Summer undergraduate biomedical research program for underrepresented minority students in a rural, low-income state.

Introduction: Diversity can enhance the agenda and quality of biomedical research, but a dearth of underrepresented minorities and women serve as biomedical researchers. The study purpose was to examine the impact of the a summer undergraduate research program on self-efficacy in research, scientific communication, and leadership as well as scientific identity, valuing objectives of the scientific community, and intent to pursue a biomedical research career. Methods: Underrepresented minority and female undergraduate students participated in a mentored research experience in a rural, low-income state. Results: Students' self-efficacy in research, scientific communication, and leadership as well as scientific identity, valuing objectives of the scientific community, and intent to pursue a biomedical research career increased post-program compared to pre-program. Conclusion: This study supports implementation of a biomedical summer undergraduate research program for URM and women in a poor, rural, settings.

Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior.

Introduction: Chemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses. Methods: Forced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers. Results and discussion: We observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.

Sulforaphane's Multifaceted Potential: From Neuroprotection to Anticancer Action.

Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a neuroprotective and anticancer agent. This review aims to critically evaluate the current evidence supporting the neuroprotective and anticancer effects of SFN and the potential mechanisms through which it exerts these effects. SFN has been shown to exert neuroprotective effects through the activation of the Nrf2 pathway, the modulation of neuroinflammation, and epigenetic mechanisms. In cancer treatment, SFN has demonstrated the ability to selectively induce cell death in cancer cells, inhibit histone deacetylase, and sensitize cancer cells to chemotherapy. SFN has also shown chemoprotective properties through inhibiting phase I metabolizing enzymes, modulating phase II xenobiotic-metabolizing enzymes, and targeting cancer stem cells. In addition to its potential as a therapeutic agent for neurological disorders and cancer treatment, SFN has shown promise as a potential treatment for cerebral ischemic injury and intracranial hemorrhage. Finally, the ongoing and completed clinical trials on SFN suggest potential therapeutic benefits, but more research is needed to establish its effectiveness. Overall, SFN holds significant promise as a natural compound with diverse therapeutic applications.

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart.

Missions into deep space will expose astronauts to the harsh space environment, and the degenerative tissue effects of space radiation are largely unknown. To assess the risks, in this study, male BALB/c mice were exposed to 500 mGy 5-ion simulated GCR (GCRsim) at the NASA Space Radiation Laboratory. In addition, male and female CD1 mice were exposed to GCRsim and administered a diet containing Transforming Growth Factor-beta (TGF-ß)RI kinase (ALK5) inhibitor IPW-5371 as a potential countermeasure. An ultrasound was performed to investigate cardiac function. Cardiac tissue was collected to determine collagen deposition, the density of the capillary network, and the expression of the immune mediator toll-like receptor 4 (TLR4) and immune cell markers CD2, CD4, and CD45. In male BALB/c mice, the only significant effects of GCRsim were an increase in the CD2 and TLR4 markers. In male CD1 mice, GCRsim caused a significant increase in total collagens and a decrease in the expression of TLR4, both of which were mitigated by the TGF-ß inhibitor diet. In female CD1 mice, GCRsim caused an increase in the number of capillaries per tissue area in the ventricles, which may be explained by the decrease in the left ventricular mass. However, this increase was not mitigated by TGF-ß inhibition. In both male and female CD1 mice, the combination of GCRsim and TGF-ß inhibition caused changes in left ventricular immune cell markers that were not seen with GCRsim alone. These data suggest that GCRsim results in minor changes to cardiac tissue in both an inbred and outbred mouse strain. While there were few GCRsim effects to be mitigated, results from the combination of GCRsim and the TGF-ß inhibitor do point to a role for TGF-ß in maintaining markers of immune cells in the heart after exposure to GCR.

Effect of Sirt3 on hippocampal MnSOD activity, mitochondrial function, physiology, and cognition in an aged murine model.

