Oregon Regional Primate Research Center Research Articles

Adaptations to maternal WSD-feeding and metformin use on fetal islets from non-human primate offspring

Given the current increased prevalence of diabetes in pregnancy, the potential relative risks and benefits of oral glycemic agents on the developing offspring should be evaluated and considered. Metformin (Met) is a common oral glycemic agent prescribed in pregnancy that is not metabolized, but is renally excreted and actively transported across the placenta. Thus, the developing fetus is exposed to near equivalent maternal adult doses with subsequent risk of adverse consequences. Using a non-human primate model of maternal overnutrition, our group previously demonstrated that developmental exposure to a Western-style diet (WSD) results in an inappropriate increase in glucose-stimulated insulin secretion and changes in expression of several ion channels involved in insulin secretion in islets from juvenile offspring. Given that maternal overnutrition results in an excess energy supply to the developing fetus while Met inhibits mitochondrial respiration, we hypothesize that maternal WSD-feeding and Met will result in maladaptive beta-cell function in the fetus. Static insulin secretion assays on islets from chow (CD) and WSD +/- Met-exposed offspring show no differences in glucose-stimulated insulin secretion. Nevertheless, islets from a mWSD+Met-exposed fetus showed lower oxygen consumption and extracellular acidification rate relative to mWSD+placebo fetal islets, suggesting that maternal diet influences fetal programming and adaptation to Met in fetal islets. Therefore, we predict that the metabolic response to intrauterine Met exposure differs depending on the maternal diet. Elucidation of the mechanisms mediating adaptations to maternal diet and Met exposure during development may provide insight on interventions to avoid beta-cell failure in the offspring as they age. All nonhuman primate studies were supported in part by the Oregon National Primate Research Center grant P51 OD011092 from the National Institutes of Health/Offce of the Director. D.T.C. was supported by the Vanderbilt University Training Program in Molecular Endocrinology (5T32 DK563-30) and a predoctoral fellowship from the NIH/NIDDK (1F31 DK135164).T.A.D., C.E.M., K.M.A., J.E.F., P.K., and M.G. were supported by NIH/NIDDK Grants R24 DK090964 and R01 DK128187. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A naturally occurring variant of MBD4 causes maternal germline hypermutation in primates.

As part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene methyl-CpG binding domain 4, DNA glycosylase (MBD4). MBD4 is responsible for the repair of C > T deamination mutations at CpG dinucleotides and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: The six offspring of the MBD4-null dam have a fourfold to sixfold increase in de novo mutation burden. This excess burden was predominantly C > T mutations at CpG dinucleotides consistent with MBD4 loss of function in the dam. There was also a significant excess of C > T at CpA sites, indicating an important, unappreciated role for MBD4 to repair deamination in CpA contexts. The MBD4-null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated with MBD4 loss of function in humans nor any obvious disease in the hypermutated offspring. This work provides the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.

A Comparison of Oocyte Yield between Ultrasound-Guided and Laparoscopic Oocyte Retrieval in Rhesus Macaques.

Obtaining quality oocytes is a prerequisite for ART-based studies. Here we describe a method for transabdominal ultrasound-guided (US) oocyte retrieval in rhesus macaques (Macaca mullata) and compare it to the standard surgical approach using laparoscopy (LAP). We analyzed oocyte yield from six continuous reproductive seasons (2017-2023) that included n = 177 US-guided and n = 136 laparoscopic oocyte retrievals. While the ultrasound-guided technique retrieved significantly fewer oocytes on average (LAP: 40 ± 2 vs. US: 27 ± 1), there was no difference in the number of mature metaphase II oocytes (MII) between the two techniques (LAP: 17 ± 1 vs. US: 15 ± 1). We show that oocytes retrieved by the ultrasound-guided approach fertilize at the same rates as those obtained via the laparoscopic procedure (LAP Fert Rate: 84% ± 2% vs. US Fert Rate: 83% ± 2%). In conclusion, minimally invasive ultrasound-guided oocyte retrieval improves animal welfare while delivering equivalent numbers of mature oocytes, which are ideal for ART. Furthermore, we show that oocyte competency, as represented by fertilization rate, is not affected by retrieval technique. Therefore, the Oregon National Primate Research Center (ONPRC) has adopted the ultrasound-guided approach as the standard technique for oocyte retrieval.

