Neuropathological Examination of Mice Chronically Exposed to Secondhand Smoke.

INTRODUCTION: Around 21.6-35% of military personnel are smokers, while 12.26% of them have been regularly exposed to second-hand smoke (SHS). Second-hand smoke is considered an important risk factor for neurological diseases because it can induce oxidative stress, DNA damage, and disrupt DNA repair pathways. MATERIAL AND METHODS: The brain of air (sham) or SHS exposed mice was cryoperserved, sectioned, and placed on a glass slide before immunoprobing them with antibodies to observe for oxidative DNA damage (8-oxoG), oxidative DNA repair (8-oxoguanine DNA glycosylase 1, Ogg1; apurinic/apyrimidinic endonuclease, Ape1), and inflammatory (glial fibrillary acidic protein) proteins. RESULTS: Nissl staining of the prefrontal cortex (PFCTX) revealed the presence of dark, shrunken cells, hippocampal thinning, and the presence of activated astrocytes in SHS exposed mice. 8-oxoG staining was also more prominent in the PFCTX and hippocampus (HIPP) of SHS exposed mice. Ogg1 staining was reduced in the PFCTX and CA3 hippocampal neurons of SHS exposed mice, whereas it was more prominent in CA1 and CA4 hippocampal neurons. In contrast, Ape1 staining was more prominent in the PFCTX and the HIPP of SHS exposed mice. CONCLUSIONS: These studies demonstrate that oxidative DNA damage (8-oxoG) was elevated and oxidative DNA repair (Ape1 and Ogg1) was altered in the brain of SHS exposed mice. In addition, activated astrocytes (i.e., glial fibrillary acidic protein) were also observed in the brain of SHS exposed mice. Therefore, SHS induces both oxidative DNA damage and repair as well as inflammation as possible underlying mechanism(s) of the cognitive decline and metabolic changes that were observed in chronically exposed mice. A better understanding of how chronic exposure to SHS induces cognitive dysfunction among military personnel could help improve the combat readiness of U.S. soldiers as well as reduce the financial burden on the DOD and veterans' families.

Inhibition of Anaplastic Lymphoma Kinase (Alk) as Therapeutic Target to Improve Brain Function in Neurofibromatosis Type 1 (Nf1).

Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in 50-70% of children with Nf1 and include specific problems with attention, visual perception, language, learning, attention, and executive function. These behavioral alterations and cognitive deficits are observed in the absence of tumors or macroscopic structural abnormalities in the central nervous system. No effective treatments for the behavioral and cognitive disabilities of Nf1 exist. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. Even if the incidence of adverse reactions of currently available Alk inhibitors was reduced to half the dose, we anticipate that a long-term treatment would pose challenges for efficacy, safety, and tolerability. Therefore, future efforts are warranted to investigate alternative, potentially less toxic and more specific strategies to inhibit Alk function.

Behavioral and Cognitive Performance Following Exposure to Second-Hand Smoke (SHS) from Tobacco Products Associated with Oxidative-Stress-Induced DNA Damage and Repair and Disruption of the Gut Microbiome.

Exposure to second-hand Smoke (SHS) remains prevalent. The underlying mechanisms of how SHS affects the brain require elucidation. We tested the hypothesis that SHS inhalation drives changes in the gut microbiome, impacting behavioral and cognitive performance as well as neuropathology in two-month-old wild-type (WT) mice and mice expressing wild-type human tau, a genetic model pertinent to Alzheimer's disease mice, following chronic SHS exposure (10 months to ~30 mg/m3). SHS exposure impacted the composition of the gut microbiome as well as the biodiversity and evenness of the gut microbiome in a sex-dependent fashion. This variation in the composition and biodiversity of the gut microbiome is also associated with several measures of cognitive performance. These results support the hypothesis that the gut microbiome contributes to the effect of SHS exposure on cognition. The percentage of 8-OHdG-labeled cells in the CA1 region of the hippocampus was also associated with performance in the novel object recognition test, consistent with urine and serum levels of 8-OHdG serving as a biomarker of cognitive performance in humans. We also assessed the effects of SHS on the percentage of p21-labeled cells, an early cellular marker of senescence that is upregulated in bronchial cells after exposure to cigarette smoke. Nuclear staining of p21-labeled cells was more prominent in larger cells of the prefrontal cortex and CA1 hippocampal neurons of SHS-exposed mice than in sham-exposed mice, and there was a significantly greater percentage of labelled cells in the prefrontal cortex and CA1 region of the hippocampus of SHS than air-exposed mice, suggesting that exposure to SHS may result in accelerated brain aging through oxidative-stress-induced injury.

