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Engle J.R.,University of Arizona | Engle J.R.,California National Primate Research Center | Barnes C.A.,University of Arizona | Barnes C.A.,California National Primate Research Center
Frontiers in Aging Neuroscience | Year: 2012

An overview is provided of the simple single-cue delay and trace eyeblink conditioning paradigms as techniques to assess associative learning and memory in the aged. We highlight and focus this review on the optimization of the parameter space of eyeblink conditioning designs in the aged to avoid and control for potential confounds that may arise when studying aged mammals. The need to examine the contribution of non-associative factors that can contribute to performance outcomes is emphasized, and how age-related changes in the central nervous system as well as peripheral sensory factors can potentially bias the interpretation of the data in the aged is discussed. The way in which slight alterations of the parameter space in the delay and trace eyeblink conditioning paradigms can lead to delayed but intact conditioning, rather than impaired performance in aged animals is also discussed. Overall, the eyeblink conditioning paradigm, when optimized for the age of the animal in the study, is an elegantly simple technique for assessment of associative learning and memory. When design caveats described above are taken into account, this important type of memory, with its well-defined neural substrates, should definitely be included in cognitive assessment batteries for the aged. © 2012 Engle and Barnes.


Broadhurst M.J.,University of California at San Francisco | Ardeshir A.,California National Primate Research Center | Kanwar B.,University of California at San Francisco | Mirpuri J.,University of Texas Southwestern Medical Center | And 9 more authors.
PLoS Pathogens | Year: 2012

Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated. © 2012 Broadhurst et al.


Maninger N.,University of California at San Francisco | Maninger N.,California National Primate Research Center | Capitanio J.P.,California National Primate Research Center | Mason W.A.,California National Primate Research Center | And 2 more authors.
Psychoneuroendocrinology | Year: 2010

Most studies on the stress-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis have focused on glucocorticoids, while few studies have investigated the adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), which is unique to primates. Monkeys were chair-restrained for 2. h per day for seven consecutive days, and blood samples were collected upon placement in the chair, and at 15, 30, 60 and 120. min later. Like cortisol, DHEAS concentrations increased throughout the initial session of chair restraint (acute stress). Unlike the cortisol response, which decreased after repeated exposure to the stressor, the DHEAS response was sustained throughout the seventh session of restraint (chronic stress) and response to the seventh session of restraint did not differ from the DHEAS response to the initial session. Like cortisol, DHEAS concentrations showed a diurnal rhythm with higher concentrations in the morning compared to the evening and a decrease in response to dexamethasone (DEX) administration. After repeated exposure to the stressor, the suppression of DHEAS in response to dexamethasone was more complete, suggesting an increase in negative feedback sensitivity. These data show that DHEAS concentrations increase in response to both acute and chronic (repeated) stress and provide another measure of HPA activity that parallels cortisol during acute responses to stress but diverges in chronic or repeated stress. © 2010.


Baxter M.G.,Mount Sinai School of Medicine | Roberts M.T.,California National Primate Research Center | Gee N.A.,California National Primate Research Center | Gee N.A.,University of California at Davis | And 4 more authors.
Neurobiology of Aging | Year: 2013

Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex. © 2013 Elsevier Inc.


Vandeleest J.J.,California National Primate Research Center | Vandeleest J.J.,University of California at Davis | Capitanio J.P.,California National Primate Research Center | Capitanio J.P.,University of California at Davis
American Journal of Primatology | Year: 2012

There is a great deal of variability in mother-infant interactions and infant behavior across the first year of life in rhesus monkeys. The current article has two specific aims: (1) to determine if birth timing predicts variability in the mother-infant relationship and infant behavior during weaning and maternal breeding, and (2) to identify predictors of infant behavior during a period of acute challenge, maternal breeding. Forty-one mother-infant pairs were observed during weaning when infants were 4.5 months old, and 33 were followed through maternal breeding. Subjective ratings of 16 adjectives reflecting qualities of maternal attitude, mother-infant interactions, and infant attitude were factor analyzed to construct factors relating to the mother-infant relationship (Relaxed and Aggressive) and infant behavior (Positive Engagement and Distress). During weaning, late born infants were more Positively Engaged than peak born infants (ANOVA, P < 0.05); however, birth timing did not affect the mother-infant relationship factors Relaxed and Aggressive or the infant attitude factor Distress. During maternal breeding, early born infants had less Relaxed relationships with their mothers than peak or late born infants, higher Positive Engagement scores than peak or late born infants, and tended to have higher Distress scores than peak born infants (repeated-measures ANOVA, P < 0.05). In addition, Distress scores were higher during maternal breeding than during the pre- and postbreeding phases. Finally, multiple regression (P < 0.05) indicated that while infant behavioral responsiveness predicted infant Positive Engagement during the acute challenge of maternal breeding, qualities of the mother-infant relationship predicted infant Distress. These data suggest that birth timing influences the patterns of mother-infant interactions during weaning and maternal breeding. Additionally, infant behavioral responsiveness and mother-infant relationship quality impact infant social engagement and affect expression, respectively. © 2012 Wiley Periodicals, Inc.