Identification of Vancomycin Resistance in Methicillin-resistant Staphylococcus aureus in two macaque species and decolonization and long-term prevention of recolonization in Cynomolgus Macaques (Macaca fascicularis).

Methicillin-resistant Staphylococcus aureus (MRSA) is a S. aureus strain with resistance to beta-lactam antibiotics, making it a global human and veterinary health concern. Specifically, immunosuppressed patients have a remarkably higher risk of clinical MRSA infections with significantly increased rates of prolonged clinical recovery, morbidity, and mortality. The current treatment of choice for MRSA is vancomycin. Importantly, we report the first known vancomycin-resistant S. aureus (VRSA) carriers in a cohort of Mauritian cynomolgus macaques (CM) imported to the Oregon National Primate Research Center (ONPRC), with a MRSA carrier rate of 76.9% (10/13 animals). All MRSA isolates also demonstrated resistance to vancomycin with prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) at 30% (3/10 MRSA-positive CMs) and VRSA at 70% (7/10 MRSA-positive CMs). Additionally, we identified VRSA in a rhesus macaque (RM) housed within the same room as the VRSA-positive CMs and identified a MRSA/VISA carrier rate of 18.8% in RMs (3/16 positive for both MRSA and VISA) in unexposed recently assigned animals directly from the ONPRC RM breeding colony. Considering that the MRSA and VRSA/VISA-positive CMs future study aims included significant immunosuppression, MRSA/VRSA/VISA decolonization treatment and expanded "MRSA-free" practices were employed to maintain this status. We report the first controlled study using in-depth analyses with appropriate diagnostic serial testing to definitively show an MRSA decolonization therapy (90% success rate) and expanded barrier practice techniques to successfully prevent recolonization (100%) of a cohort of CMs MRSA-free (up to 529 days with a total of 4,806 MRSA-free NHP days).

The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

Rhesus macaque fetal and placental growth demographics: A resource for laboratory animal researchers.

Rhesus macaques (Macaca mulatta) are amongst the most common nonhuman primate species used in biomedical research. These animals provide a precious resource for translational studies and opportunities to maximize rhesus data use are encouraged. Here we compile data produced from 10 years of investigator-driven pregnancy studies conducted at the Oregon National Primate Research Center (ONPRC). All pregnancies were generated within the consistent and reproducible protocols of the ONPRC time-mated breeding program. The data included are from control animals who did not experience in utero perturbations or experimental manipulations. A total of 86pregnant rhesus macaques were delivered by cesarean section over a range of gestational days (G) 50 to G159 (where term is G165 ± 10 days in the rhesus macaque), with subsequent immediate tissue harvesting following standardized protocols. Fetal and placental growth measures, and all major organ weights are reported. All data are presented relative to gestational age for the entire cohort and in addition, data are stratified by fetal sex. The outcome is a large reference resource for use by laboratory animal researchers in future comparative fetal development studies.

Ultrasound evaluation of normal rhesus macaque fetal biometry and uteroplacental hemodynamics.

Nonhuman primates are important preclinical models for translational, reproductive, and developmental science. Clinical evaluation of human fetal development is performed using standard sonographic-derived fetal biometry, assessments of amniotic fluid, and uteroplacental hemodynamics. These noninvasive in utero measurements provide important information regarding fetal growth and pregnancy well-being. Abnormalities in fetal growth, amniotic fluid volume, or placental vascular function are associated with placental insufficiency and adverse perinatal outcomes including stillbirth. The fetal biometric parameters most commonly assessed are biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Evaluation of amniotic fluid volume includes measuring the fluid in four quadrants of the uterus to generate an Amniotic Fluid Index. Measures of uteroplacental hemodynamics typically include doppler assessment of the umbilical artery and ductus venosus, but can also include interrogation of the uterine artery and umbilical vein. In this study, we compile prenatal ultrasound data of fetal biometry, amniotic fluid measurements, and uteroplacental hemodynamics obtained from pregnancy studies conducted at the Oregon National Primate Research Center. The data included are from control unperturbed pregnant animals who have not undergone in utero experimental manipulations. This is the first report of comprehensive sonographic measurements following standardized clinical obstetric protocols utilized in rhesus macaques. The outcome is a large, prenatal ultrasound resource to be used by laboratory animal researchers in future nonhuman primate pregnancy studies for antenatal assessment.

