Approximately 14% (159) of the proteins detected in hippocampal proteome of sham rats were not detected in the Ti-exposed rats. We explored the possibility that the loss of the Sham-only proteins may arise as a result of SR-induced changes in protein homeostasis. SR-exposure was associated with a switch towards increased pro-ubiquitination proteins from that seen in Sham. These data suggest that the role of the ubiquitin-proteome system as a determinant of SR-induced neurocognitive deficits needs to be more thoroughly investigated.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System

Tidmore

Dutta

Fesshaye

et al. 2021

IJMS

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“…Many of the foregoing changes portend potential neurobehavioral decrements, and significant past work with rodents has demonstrated that whole-body exposure to charged particles can disrupt behavioral performance that can be linked to impairments in the hippocampus (Britten et al, 2001(Britten et al, , 2016Cacao et al, 2018;Carr et al, 2018), amygdala (Rabin et al, 2014;Parihar et al, 2016), basal forebrain (Britten et al, 2014), mPFC (Britten et al, 2014(Britten et al, , 2016Parihar et al, 2015a), and other regions (Britten et al, 2014;Davis et al, 2014Davis et al, , 2015Parihar et al, 2015aParihar et al, , 2016. Individual animals often exhibit deficits in multiple behavioral paradigms (Parihar et al, 2015b(Parihar et al, , 2016(Parihar et al, , 2018Britten et al, 2020), and many of these decrements transpiring over 6-15 weeks have been found to coincide with a marked structural plasticity of neurons and glia and elevated neuroinflammation (Parihar et al, 2015b(Parihar et al, , 2018. The latter effect is particularly prominent, and increased yields of activated microglia found as long as 1 year after exposure provide a chronic ''footprint'' of radiation injury (Parihar et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

Parihar

Angulo

Allen

et al. 2020

Front. Behav. Neurosci.

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The radiation fields in space define tangible risks to the health of astronauts, and significant work in rodent models has clearly shown a variety of exposure paradigms to compromise central nervous system (CNS) functionality. Despite our current knowledge, sex differences regarding the risks of space radiation exposure on cognitive function remain poorly understood, which is potentially problematic given that 30% of astronauts are women. While work from us and others have demonstrated pronounced cognitive decrements in male mice exposed to charged particle irradiation, here we show that female mice exhibit significant resistance to adverse neurocognitive effects of space radiation. The present findings indicate that male mice exposed to low doses (≤30 cGy) of energetic (400 MeV/n) helium ions (4 He) show significantly higher levels of neuroinflammation and more extensive cognitive deficits than females. Twelve weeks following 4 He ion exposure, irradiated male mice demonstrated significant deficits in object and place recognition memory accompanied by activation of microglia, marked upregulation of hippocampal Toll-like receptor 4 (TLR4), and increased expression of the pro-inflammatory marker high mobility group box 1 protein (HMGB1). Additionally, we determined that exposure to 4 He ions caused a significant decline in the number of dendritic branch points and total dendritic length along with the hippocampus neurons in female mice. Interestingly, only male mice showed a significant decline of dendritic spine density following irradiation. These data indicate that fundamental differences in inflammatory cascades between male and female mice may drive divergent CNS radiation responses that differentially impact the structural plasticity of neurons and neurocognitive outcomes following cosmic radiation exposure.