Gastrointestinal Dysfunction in Neurological and Neurodegenerative Disorders.

Increasing research links the gut microbiome to neurodegenerative disorders. The gut microbiome communicates with the central nervous system via the gut-brain axis and affects behavioral and cognitive phenotypes. Dysbiosis (a dysfunctional microbiome) drives increased intestinal permeability and inflammation that can negatively affect the brain via the gut-brain axis. Healthier metabolic and lipid profiles and cognitive phenotypes are observed in individuals with more distinct microbiomes. In this review, we discuss the role of the gut microbiome and gut-brain axis in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease and related animal models, in cancer and cancer treatments, and in metabolic syndrome. We also discuss strategies to improve the gut microbiome and ultimately brain function. Because healthier cognitive phenotypes are observed in individuals with more distinct microbiomes, increased efforts are warranted to develop therapeutic strategies for those at increased risk of developing neurological disorders and patients diagnosed with those disorders.

Examining the Mechanisms behind Exercise's Multifaceted Impacts on Body Composition, Cognition, and the Gut Microbiome in Cancer Survivors: Exploring the Links to Oxidative Stress and Inflammation.

This review focuses on the effects of exercise on various health-related outcomes in cancer survivors, encompassing body composition, cognitive function (including sleep), and gut microbiome health. By analyzing multiple studies, we aimed to summarize the existing evidence and shed light on underlying mechanisms. The findings strongly suggest that exercise serves as a multifaceted non-pharmacological strategy, playing a significant role in improving the overall health of cancer survivors by effectively reducing inflammation and oxidative stress. Exercise plays a crucial role in preventing muscle wasting, diminishing the presence of reactive oxygen species and pro-inflammatory cytokines, and enhancing antioxidant systems. Furthermore, exercise displays notable benefits in terms of executive cognitive functioning and fatigue alleviation, largely attributed to its anti-inflammatory impact on the central nervous system and its ability to induce neurogenesis via growth factors. Additionally, exercise positively influences microbial diversity, reduces gut inflammation, and enhances neurogenesis through the gut-brain axis. Our key findings underscore the reduction of oxidative stress and inflammation as primary mechanisms by which exercise effectively enhances health outcomes in cancer survivors. By delving deeper into these candidate mechanisms, we aim to provide valuable guidance for future research and interventions targeting the symptoms experienced by cancer survivors.

Postsynaptic density radiation signature following space irradiation.

Introduction: The response of the brain to space radiation is an important concern for astronauts during space missions. Therefore, we assessed the response of the brain to 28Si ion irradiation (600 MeV/n), a heavy ion present in the space environment, on cognitive performance and whether the response is associated with altered DNA methylation in the hippocampus, a brain area important for cognitive performance. Methods: We determined the effects of 28Si ion irradiation on object recognition, 6-month-old mice irradiated with 28Si ions (600 MeV/n, 0.3, 0.6, and 0.9 Gy) and cognitively tested two weeks later. In addition, we determined if those effects were associated with alterations in hippocampal networks and/or hippocampal DNA methylation. Results: At 0.3 Gy, but not at 0.6 Gy or 0.9 Gy, 28Si ion irradiation impaired cognition that correlated with altered gene expression and 5 hmC profiles that mapped to specific gene ontology pathways. Comparing hippocampal DNA hydroxymethylation following proton, 56Fe ion, and 28Si ion irradiation revealed a general space radiation synaptic signature with 45 genes that are associated with profound phenotypes. The most significant categories were glutamatergic synapse and postsynaptic density. Discussion: The brain's response to space irradiation involves novel excitatory synapse and postsynaptic remodeling.

Behavioral and cognitive performance of humanized APOEε3/ε3 liver mice in relation to plasma apolipoprotein E levels.