Why I Will Boycott Complex Family Planning Board Certification.

Corresponding author: Jeffrey T. Jensen, MD, MPH, Department of Obstetrics & Gynecology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR; email: [email protected]. Financial Disclosure The author did not report any potential conflicts of interest. Department of Obstetrics & Gynecology and the Women's Health Research Unit, Oregon Health & Science University, and the Oregon National Primate Research Center, Portland, Oregon. Peer reviews and author correspondence are available at https://links.lww.com/AOG/C759.

RhCMV/SIV tropism modulation programs unconventional CD8+ T cell priming and vaccine efficacy

Abstract Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens demonstrate a vaccine efficacy where 50–60% of vaccinated rhesus macaques are protected from SIV challenge. Intriguingly, RhCMV/SIV vectors elicit CD8+ T cells recognizing epitopes presented by MHC-II and MHC-E instead of MHC-Ia. We are studying how these unconventional T cell responses are elicited and contribute to the efficacy against SIV challenge. Here we utilize host microRNA (miRNA)-mediated vector tropism restriction to show that MHC-II- and MHC-E-restricted responses are primed by directly infected, non-overlapping cell types in rhesus macaques. Targeting essential RhCMV genes with myeloid cell-selective miR-142-3p eliminated MHC-E-restricted CD8+ T cell priming, yielding an exclusively MHC-II-restricted response, whereas endothelial cell-selective miR-126-3p targeting eliminated MHC-II-restricted CD8+ T cell priming, yielding an exclusively MHC-E-restricted response. Incorporation of both restriction elements reverts CD8+ T cell responses back to conventional MHC-Ia restriction. Using these otherwise isogenic vectors we show that although they demonstrate similar overall immunogenicity, only the vectors programmed to elicit MHC-E-restricted CD8+ T cell responses provided protection against SIV challenge. The MHC-E-only RhCMV/SIV vaccine efficacy did not exceed that of the parental 68-1 RhCMV/SIV vectors (that elicits both MHC-II and MHC-E responses) indicating that while the MHC-II-restricted CD8+ T cell responses are neutral to overall vaccine efficacy, an additional component of 68-1 RhCMV/SIV-induced immunity contributes to overall vaccine efficacy. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI124377 and U19 AI128741 to LJP; the Oregon National Primate Research Center Core grant from the National Institutes of Health, Office of the Director (P51 OD011092); contracts from the National Cancer Institute (# HHSN261200800001E) to JDL; and the Bill and Melinda Gates Foundation grant OPP1107409.

The people behind the papers - Kelsey Brooks and Shawn Chavez.

Aneuploidy can occur in embryos due to errors in chromosome segregation during the first mitotic cleavage divisions, and often results in developmental arrest. A new paper in Development characterises the molecular events that lead to abnormal chromosome numbers in the cells of bovine embryos. We caught up with first author Kelsey Brooks and corresponding author Shawn Chavez, Associate Professor at the Oregon National Primate Research Center and Oregon Health & Science University, to find out more about their research and the impact it may have on in vitro fertilisation procedures in the future.

Dominance rank, female choice, and reproductive success in semi-free ranging adult male Japanese macaques (Macaca fuscata).