The NAD(+)-dependent deacetylase SIRT3 is a proven mitochondrial metabolic stress sensor. It has been linked to the regulation of the mitochondrial acetylome and activation of several metabolic enzymes (e.g., manganese superoxide dismutase [MnSOD]) to protect mitochondrial function and redox homeostasis, which are vital for survival, excitability, and synaptic signaling of neurons mediating short- and long-term memory formation as well as retention. Eighteen-month-old male and female wild-type (WT) and Sirt3-/- mice were behaviorally tested for hippocampus-dependent cognitive performance in a Morris water maze paradigm. Cognitive impairment was displayed during the probe trial by female and male Sirt3-/- mice but not WT mice. Upon sacrifice, brains were fixed, and morphological assessments were conducted on hippocampal tissues. Both female and male Sirt3-/- mice demonstrated impaired spatial memory retention implying that SIRT3 plays a role in long-term memory function. Golgi-staining studies revealed decreased dendritic arborization and dendritic length in the hippocampi of male Sirt3-/- compared to WT animals. Sirt3 deletion significantly increased NR1, NR2A, and NR2B expression in the hippocampus of female mice only. Enzymatic activity of MnSOD, a major mitochondrial deacetylation target of SIRT3, was significantly decreased in both female and male Sirt3-/- mice. Similarly, both female and male Sirt3-/- mice demonstrated a significant decrease in their respiratory control ratio during Complex I-driven respiration, which was apparent only in female Sirt3-/- mice during Complex II-driven respiration.

Chemotherapy induced oxidative stress in the ovary: drug-dependent mechanisms and potential interventions†.

Cancer incidence and relative survival are expected to increase over the next few decades. With the majority of patients receiving combinatorial chemotherapy, an increasing proportion of patients experience long-term side effects from treatment-including reproductive disorders and infertility. A limited number of studies have examined mechanisms of single-agent chemotherapy-induced gonadotoxicity, with chemotherapy-induced oxidative stress being implicated in the loss of reproductive functions. Current methods of female fertility preservation are costly, invasive, only moderately successful, and seldom presented to cancer patients. The potential of antioxidants to alleviate chemotherapy has been overlooked at a time when it is becoming increasingly important to develop strategies to protect reproductive functions during chemotherapy. This review will summarize the importance of reactive oxygen species homeostasis in reproduction, chemotherapy-induced mitochondrial dysfunction in oocytes, chemotherapy-induced oxidative stress, and several promising natural adjuvants.

Outcomes of the UAMS summer undergraduate research program to increase diversity in research and health professions.

The University of Arkansas for Medical Sciences (UAMS) Summer Undergraduate Research Program (SURP) aims to increase diversity in research and health-related careers. The SURP provides underrepresented minority (URM) and disadvantaged students with research, mentoring, and networking experiences; real-life surgical observations; and simulated cardiovascular demonstrations. A postprogram survey was developed to assess program outcomes and explore ways of improving the program to stimulate URM and disadvantaged students' interest in research and health-related careers. This is a report of those postprogram survey findings. Using a survey research design, an online survey was emailed to participants (n = 88). Data were collected for 6 weeks beginning March 2020. There were 37 multiple-choice and open-ended questions regarding education, career choices, and program experiences. Responses were downloaded to statistical software for analyses. Quantitative data were analyzed using descriptive statistics. Major themes were identified for qualitative data. Responses were received from 44.3% (n = 39) of former SURP participants. Overall, 59% stated that the SURP influenced their career goals. When asked about mentor-mentee relationships, 69.3% responded that their interactions were excellent or good; 61.5% maintained contact with their mentor after the SURP. Finally, 79% indicated their SURP experience was excellent or good, and 84.6% would recommend the SURP to others. The SURP has been successful at providing URM and disadvantaged students with positive research experiences and long-term mentor-mentee relationships and has influenced educational and/or career goals. Programs that expose URM and disadvantaged students to basic, clinical, and/or translational research are beneficial for stimulating interest in research and health-related careers.NEW & NOTEWORTHY Mentor-mentee relationships were extremely beneficial as many of the former participants maintained contact with their summer mentor after the program ended. This assessment also revealed that exposing underrepresented and minority students to research has a long-lasting effect on career and educational goals.