Plasma apolipoprotein E levels were previously associated with the risk of developing Alzheimer's disease (AD), levels of cerebrospinal fluid AD biomarkers, cognition and imaging brain measures. Outside the brain, the liver is the primary source of apoE and liver transplantation studies have demonstrated that liver-derived apoE does not cross the blood-brain-barrier. How hepatic apoE may be implicated in behavioral and cognitive performance is not clear. In the current study, we behaviorally tested FRGN mice with humanized liver harboring the ε3/ε3 genotype (E3-human liver (HL)) and compared their behavioral and cognitive performance with that of age-matched ε3/ε3 targeted replacement (E3-TR) mice, the latter produces human apoE3 throughout the body whereas the E3-HL mice endogenously produce human apoE3 only in the liver. We also compared the liver weights and plasma apoE levels, and assessed whether plasma apoE levels were correlated with behavioral or cognitive measures in both models. E3-HL were more active but performed cognitively worse than E3-TR mice. E3-HL mice moved more in the open field containing objects, showed higher activity levels in the Y maze, showed higher activity levels during the baseline period in the fear conditioning test than E3-TR mice, and swam faster than E3-TR mice during training to locate the visible platform in the water maze. However, E3-HL mice showed reduced spatial memory retention in the water maze and reduced fear learning and contextual and cued fear memory than E3-TR mice. Liver weights were greater in E3-HL than E3-TR mice and sex-dependent only in the latter model. Plasma apoE3 levels were similar to those found in humans and comparable in female and male E3-TR mice but higher in female E3-HL mice. Finally, we found correlations between plasma apoE levels and behavioral and cognitive measures which were predominantly model-dependent. Our study demonstrates mouse-model dependent associations between plasma apoE levels, behavior and cognition in an 'AD-neutral' setting and suggests that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes.

Association of fall rate and functional status by APOE genotype in cancer survivors after exercise intervention.

PURPOSE/OBJECTIVES: Cancer treatment survivors often report impaired functioning and increased falls. Not all survivors experience the same symptom burden, suggesting individual susceptibilities. APOE genotype is a potential genetic risk factor for cancer treatment related side effects. Lifestyle factors such as physical activity can mitigate the effect of APOE genotype on measures of clinical interest in individuals without a history of cancer. We tested the hypothesis that APOE genotype influences cancer treatment related side effects and symptoms as well as response to exercise intervention. MATERIALS AND METHODS: Data from a subsample of a study of fall prevention exercise in post-treatment female cancer survivors aged 50-75 years old (https://clinicaltrials.gov NCT01635413) were used to conduct a secondary data analysis. ApoE genotype was determined by serum sampling. Physical functioning, frequency of falls, and symptom burden were assessed using survey instruments. RESULTS: Data from 126 female cancer survivors a median of 49 months out from cancer diagnosis were analyzed. ApoE4 carriers trended toward a higher fall rate at baseline (p = 0.059), but after exercise intervention had a fall rate lower than E4 non-carriers both immediately after structured intervention (p = 0.013) and after 6 months of follow up (p = 0.002). E2 carriers did not show improved measures of depressive symptoms and self-report disability after exercise intervention. E3 homozygotes showed increased self report physical activity after the 6 month exercise intervention, but E4 and E2 carriers did not. CONCLUSIONS: APOE genotype may modulate cancer treatment related side effects and symptoms and response to exercise intervention.

An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory.

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.

Infusion of etoposide in the CA1 disrupts hippocampal immediate early gene expression and hippocampus-dependent learning.

Tight regulation of immediate early gene (IEG) expression is important for synaptic plasticity, learning, and memory. Recent work has suggested that DNA double strand breaks (DSBs) may have an adaptive role in post-mitotic cells to induce IEG expression. Physiological activity in cultured neurons as well as behavioral training leads to increased DSBs and subsequent IEG expression. Additionally, infusion of etoposide-a common cancer treatment that induces DSBs-impairs trace fear memory. Here, we assessed the effects of hippocampal infusion of 60 ng of etoposide on IEG expression, learning, and memory in 3-4 month-old C57Bl/6J mice. Etoposide altered expression of the immediate early genes cFos and Arc in the hippocampus and impaired hippocampus-dependent contextual fear memory. These data add to the growing evidence that DSBs play an important role in IEG expression, learning, and memory, opening avenues for developing novel treatment strategies for memory-related disorders.

Biochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice.

BACKGROUND: Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease. OBJECTIVE: To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice. DESIGN: C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels. RESULTS: Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory. CONCLUSION: Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH-/- are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.

Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.

DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3-4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.

Long-term effects of pharmacological inhibition of anaplastic lymphoma kinase in neurofibromatosis 1 mutant mice.

Neurofibromatosis type 1 (NF1) is associated with behavioral alterations and cognitive impairments. There is a genetic interaction between NF1 and the receptor tyrosine kinase Alk. Short-term pharmacological Alk inhibition, with a compound FDA-approved for cancer starting 10 days prior to cognitive testing, was shown to improve cognitive performance of NF1 heterozygous (HET) mice. However, effects of long-term Alk inhibition on behavioral cognitive performance are not known. Therefore, in the study described below we determine the effects of prolonged pharmacological Alk inhibition for 24 weeks on behavioral and cognitive performance of NF1 HET mice. As these studies have the ultimate objective of developing a treatment for humans with neurofibromatosis and acceptable side effects in the context of cancer are not acceptable in the context of long-term treatment of patients with neurofibromatosis, we included additional behavioral tests of anxiety-like and depressive-like behaviors as well. Long-term effects of Alk inhibition had genotype-dependent effects, consistent with a specific interaction between Alk and NF1. Beneficial effects of long-term Alk inhibition in NF1 HET mice included rescue of impairments in object recognition in NF1 HET males and females, and improved cognitive performance of NF1 HET males and females in the water maze test. In contrast, long-term Alk inhibition had detrimental effects in WT mice not seen after short-term treatments. As longer treatments are translationally more relevant for NF1 patients, these data highlight the important to assess long-term effects of drugs, especially of repurposed drugs used originally as part of cancer therapy.