The assumed evolutionary advantage of dominance is increased reproductive success. However, the efficacy of dominance as a mating strategy may be interrupted by any number of variables including female choice, estrous synchrony, and mating by non-troop males. In Japanese macaques (Macaca fuscata), there is evidence both for and against dominance as conferring reproductive success for adult males, with many discussions pointing to the importance of female choice in governing reproductive success in certain populations. In this study, we aimed to evaluate dominance-based versus female choice-based male behavioral strategies and their impact on reproductive success. This study was conducted on a group of Japanese macaques at the Oregon National Primate Research Center. We collected a total of 512 h of behavioral data across two summer study periods in 2018 and 2019. We conducted 15-min focal follows with 1-min instantaneous scans on 17 adult males. Reproductive data were available from genetic records. Using principal components analysis (PCA), we identified males that cluster according to similar behavioral strategies. We then used analysis of variance (ANOVA) and non-parametric ANOVA on ranks to ascertain significant variation in rank and reproductive success between clusters. We found that males that clustered based on high directed aggression held higher rank than less-aggressive male clusters (F = 27.21, df = 4, p < .0001). However, less aggressive male clusters had higher reproductive success (F = 3.50, df = 4, p = .04). There was no variation between affiliative clusters in reproductive success (F = 1.77, df = 3, p = .15). The highly aggressive strategy is effective for attaining high rank, but only resulted in high reproductive success for a single male which likely necessitates alternative strategies. We suggest the operation of female choice within this population, with females preferentially mating with males who are not only affiliative but also less aggressive.

Colon volvulus in rhesus macaques (Macaca mulatta) at the Oregon National Primate Research Center-Retrospective analysis.

Colonic volvulus is an uncommon, often life-threatening condition, in non-human primates. Twenty-six cases of colonic volvulus in rhesus macaques (Macaca mulatta) were identified in necropsy records spanning 38years at the Oregon National Primate Research Center (ONPRC). This report represents the largest collection of colonic volvuli in rhesus macaques.

Neuro-pharmacological reinstatement of ovulation and associated neurobiology in a macaque model of functional hypothalamic amenorrhoea.

What is the underlying neuropathology in a cynomolgus macaque model of functional hypothalamic amenorrhoea (FHA) and can it be normalized to restore ovulation? Anovulatory monkeys exhibited increased hypothalamic norepinephrine (NE), kisspeptin and gonadotropin-releasing hormone (GnRH) in the early follicular phase, but administration of the NE reuptake inhibitor (NRI), reboxetine (REB), restored ovulation during stress and normalized NE, kisspeptin and GnRH. Female cynomolgus macaques, like women, show individual reproductive sensitivity to modest psychosocial and metabolic stress. During stress, resilient females ovulate through two menstrual cycles whereas stress-sensitive (SS) macaques immediately cease ovulation. On Day 5 of a non-stressed menstrual cycle, resilient macaques have less NE synthesizing enzyme [dopamine β-hydroxylase (DBH)], kisspeptin and GnRH innervation of the medial basal hypothalamus but more endogenous serotonin than SS macaques. Stress increased DBH/NE, kisspeptin and GnRH but did not alter serotonin. In a longitudinal design, 27 adult (7-13 years) female cynomolgus macaques (Macaca fascicularis) with three different levels of sensitivity to stress were monitored with daily vaginal swabs and frequent serum progesterone (P) measurements. Three 90-day experimental periods called 'Cycle Sets' were monitored. A Cycle Set consisted of one ovulatory menstrual cycle without stress, and two cycles, or 60 days, with modest stress. Each Cycle Set was followed by a rest period. During a Cycle Set, individuals were either untreated (placebo) or administered escitalopram (CIT) or REB. Ultimately, half of each sensitivity group was euthanized during stress with CIT or REB treatment and the hypothalamus was obtained. Neurobiological endpoints were compared between CIT and REB treatment groups in stress resilient and SS monkeys. The monkeys were housed at the University of Pittsburgh primate facility for the duration of the experiments. Upon euthanasia, their brains and serum samples were shipped to the Oregon National Primate Research Center. The hypothalamus was examined with immunohistochemistry for the expression of DBH (a marker for NE axons), kisspeptin and GnRH. P was measured in the serum samples by radioimmunoassay. Daily administration of REB restored ovulation in 9 of 10 SS animals during stress. Of note, REB significantly increased P secretion during stress in the most sensitive group (P = 0.032), which indicates ovulation. CIT lacked efficacy. REB significantly reduced DBH/NE, kisspeptin and GnRH axon density in the hypothalamus relative to CIT treatment (P = 0.003. 0.018 and 0.0001, respectively) on Day 5 of the menstrual cycle in resilient and sensitive groups. N/A. The US FDA has not approved REB for human use, although it is used in Europe for the treatment of depression/anxiety as EdronaxTR. Whether REB could be useful for the treatment of FHA in women has not been determined. The use of an NRI to treat FHA is a novel approach and the potential reinstatement of ovulation could be straightforward compared to current treatment protocols. The underlying neurobiology provides a compelling case for treating the origin of the pathology, i.e. elevated NE, rather than circumventing the hypothalamus altogether with gonadotropins, which have associated risks such as hyperstimulation syndrome or multiple births. Portions of this study were supported by NIH grant HD062864 to C.L.B., NIH grant HD62618 to J.L.C. and C.L.B. and 1P51 OD011092 for the operation of the Oregon National Primate Research Center. There were no competing interests.