Evaluating the effects of low-dose simulated galactic cosmic rays on murine hippocampal-dependent cognitive performance.

Space exploration has advanced substantially over recent decades and plans to increase the duration of deep space missions are in preparation. One of the primary health concerns is potential damage to the central nervous system (CNS), resulting in loss of cognitive abilities and function. The majority of ground-based research on space radiation-induced health risks has been conducted using single particle simulations, which do not effectively model real-world scenarios. Thus, to improve the safety of space missions, we must expand our understanding of the effects of simulated galactic cosmic rays (GCRs) on the CNS. To assess the effects of low-dose GCR, we subjected 6-month-old male BALB/c mice to 50 cGy 5-beam simplified GCR spectrum (1H, 28Si, 4He, 16O, and 56Fe) whole-body irradiation at the NASA Space Radiation Laboratory. Animals were tested for cognitive performance with Y-maze and Morris water maze tests 3 months after irradiation. Irradiated animals had impaired short-term memory and lacked spatial memory retention on day 5 of the probe trial. Glial cell analysis by flow cytometry showed no significant changes in oligodendrocytes, astrocytes, microglia or neural precursor cells (NPC's) between the sham group and GCR group. Bone marrow cytogenetic data showed a significant increase in the frequency of chromosomal aberrations after GCR exposure. Finally, tandem mass tag proteomics identified 3,639 proteins, 113 of which were differentially expressed when comparing sham versus GCR exposure (fold change > 1.5; p < 0.05). Our data suggest exposure to low-dose GCR induces cognitive deficits by impairing short-term memory and spatial memory retention.

Mitochondria-Targeted Human Catalase in the Mouse Longevity MCAT Model Mitigates Head-Tilt Bedrest-Induced Neuro-Inflammation in the Hippocampus.

Microgravity (modeled by head-tilt bedrest and hind-limb unloading), experienced during prolonged spaceflight, results in neurological consequences, central nervous system (CNS) dysfunction, and potentially impairment during the performance of critical tasks. Similar pathologies are observed in bedrest, sedentary lifestyle, and muscle disuse on Earth. In our previous study, we saw that head-tilt bedrest together with social isolation upregulated the milieu of pro-inflammatory cytokines in the hippocampus and plasma. These changes were mitigated in a MCAT mouse model overexpressing human catalase in the mitochondria, pointing out the importance of ROS signaling in this stress response. Here, we used a head-tilt model in socially housed mice to tease out the effects of head-tilt bedrest without isolation. In order to find the underlying molecular mechanisms that provoked the cytokine response, we measured CD68, an indicator of microglial activation in the hippocampus, as well as changes in normal in-cage behavior. We hypothesized that hindlimb unloading (HU) will elicit microglial hippocampal activations, which will be mitigated in the MCAT ROS-quenching mice model. Indeed, we saw an elevation of the activated microglia CD68 marker following HU in the hippocampus, and this pathology was mitigated in MCAT mice. Additionally, we identified cytokines in the hippocampus, which had significant positive correlations with CD68 and negative correlations with exploratory behaviors, indicating a link between neuroinflammation and behavioral consequences. Unveiling a correlation between molecular and behavioral changes could reveal a biomarker indicative of these responses and could also result in a potential target for the treatment and prevention of cognitive changes following long space missions and/or muscle disuse on Earth.

Fractionated Proton Irradiation Does Not Impair Hippocampal-Dependent Short-Term or Spatial Memory in Female Mice.