Brogan R.S.,Loyola College in Maryland | Mix S.,Loyola College in Maryland | Puttabyatappa M.,University of Maryland Baltimore County | VandeVoort C.A.,California National Primate Research Center | Chaffin C.L.,University of Maryland Baltimore County
Fertility and Sterility | Year: 2010

Objective: To determine intrafollicular hormone levels and characterize the mRNA expression of the insulin-like growth factor (IGF) receptors, IGF binding proteins (IGFBP), and pregnancy-associated plasma protein-A (PAPP-A) in granulosa cells before and after an ovulatory hCG stimulus. Design: Experimental animal study. Setting: Academic medical center. Animal(s): Adult rhesus macaques. Intervention(s): Animals received exogenous FSH to promote the development of multiple preovulatory follicles. Follicles were aspirated before (0 hours) or 3, 6, 12, or 24 hours after an ovulatory hCG bolus. Main Outcome Measure(s): IGF1, IGF2, and insulin levels in follicular fluid were determined by radioimmunoassay. Messenger RNA (mRNA) levels in granulosa cells were determined by real-time reverse transcriptase-polymerase chain reaction. IGFBPs and PAPP-A in follicular fluid were determined by Western blot analysis and enzyme-linked immunosorbent assay. Result(s): IGF1, IGF2, and insulin in follicular fluid did not change during luteinization. IGF1R, IGFBP1, and IGFBP2 mRNAs were unchanged by hCG. IGF2R, IGFBP3, -5, and -6 and PAPP-A mRNA levels increased after hCG administration, while insulin receptor and IGFBP4 mRNA levels decreased after hCG administration. IGFBP3 and -6 and PAPP-A protein increased after hCG administration. Conclusion(s): Dynamic changes in the expression of the IGFBPs and PAPP-A suggest tight regulation of IGF action during ovulation and corpus luteum formation. © 2010 American Society for Reproductive Medicine.


Machado C.J.,University of California | Machado C.J.,California National Primate Research Center | Whitaker A.M.,University of California | Whitaker A.M.,California National Primate Research Center | And 4 more authors.
Biological Psychiatry | Year: 2015

Background Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions. Methods We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study. Results As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images. Conclusions In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia. © 2015 Society of Biological Psychiatry.


VandeVoort C.A.,California National Primate Research Center | VandeVoort C.A.,University of California at Davis | Hill D.L.,California National Primate Research Center | Chaffin C.L.,University of Maryland Baltimore County | Conley A.J.,University of California at Davis
Alcoholism: Clinical and Experimental Research | Year: 2011

Background: The timing of the origins of fetal alcohol syndrome has been difficult to determine, in part because of the challenge associated with in vivo studies of the peri-implantation stage of embryonic development. Because embryonic stem cells (ESCs) are derived from blastocyst stage embryos, they are used as a model for early embryo development. Methods: Rhesus monkey ESC lines (ORMES-6 and ORMES-7) were treated with 0, 0.01, 0.1, or 1.0% ethanol, 1.0% ethanol with estradiol, or 0.00025% acetaldehyde with or without estradiol for 4weeks. Results: Although control ESCs remained unchanged, abnormal morphology of ESCs in the ethanol and acetaldehyde treatment groups was observed before 2weeks of treatment. Immunofluorescence staining of key pluripotency markers (TRA-1-81 and alkaline phosphatase) indicated a loss of ESC pluripotency in the 1.0% ethanol group. ORMES-7 was more sensitive to effects of ethanol than ORMES-6. Conclusions: Estradiol appeared to increase sensitivity to ethanol in the ORMES-6 and ORMES-7 cell line. The morphological changes and labeling for pluripotency, proliferation, and apoptosis demonstrated that how ethanol affects these early cells that develop in culture, their differentiation state in particular. The effects of ethanol may be mediated in part through metabolic pathways regulating acetaldehyde formation, and while potentially accentuated by estradiol in some individuals, how remains to be determined. © 2011 by the Research Society on Alcoholism.