Individual and combined effects of 5-year exposure to hyperandrogenemia and Western-style diet on metabolism and reproduction in female rhesus macaques.

What is the impact of prolonged exposure to hyperandrogenemia (T), Western-style diet (WSD) and the combination on metabolic and reproductive function in female rhesus macaques, particularly in the post-partum period? Combined T + WSD worsened measures of insulin sensitivity and parameters of cyclicity following prolonged (5 years) exposure, but there was no effect on post-partum metabolic function. Women with hyperandrogenemia due to polycystic ovary syndrome are at higher risk for gestational diabetes and Type 2 diabetes post-partum, but it is unknown if this is related to hyperandrogenemia. Hyperandrogenemia in the presence of a WSD worsens metabolic function in female nonhuman primates. Female rhesus macaques began treatment near menarche (roughly 2.5 years of age) consisting of either cholesterol (control; C) or testosterone (T) implants (average serum levels 1.4 ng/ml) and exposure to standard monkey chow or a WSD (15 vs 36% of calories from fat, respectively). The four groups were maintained on treatment for 3 years, underwent a fertility trial in Year 4 and continued with treatments through Year 5. Metabolic measurements (glucose tolerance tests and double X-ray absorptiometry scans) were performed yearly, and results from 5 years of treatment are reported for all animals. Animals were bled daily for 30 days at 5 years to capture changes in ovarian cycle hormones, and ultrasound measurements were performed during the early follicular and luteal phase. After 5 years of treatment, WSD exposure moderately increased body weight and body fat, although control animals also had a high body mass index due to ad libitum feeding. Animals in the T + WSD group had increased fasting insulin and insulin secretion during an intravenous glucose tolerance test. WSD exposure also altered ovarian cycles, delaying the time to the E2 surge, decreasing progesterone and anti-Müllerian hormone levels and increasing the number of antral follicles present by ultrasound. Longitudinal assessment of metabolic function for only those animals that became pregnant in Year 4 of treatment revealed no differences in post-partum metabolism between groups, although WSD resulted in overall elevated weights, body fat and measures of insulin resistance. None. The small sample size and heterogeneity in metabolic effects observed in the T + WSD group are limitations of the current study, with only a subset of animals in this group showing impaired insulin resistance relative to controls. In addition, obesity in the C group prevented comparisons to lean animals. Hyperandrogenemia combined with WSD had a greater impact on insulin sensitivity and ovarian function than either treatment alone. This work was supported by NIH grant P50 HD071836 to C.T.R., J.H. and C.T. and P51 OD011092 for support of the Oregon National Primate Research Center. All authors declare no competing interests.