The environment outside the Earth's protective magnetosphere is a much more threatening and complex space environment. The dominant causes for radiation exposure, solar particle events and galactic cosmic rays, contain high-energy protons. In space, astronauts need healthy and highly functioning cognitive abilities, of which the hippocampus plays a key role. Therefore, understanding the effects of 1H exposure on hippocampal-dependent cognition is vital for developing mitigative strategies and protective countermeasures for future missions. To investigate these effects, we subjected 6-month-old female CD1 mice to 0.75 Gy fractionated 1H (250 MeV) whole-body irradiation at the NASA Space Radiation Laboratory. The cognitive performance of the mice was tested 3 months after irradiation using Y-maze and Morris water maze tests. Both sham-irradiated and 1H-irradiated mice significantly preferred exploration of the novel arm compared to the familiar and start arms, indicating intact spatial and short-term memory. Both groups statistically spent more time in the target quadrant, indicating spatial memory retention. There were no significant differences in neurogenic and gliogenic cell counts after irradiation. In addition, proteomic analysis revealed no significant upregulation or downregulation of proteins related to behavior, neurological disease, or neural morphology. Our data suggests 1H exposure does not impair hippocampal-dependent spatial or short-term memory in female mice.

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment.

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient's quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.

Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC's antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.

Combined Mechanical and Enzymatic Dissociation of Mouse Brain Hippocampal Tissue.

This neural dissociation protocol (an adaptation of the protocol accompanying a commercial adult brain dissociation kit) optimizes tissue processing in preparation for detailed downstream analysis such as flow cytometry or single-cell sequencing. Neural dissociation can be conducted via mechanical dissociation (such as using filters, chopping techniques, or pipette trituration), enzymatic digestion, or a combination thereof. The delicate nature of neuronal cells can complicate efforts to obtain the highly viable, true single-cell suspension with minimal cellular debris that is required for single-cell analysis. The data demonstrate that this combination of automated mechanical dissociation and enzymatic digestion consistently yields a highly viable (>90%) single-cell suspension, overcoming the aforementioned difficulties. While a few of the steps require manual dexterity, these steps lessen sample handling and potential cell loss. This manuscript details each step of the process to equip other laboratories to successfully dissociate small quantities of neural tissue in preparation for downstream analysis.

The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice.

5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a p-value of <0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.

Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice.

Space is a high-stress environment. One major risk factor for the astronauts when they leave the Earth's magnetic field is exposure to ionizing radiation from galactic cosmic rays (GCR). Several adverse changes occur in mammalian anatomy and physiology in space, including bone loss. In this study, we assessed the effects of simplified GCR exposure on skeletal health in vivo. Three months following exposure to 0.5 Gy total body simulated GCR, blood, bone marrow and tissue were collected from 9 months old male mice. The key findings from our cell and tissue analysis are (1) GCR induced femoral trabecular bone loss in adult mice but had no effect on spinal trabecular bone. (2) GCR increased circulating osteoclast differentiation markers and osteoclast formation but did not alter new bone formation or osteoblast differentiation. (3) Steady-state levels of mitochondrial reactive oxygen species, mitochondrial and non-mitochondrial respiration were increased without any changes in mitochondrial mass in pre-osteoclasts after GCR exposure. (4) Alterations in substrate utilization following GCR exposure in pre-osteoclasts suggested a metabolic rewiring of mitochondria. Taken together, targeting radiation-mediated mitochondrial metabolic reprogramming of osteoclasts could be speculated as a viable therapeutic strategy for space travel induced bone loss.

Tocotrienols as an Anti-Breast Cancer Agent.

In the past few years, breast cancer has become the most prevalent type of cancer. The majority of patients receive combinatorial chemotherapy treatments, which may result in increased risk of developing drug resistance, a reduced quality of life, and substantial side effects. Treatment modalities that could lessen the physical toll of standard treatments or act in synergy with chemotherapeutic treatments would benefit women worldwide. Research into tocotrienols has thus far demonstrated their potential to be such an agent, with tocotrienols surpassing the pharmacological potential of tocopherols. Further research using in vitro and preclinical breast cancer models to support clinical trials is needed. This review uses bibliometric analysis to highlight this gap in research and summarizes the current and future landscape of tocotrienols as an anti-breast cancer agent.

A Bibliometric Analysis of Cyclophosphamide, Methotrexate, and Fluorouracil Breast Cancer Treatments: Implication for the Role of Inflammation in Cognitive Dysfunction.