Bales K.L.,University of California at Davis | Bales K.L.,California National Primate Research Center | Saltzman W.,University of California at Riverside
Hormones and Behavior | Year: 2016

This article is part of a Special Issue "Parental Care". Paternal care, though rare among mammals, is routinely displayed by several species of rodents. Here we review the neuroanatomical and hormonal bases of paternal behavior, as well as the behavioral and neuroendocrine consequences of paternal behavior for offspring. Fathering behavior is subserved by many of the same neural substrates which are also involved in maternal behavior (for example, the medial preoptic area of the hypothalamus). While gonadal hormones such as testosterone, estrogen, and progesterone, as well as hypothalamic neuropeptides such as oxytocin and vasopressin, and the pituitary hormone prolactin, are implicated in the activation of paternal behavior, there are significant gaps in our knowledge of their actions, as well as pronounced differences between species. Removal of the father in biparental species has long-lasting effects on behavior, as well as on these same neuroendocrine systems, in offspring. Finally, individual differences in paternal behavior can have similarly long-lasting, if more subtle, effects on offspring behavior. Future studies should examine similar outcome measures in multiple species, including both biparental species and closely related uniparental species. Careful phylogenetic analyses of the neuroendocrine systems presumably important to male parenting, as well as their patterns of gene expression, will also be important in establishing the next generation of hypotheses regarding the regulation of male parenting behavior. © 2015 Elsevier Inc.


The male contraceptive gel Vasalgel was shown effective in preventing pregnancies in trials conducted on a group of rhesus monkeys. Results of the trial, which was published in Basic and Clinical Andrology on Feb. 7, showed that despite typically high pregnancy rates of about 80 percent in female monkeys housed with males, no pregnancy occurred over the study period covering at least one breeding season when the males were treated with the contraceptive gel. The findings offer hope for a new birth control method that men can use. If proven effective and safe enough for humans, Vasalgel could be an alternative for vasectomy. "One of the great things about the monkey model is that the male reproductive tract is very similar to humans and they have even more sperm than humans do," said Catherine VandeVoort, from the California National Primate Research Center. "Chances are, it's going to be effective in humans." Withdrawal method and condoms are currently the best option for these men but withdrawal method poses high pregnancy risk and condoms can disrupt spontaneity during sexual contact. Although vasectomy is highly effective, it is poorly reversible, which means it is not the best option for those who need temporary protection. Based on earlier trials involving rabbits, Vasalgel could be a sort of a reversible vasectomy albeit results of animal studies still need to be replicated in humans. While other studies are also being conducted to develop a male hormonal contraceptive that can be as effective as the birth control pills taken by women, scientists are concerned over the unwanted side effects of these types treatment which include depression and soaring libido. The Vasalgel though does not interfere with the production of sperm nor changes the hormone levels in the body, which means that the side effects seen in hormone-altering pills, gels, and injections would not be an issue. While VandeVoort and colleagues reported that use of Vasalgel was well tolerated in monkey subjects, there are still issues and complications that arose due to use of the contraceptive gel. The researchers, for instance, inserted the gel into one of the 16 monkeys involved in the trial incorrectly. "Complications during Vasalgel placement in one animal (Animal 3) were associated with damage to the wall of the vas deferens, likely as a result of incorrect placement of the catheter, resulting in incomplete penetration of the wall of the vas deferens," the study researchers wrote in their study. "This resulted in extraluminal leakage of Vasalgel within the thin fibrous sheath surrounding the vas, likely weakening the overall structure." Another subject also developed sperm granuloma. The condition, which is caused by leaking sperm, is characterized by a lump of sperm forming at the site where the vas deferens, the tube that carries the sperm from the testes to the penis, is tied off. Granuloma commonly occurs after vasectomy. Inflammation, which also commonly occurs after vasectomy, however, was minimal with Vasalgel. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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