Variation in Adult Male-Juvenile Affiliative Behavior in Japanese Macaques (Macaca fuscata)

Adult males of some primate species are known to positively interact with juveniles. In cases where paternal certainty is high, these behaviors have been largely attributed to the paternal investment hypothesis. Males have also been observed to interact with nonkin juveniles, which has often been explained in terms of mating effort. Here, we examined variation in adult male-juvenile affiliation in semi-free ranging Japanese macaques (Macaca fuscata) at the Oregon National Primate Research Center against possible influencing factors such as age, dominance rank, and female affiliation, and we also tested for fitness benefits. We conducted 154 h of focal observations of 14 adult males from June to September 2018. Males differed significantly in their rate of juvenile-directed affiliation, but not in their fitness in terms of number of offspring. There was a significant positive correlation between rank and age in the group, indicating that, in this group, rank does not conform to the classic inverted-U pattern observed elsewhere in this species. Although there was a significant positive correlation between rank and juvenile-directed affiliation, the highest-ranking male had few offspring and exhibited little juvenile-directed affiliation. These results suggest little to no preliminary support for either the paternal investment or mating effort hypotheses as explanations for juvenile-directed affiliation. This study suggests that there are multiple behavioral strategies for older males that may influence reproductive success.

Combined androgen excess and Western-style diet accelerates adipose tissue dysfunction in young adult, female nonhuman primates.

What are the separate and combined effects of mild hyperandrogenemia and consumption of a high-fat Western-style diet (WSD) on white adipose tissue (WAT) morphology and function in young adult female nonhuman primates? Combined exposure to mild hyperandrogenemia and WSD induces visceral omental (OM-WAT) but not subcutaneous (SC-WAT) adipocyte hypertrophy that is associated with increased uptake and reduced mobilization of free fatty acids. Mild hyperandrogenemia in females, principally in the context of polycystic ovary syndrome, is often associated with adipocyte hypertrophy, but the mechanisms of associated WAT dysfunction and depot specificity remain poorly understood. Female rhesus macaques were randomly assigned at 2.5 years of age (near menarche) to receive either cholesterol (C; n = 20) or testosterone (T; n = 20)-containing silastic implants to elevate T levels 5-fold above baseline. Half of each of these groups was then fed either a low-fat monkey chow diet or WSD, resulting in four treatment groups (C, control diet; T alone; WSD alone; T + WSD; n = 10/group) that were maintained until the current analyses were performed at 5.5 years of age (3 years of treatment, young adults). OM and SC-WAT biopsies were collected and analyzed longitudinally for in vivo changes in adipocyte area and blood vessel density, and ex vivo basal and insulin-stimulated fatty acid uptake and basal and isoproterenol-stimulated lipolysis. In years 2 and 3 of treatment, the T + WSD group exhibited a significantly greater increase in OM adipocyte size compared to all other groups (P < 0.05), while the size of SC adipocytes measured at the end of the study was not significantly different between groups. In year 3, both WAT depots from the WSD and T + WSD groups displayed a significant reduction in local capillary length and vessel junction density (P < 0.05). In year 3, insulin-stimulated fatty acid uptake in OM-WAT was increased in the T + WSD group compared to year 2 (P < 0.05). In year 3, basal lipolysis was blunted in the T and T + WSD groups in both WAT depots (P < 0.01), while isoproterenol-stimulated lipolysis was significantly blunted in the T and T + WSD groups only in SC-WAT (P < 0.01). At this stage of the study, subjects were still relatively young adults, so that the effects of mild hyperandrogenemia and WSD may become more apparent with increasing age. The combination of mild hyperandrogenemia and WSD accelerates the development of WAT dysfunction through T-specific (suppression of lipolytic response by T), WSD-dependent (reduced capillary density) and combined T + WSD (increased fatty acid uptake) mechanisms. These data support the idea that combined hyperandrogenemia and WSD increases the risk of developing obesity in females. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number P50 HD071836 to C.T.R. and award number OD 011092 from the Office of the Director, National Institutes of Health, for operation of the Oregon National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Differential Expression of Genes Involved in Inflammatory Immune Response and Protein Ubiquitination in the Prefrontal Cortex of Rhesus Macaque with High and Low Lutein Content