Amifostine (WR-2721) Mitigates Cognitive Injury Induced by Heavy Ion Radiation in Male Mice and Alters Behavior and Brain Connectivity.

The deep space environment contains many risks to astronauts during space missions, such as galactic cosmic rays (GCRs) comprised of naturally occurring heavy ions. Heavy ion radiation is increasingly being used in cancer therapy, including novel regimens involving carbon therapy. Previous investigations involving simulated space radiation have indicated a host of detrimental cognitive and behavioral effects. Therefore, there is an increasing need to counteract these deleterious effects of heavy ion radiation. Here, we assessed the ability of amifostine to mitigate cognitive injury induced by simulated GCRs in C57Bl/6J male and female mice. Six-month-old mice received an intraperitoneal injection of saline, 107 mg/kg, or 214 mg/kg of amifostine 1 h prior to exposure to a simplified five-ion radiation (protons, 28Si, 4He, 16O, and 56Fe) at 500 mGy or sham radiation. Mice were behaviorally tested 2-3 months later. Male mice that received saline and radiation exposure failed to show novel object recognition, which was reversed by both doses of amifostine. Conversely, female mice that received saline and radiation exposure displayed intact object recognition, but those that received amifostine prior to radiation did not. Amifostine and radiation also had distinct effects on males and females in the open field, with amifostine affecting distance moved over time in both sexes, and radiation affecting time spent in the center in females only. Whole-brain analysis of cFos immunoreactivity in male mice indicated that amifostine and radiation altered regional connectivity in areas involved in novel object recognition. These data support that amifostine has potential as a countermeasure against cognitive injury following proton and heavy ion irradiation in males.

Apolipoprotein E levels in the amygdala and prefrontal cortex predict relative regional brain volumes in irradiated Rhesus macaques.

In the brain, apolipoprotein E (apoE) plays an important role in lipid transport and response to environmental and age-related challenges, including neuronal repair following injury. While much has been learned from radiation studies in rodents, a gap in our knowledge is how radiation might affect the brain in primates. This is important for assessing risk to the brain following radiotherapy as part of cancer treatment or environmental radiation exposure as part of a nuclear accident, bioterrorism, or a nuclear attack. In this study, we investigated the effects of ionizing radiation on brain volumes and apoE levels in the prefrontal cortex, amygdala, and hippocampus of Rhesus macaques that were part of the Nonhuman Primate Radiation Survivor Cohort at the Wake Forest University. This unique cohort is composed of Rhesus macaques that had previously received single total body doses of 6.5-8.05 Gy of ionizing radiation. Regional apoE levels predicted regional volume in the amygdala and the prefrontal cortex. In addition, apoE levels in the amygdala, but not the hippocampus, strongly predicted relative hippocampal volume. Finally, radiation dose negatively affected relative hippocampal volume when apoE levels in the amygdala were controlled for, suggesting a protective compensatory role of regional apoE levels following radiation exposure. In a supplementary analysis, there also was a robust positive relationship between the neuroprotective protein α-klotho and apoE levels in the amygdala, further supporting the potentially protective role of apoE. Increased understanding of the effects of IR in the primate brain and the role of apoE in the irradiated brain could inform future therapies to mitigate the adverse effects of IR on the CNS.

Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice.

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.

Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice.

BACKGROUND: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. OBJECTIVE: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. METHODS: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. RESULTS: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer's disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. CONCLUSION: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation.

The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Effects of Chronic Secondhand Smoke (SHS) Exposure on Cognitive Performance and Metabolic Pathways in the Hippocampus of Wild-Type and Human Tau Mice.

BACKGROUND: Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3-4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline. OBJECTIVE: The goal of this study was to assess the effects of chronic SHS exposure (10 months' exposure to ∼30 mg/m3) on behavioral and cognitive function, metabolism, and neuropathology in mice. METHODS: Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExpose™ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression. RESULTS: Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, IGF1ß, and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice. DISCUSSION: The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. https://doi.org/10.1289/EHP8428.