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“…In these animal model studies, cancer ( Cucinotta et al, 2011 ; Sridharan et al, 2015 ; Blattnig and Chappell, 2016 ), cardiovascular issues ( Baker et al, 2011 ; Boerma, 2015 ), and central nervous system (CNS) damage ( Rabin et al, 2005 ; Cucinotta et al, 2014 ; Parihar et al, 2015 ; Cekanaviciute et al, 2018 ) represent pathologies frequently attributed to a deleterious ionizing radiation dose. Moreover, exposure to high-energy protons, or high-atomic number and energy (HZE) ions produces CNS damage leading to decremental behavioral changes in rodents ( Rabin et al, 1998 , 2015 ; Britten et al, 2012 , 2014 , 2020 , 2018 ; Lonart et al, 2012 ; Haley et al, 2013 ; Cucinotta et al, 2014 ; Hadley et al, 2016 ; Parihar et al, 2016 , 2018 ; Blackwell et al, 2018 ; Carr et al, 2018 ; Jewell et al, 2018 ; Mange et al, 2018 ; Shukitt-hale et al, 2018 ; Kiffer et al, 2019 ) and mission success, as spaceflights require constant alertness and readiness to address critical situations. Many studies utilize the novel object recognition, Barnes maze, Morris water maze, active avoidance, open field, or operant responding as the appropriate behavioral assays to evaluate rodents’ cognitive impairment ( Rabin et al, 1998 , 2011 , 2015 ; Britten et al, 2012 ; Lonart et al, 2012 ; Haley et al, 2013 ; Hadley et al, 2016 ; Parihar et al, 2016 , 2018 ; Carr et al, 2018 ; Jewell et al, 2018 ; Shukitt-hale et al, 2018 ; Kiffer et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…Performance in the simple discrimination (SD) stage is impaired after 5 cGy of 28 Si ( Britten et al, 2018 ), compound discrimination (CD) and compound discrimination reversal (CDR) after 20 cGy of 48 Ti ( Hadley et al, 2016 ), and SD and CD after ≤15 cGy of 56 Fe or ≤10 cGy of 4 He ( Jewell et al, 2018 ; Burket et al, 2021 ). These decrements and most behavioral deficits in the studies listed above are reported as a change in the irradiated cohort’s test score from the corresponding non-irradiated group’s score ( Rabin et al, 2005 , 2011 , 2012 , 2019 , 2015 ; Cucinotta et al, 2014 ; Acharya et al, 2015 ; Parihar et al, 2015 ; Cekanaviciute et al, 2018 ; Shukitt-hale et al, 2018 ; Britten et al, 2020 ). We define this non-irradiated group as sham.…”

Section: Introductionmentioning

confidence: 99%

Machine Learning Models to Predict Cognitive Impairment of Rodents Subjected to Space Radiation

Matar

Gökoğlu

Prelich

et al. 2021

Front. Syst. Neurosci.

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This research uses machine-learned computational analyses to predict the cognitive performance impairment of rats induced by irradiation. The experimental data in the analyses is from a rodent model exposed to ≤15 cGy of individual galactic cosmic radiation (GCR) ions: 4He, 16O, 28Si, 48Ti, or 56Fe, expected for a Lunar or Mars mission. This work investigates rats at a subject-based level and uses performance scores taken before irradiation to predict impairment in attentional set-shifting (ATSET) data post-irradiation. Here, the worst performing rats of the control group define the impairment thresholds based on population analyses via cumulative distribution functions, leading to the labeling of impairment for each subject. A significant finding is the exhibition of a dose-dependent increasing probability of impairment for 1 to 10 cGy of 28Si or 56Fe in the simple discrimination (SD) stage of the ATSET, and for 1 to 10 cGy of 56Fe in the compound discrimination (CD) stage. On a subject-based level, implementing machine learning (ML) classifiers such as the Gaussian naïve Bayes, support vector machine, and artificial neural networks identifies rats that have a higher tendency for impairment after GCR exposure. The algorithms employ the experimental prescreen performance scores as multidimensional input features to predict each rodent’s susceptibility to cognitive impairment due to space radiation exposure. The receiver operating characteristic and the precision-recall curves of the ML models show a better prediction of impairment when 56Fe is the ion in question in both SD and CD stages. They, however, do not depict impairment due to 4He in SD and 28Si in CD, suggesting no dose-dependent impairment response in these cases. One key finding of our study is that prescreen performance scores can be used to predict the ATSET performance impairments. This result is significant to crewed space missions as it supports the potential of predicting an astronaut’s impairment in a specific task before spaceflight through the implementation of appropriately trained ML tools. Future research can focus on constructing ML ensemble methods to integrate the findings from the methodologies implemented in this study for more robust predictions of cognitive decrements due to space radiation exposure.

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Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of 28Si Radiation

Cited by 31 publications

References 59 publications

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

Machine Learning Models to Predict Cognitive Impairment of Rodents Subjected to Space Radiation

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