Lutein, a carotenoid with antioxidant and anti‐inflammatory functions, accumulates in the primate brain. Studies have shown that brain levels of lutein are more consistently related to better cognitive test scores in humans than other antioxidants found in higher concentrations in the brain, such as vitamin E. Supplementation with lutein can improve verbal fluency, memory scores, and rates of learning in older adults. However, the mechanism by which lutein functions in cognition is unclear. The aim of this study was to determine the relationship between lutein concentration and gene expression profiles in rhesus macaque brain. Brain tissue was dissected from monkeys fed a chow diet containing lutein (~16 μmol/kg diet). Next generation RNA sequencing was used to determine differentially expressed genes in the prefrontal cortex of monkeys (11–13y) with high lutein content (mean=34.5 pg/mg wet weight, n=3) versus those with low lutein content (mean=11.8 pg/mg wet weight, n=3). Lutein concentrations were determined in these brain samples using HPLC. A total of 415 genes were differentially expressed between the two groups. Ingenuity Pathway Analysis (IPA) revealed the up‐regulation of pro‐inflammatory immune response pathways, such as chemokine signaling, antigen presentation, leukocyte extravasation, and neuropathic pain signaling, in brains with low lutein content. A total of 16 genes were upregulated in this pro‐inflammatory network, with specific genes of interest including beta‐2‐microglobulin and p38 MAPK (1.5 fold change for each), which are both associated with age‐related cognitive impairment and neurodegeneration. Additionally, up‐regulation of the protein ubiquitination pathway (9 genes), a hallmark of Alzheimer's disease, was observed in brains with low lutein content. These results indicate that lutein may play a role in suppressing neuroinflammation at the transcription level, and provide the first steps towards understanding the mechanisms underlying the beneficial effect of lutein on cognition.Support or Funding InformationThis work was supported by grants from Abbott Nutrition through the Center for Nutrition, Learning, and Memory at the University of Illinois, USDA (58‐1950‐4‐003), and NIH grant P51OD011092 to the Oregon National Primate Research Center

Lutein and DHA Co‐localize in Cell Membranes of Brain Regions Controlling Cognition in the Rhesus Macaque

Lutein, a xanthophyll with antioxidant properties, preferentially accumulates in primate brain. Brain concentrations of lutein are associated with higher cognitive test scores and supplementation with lutein improves cognitive performance in older adults. The mechanism underlying this beneficial effect, however, remains unknown. Recent studies suggest the association between brain lutein and cognition may be dependent on brain docosahexaenoic acid (DHA) levels, which are also related to better cognitive function. Furthermore, supplementation with both lutein and DHA has been shown to provide additional cognitive benefits in older adults compared to supplementation with either alone. Therefore, lutein and DHA may function together to influence cognition. Given that both compounds accumulate in membranes, the objective of this study was to determine the co‐localization of lutein and DHA in membranes of brain regions controlling different domains of cognitive function in adult rhesus monkeys (age 7–20 y; n=11). Nuclear, myelin, mitochondrial, and neuronal plasma membranes were isolated from prefrontal cortex, cerebellum and striatum tissue using differential centrifugation with a Ficoll density gradient. Lutein and DHA were measured using high performance liquid chromatography and gas chromatography, respectively. Results document that both lutein and DHA were differentially distributed among nuclear, myelin, mitochondrial, and neuronal plasma membranes, with levels being the lowest in mitochondrial membranes (one‐way ANOVA with Tukey HSD, P&lt;0.05). Both followed a similar distribution pattern in the prefrontal cortex and striatum, but not cerebellum. In the prefrontal cortex, age adjusted lutein and DHA levels were inversely associated in myelin membranes only (r = −0.73, P&lt;0.03), while in the striatum, lutein and DHA were positively related in nuclear (r = 0.77, P&lt;0.02) and mitochondrial membranes (r = 0.88, P&lt;0.004). Co‐localization of lutein and DHA in some membranes and regions, but not others, may be indicative of varied, and specific, functions of lutein in different brain regions. Results from this study provide the first steps toward understanding lutein's mechanism of action in the brain and its relationship to DHA.Support or Funding InformationThis work was supported by grants from Abbott Nutrition through the Center for Nutrition, Learning, and Memory at the University of Illinois, DSM Nutritional Products, and USDA (58‐1950‐4‐003), and NIH grant P51OD011092 to the Oregon National Primate Research Center