Inflammation is considered one of the possible mechanisms behind long-term cognitive dysfunction persistent after chemotherapy treatment. The chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) was one of the older methods of treating breast cancer patients. Decades later, these patients still report experiencing cognitive side effects. In this present bibliometric review, we applied the VOSviewer tool to describe the existing landscape on literature concerning inflammation as it relates to CMF and cognitive dysfunctions. As time progressed, we saw an increase in interest in the topic. By the mid-2010s there were approximately 1,000 publications per year. Terms related to the brain and CNS did not appear until the later years, and terms related to inflammation and breast cancer were very prevalent throughout the three decades. Also, in more recent years, inflammatory markers and plant-derived compounds used to alleviate side effects of the inflammatory response appeared in the search results. The USA remained the most prolific producer of CMF-, inflammation-, and cognitive dysfunction-related papers throughout the three decades followed by Asia and Europe. As research of cognitive dysfunction caused by inflammation due to chemotherapy treatment progresses, more opportunities emerge for therapeutic methods to improve the quality of life for long-term survivors.

Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation.

Isolation on Earth can alter physiology and signaling of organs systems, including the central nervous system. Although not in complete solitude, astronauts operate in an isolated environment during spaceflight. In this study, we determined the effects of isolation and simulated microgravity solely or combined, on the inflammatory cytokine milieu of the hippocampus. Adult female wild-type mice underwent simulated microgravity by hindlimb unloading for 30 days in single or social (paired) housing. In hippocampus, simulated microgravity and isolation each regulate a discrete repertoire of cytokines associated with inflammation. Their combined effects are not additive. A model for mitochondrial reactive oxygen species (ROS) quenching via targeted overexpression of the human catalase gene to the mitochondria (MCAT mice), are protected from isolation- and/or simulated microgravity-induced changes in cytokine expression. These findings suggest a key role for mitochondrial ROS signaling in neuroinflammatory responses to spaceflight and prolonged bedrest, isolation, and confinement on Earth.

Consequences of space radiation on the brain and cardiovascular system.

Staying longer in outer space will inevitably increase the health risks of astronauts due to the exposures to galactic cosmic rays and solar particle events. Exposure may pose a significant hazard to space flight crews not only during the mission but also later, when slow-developing adverse effects could finally become apparent. The body of literature examining ground-based outcomes in response to high-energy charged-particle radiation suggests differential effects in response to different particles and energies. Numerous animal and cellular models have repeatedly demonstrated the negative effects of high-energy charged-particle on the brain and cognitive function. However, research on the role of space radiation in potentiating cardiovascular dysfunction is still in its early stages. This review summarizes the available data from studies using ground-based animal models to evaluate the response of the brain and heart to the high-energy charged particles of GCR and SPE, addresses potential sex differences in these effects, and aims to highlight gaps in the current literature for future study.

Effects of 16O charged-particle irradiation on cognition, hippocampal morphology and mutagenesis in female mice.

The effects of radiation in space on human cognition are a growing concern for NASA scientists and astronauts as the possibility for long-duration missions to Mars becomes more tangible. Oxygen (16O) radiation is of utmost interest considering that astronauts will interact with this radiation frequently. 16O radiation is a class of galactic cosmic ray (GCR) radiation and also present within spacecrafts. Whole-body exposure to high linear energy transfer (LET) radiation has been shown to affect hippocampal-dependent cognition. To assess the effects of high-LET radiation, we gave 6-month-old female C57BL/6 mice whole-body exposure to 16O at 0.25 or 0.1 Gy at NASA's Space Radiation Laboratory. Three months following irradiation, animals were tested for cognitive performance using the Y-maze and Novel Object Recognition paradigms. Our behavioral data shows that 16O radiation significantly impairs object memory but not spatial memory. Also, dendritic morphology characterized by the Sholl analysis showed that 16O radiation significantly decreased dendritic branch points, ends, length, and complexity in 0.1 Gy and 0.25 Gy dosages. Finally, we found no significant effect of radiation on single nucleotide polymorphisms in hippocampal genes related to oxidative stress, inflammation, and immediate early genes. Our data suggest exposure to heavy ion 16O radiation modulates hippocampal neurons and induces behavioral deficits at a time point of three months after exposure in female mice.