Neuro diffusion MRI beyond myelinated white matter: cell structures that influence water diffusion in the fetal brain

Event Abstract Back to Event Neuro diffusion MRI beyond myelinated white matter: cell structures that influence water diffusion in the fetal brain Christopher Kroenke1 and Xiaojie Wang1* 1 Oregon Health & Science University, Advanced Imaging Research Center and Oregon National Primate Research Center, United States Distinct populations of neurons and glial cells are stratified in the fetal primate brain across several layers that span from the inner ventricular surface to the outer-most layer of the cerebral cortex. Changes in the sizes of these layers and the morphology of the cells within each layer accompany normal brain development, and the ability to detect deviations from the normal developmental trajectory is highly relevant to the study of many neurodevelopmental disorders. As an example, we have previously demonstrated that water diffusion is very anisotropic in the cerebral cortex at mid-gestation, and that diffusion anisotropy within this tissue layer decreases with maturation. In our modeling approach, we have linked anisotropy in water diffusion to dispersion in the orientation of axonal and dendritic cellular processes. In animal models of three neurodevelopmental disorders, fetal alcohol spectrum disorders, perinatal hypoxia/ischemia, and sensory deprivation, we have demonstrated that alterations in morphological development of cerebral cortical neurons can be revealed by diffusion MRI. Here, we focus on the remaining layers of the mid-gestation brain. A diffusion tensor analysis of post-mortem rhesus macaque brain reveals five distinct tissue layers, including the cerebral cortex. These layers are registered to previously-defined tissue zones identified by histological analyses. Interestingly, two of the MRI-defined zones, which exhibit strikingly different water apparent diffusion coefficients, reside within the subplate zone defined in histological studies. Subsequent to diffusion MRI performed histological analyses on the tissue. We find that multiple different cellular processes (axons, radial glial processes, and dendrites) contribute to diffusion anisotropy within each zone. For each of the five layers, these relationships are described, and unanswered questions related to the determinants of the water apparent diffusion coefficient are identified. Keywords: Diffusion, MRI, dMRI, multidimensional, diffusion encoding Conference: New dimensions in diffusion encoding, Fjälkinge, Sweden, 11 Jan - 14 Jan, 2016. Presentation Type: Oral presentation Topic: New Dimensions in Diffusion Encoding Citation: Kroenke C and Wang X (2016). Neuro diffusion MRI beyond myelinated white matter: cell structures that influence water diffusion in the fetal brain. Front. Phys. Conference Abstract: New dimensions in diffusion encoding. doi: 10.3389/conf.FPHY.2016.01.00027 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Jul 2016; Published Online: 07 Jul 2016. * Correspondence: PhD. Xiaojie Wang, Oregon Health & Science University, Advanced Imaging Research Center and Oregon National Primate Research Center, Portland, Oregon, OR 97239, United States, waxia@ohsu.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Christopher Kroenke Xiaojie Wang Google Christopher Kroenke Xiaojie Wang Google Scholar Christopher Kroenke Xiaojie Wang PubMed Christopher Kroenke Xiaojie Wang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis

Japanese macaque encephalomyelitis (JME) is an inflammatory demyelinating disease that occurs spontaneously in a colony of Japanese macaques (JM) at the Oregon National Primate Research Center. Animals with JME display clinical signs resembling multiple sclerosis (MS), and magnetic resonance imaging reveals multiple T2-weighted hyperintensities and gadolinium-enhancing lesions in the central nervous system (CNS). Here we undertook studies to determine if JME possesses features of an immune-mediated disease in the CNS. Comparable to MS, the CNS of animals with JME contain active lesions positive for IL-17, CD4+ T cells with Th1 and Th17 phenotypes, CD8+ T cells, and positive CSF findings.