Primates Rhesus Research Articles

Obesity to Type 2 Diabetes Mellitus: Importance of Longitudinal Characterization of the Progressive Phases as Identified in Rhesus Monkeys Maintained Under Constant Diet and Environmental Conditions

The complex physiological mechanisms that underlie the links between obesity and T2DM involve “adiposity-induced” alterations in beta cell function —not yet mechanistically understood. Clearly the changes in beta cell function are greatly increased during the progression of obesity, --not reduced!! AND multiorgan insulin resistance whose mechanisms are unknown (although likely reduced by weight loss). Rhesus monkeys have shown these and have provided an amazing look at the Phases that lead to T2DM. We have previously summarized, in a table of 49 variables, the many ways that the nonhuman primate rhesus monkey offers exciting opportunities for insight into these extraordinary conditions compared to the human with T2DM. The Importance of longitudinal characterization, with a number of measurements that are regularly and periodically carried out to assess longitudinally some of the pathophysiological processes that develop spontaneously and naturally in these monkeys as they progress from normal, lean, young animals to obese animals with or without various physiological disturbances undergo the aging process. Usually these disturbances develop at varying rates in different monkeys and include hypertension, hyperlipidemia, hyperinsulinemia, hyperglycemia, impaired glucose tolerance, insulin resistance, peripheral neuropathy, impaired renal clearance, and cardiovascular disease—in short, the entire syndrome that becomes manifest in aged and diabetic humans. The longitudinal studies depend specifically on regular assessment of each animal and determination of the rate at which that animal is or is not progressing in the development of pathophysiological disturbances. Identification of phases allows one to estimate where a given monkey is in regard to the progression to overt diabetes. Application to humans will greatly increase our predictive ability to understand the mechanisms underlying both obesity and T2DM. NIA NO1AG3 1012. 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.

Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Nuclear transfer improves the developmental potential of embryos derived from cytoplasmic deficient oocytes

Embryo development after fertilization is largely determined by the oocyte quality, which is in turn dependent on the competence of both the cytoplasm and nucleus. Here, to improve the efficiency of embryo development from developmentally incompetent oocytes, we performed spindle-chromosome complex transfer (ST) between invitro matured (IVM) and invivo matured (IVO) oocytes of the non-human primate rhesus monkey. We observed that the blastocyst rate of embryos derived from transferring the spindle-chromosome complex (SCC) of IVM oocytes into enucleated IVO oocytes was comparable with that of embryos derived from IVO oocytes. After transferring the reconstructed embryos into the uterus of surrogate mothers, two live rhesus monkeys were obtained, indicating that the nuclei of IVM oocytes support both the pre-and post-implantation embryo development of non-human primates.

Humans recognize affective cues in primate vocalizations: acoustic and phylogenetic perspectives

Humans are adept at extracting affective information from vocalizations of humans and other animals. However, the extent to which human recognition of vocal affective cues of other species is due to cross-taxa similarities in acoustic parameters or the phylogenetic closeness between species is currently unclear. To address this, we first analyzed acoustic variation in 96 affective vocalizations, taken from agonistic and affiliative contexts, of humans and three other primates—rhesus macaques (Macaca mulatta), chimpanzees and bonobos (Pan troglodytes and Pan paniscus). Acoustic analyses revealed that agonistic chimpanzee and bonobo vocalizations were similarly distant from agonistic human voices, but chimpanzee affiliative vocalizations were significantly closer to human affiliative vocalizations, than those of bonobos, indicating a potential derived vocal evolution in the bonobo lineage. Second, we asked 68 human participants to categorize and also discriminate vocalizations based on their presumed affective content. Results showed that participants reliably categorized human and chimpanzee vocalizations according to affective content, but not bonobo threat vocalizations nor any macaque vocalizations. Participants discriminated all species calls above chance level except for threat calls by bonobos and macaques. Our results highlight the importance of both phylogenetic and acoustic parameter level explanations in cross-species affective perception, drawing a more complex picture to the origin of vocal emotions.

A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.

BackgroundScrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed.Methodology/principle findingsWe evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses.Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function.Conclusions/significanceThis study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development.

Non-human Primate Macaca mulatta as an Animal Model for Testing Efficacy of Amixicile as a Targeted Anti-periodontitis Therapy.

Periodontitis is an inflammatory condition triggered by selected oral microbiota; thus treatment strategies should be aimed at reducing the abundance of the pathogenic bacteria. An obstacle to preclinical testing of such strategies is the availability of reliable animal models. Here, a non-human primate (NHP), Macaca mulatta, was used to examine the effectiveness of a novel antimicrobial, amixicile, which inhibits pyruvate–ferredoxin oxidoreductase (PFOR) present in anaerobic bacteria. Animals were assessed for their periodontal health, including radiography, clinical attachment loss (CAL), presence of plaque (PI), bleeding on probing (BOP) and pocket depth (PD), and sampled for saliva, gingival crevicular fluid (GCF), and subgingival plaque to determine their baseline clinical status. Amixicile was then administered for 2 weeks (40 mg/kg/day) and the animals were monitored for periodontal health immediately after the antibiotic treatment, then at 1 month-, 3 months-, and 6-months posttreatment. Microbial species present in plaque and saliva were determined through 16S rDNA sequencing. Baseline assessment of the microbiome has shown a significant proportion of bacteria belonging to the Streptococcus, Haemophilus, Porphyromonas, Gemella, and Fusobacterium genera. The abundance of Porphyromonas and Fusobacterium was reduced following treatment with amixicile, whereas that of Escherichia, Haemophilus, and Gemella were elevated. CAL, PD, and BOP were also significantly reduced following the treatment. In conclusion, the NHP model proves useful for preclinical studies of strategies targeting selected members of the oral microbiome. We show that amixicile reduces the levels of anaerobic bacteria under in vivo conditions, correlating with a reduction in CAL, PD, and BOP, thus validating its usefulness as an antimicrobial strategy.

Clinicopathologic and Transcriptomic Analysis of Radiation-Induced Lung Injury in Nonhuman Primates.

Radiation-induced lung injury (RILI) is a progressive condition with an early phase (radiation pneumonitis) and a late phase (lung fibrosis). RILI may occur after partial-body ionizing radiation exposures or internal radioisotope exposure, with wide individual variability in timing and extent of lung injury. This study aimed to provide new insights into the pathogenesis and progression of RILI in the nonhuman primate (NHP) rhesus macaque model. We used an integrative approach to understand RILI and its evolution at clinical and molecular levels in 17 NHPs exposed to 10 Gy of whole-thorax irradiation in comparison with 3 sham-irradiated control NHPs. Clinically, we monitored respiratory rates, computed tomography (CT) scans, plasma cytokine levels, and bronchoalveolar lavage (BAL) over 8 months and lung samples collected at necropsy for molecular and histopathologic analyses using RNA sequencing and immunohistochemistry. Elevated respiratory rates, greater CT density, and more severe pneumonitis with increased macrophage content were associated with early mortality. Radiation-induced lung fibrosis included polarization of macrophages toward the M2-like phenotype, TGF-β signaling, expression of CDKN1A/p21 in epithelial cells, and expression of α-SMA in lung stroma. RNA sequencing analysis of lung tissue revealed SERPINA3, ATP12A, GJB2, CLDN10, TOX3, and LPA as top dysregulated transcripts in irradiated animals. In addition to transcriptomic data, we observed increased protein expression of SERPINA3, TGF-β1, CCL2, and CCL11 in BAL and plasma samples. Our combined clinical, imaging, histologic, and transcriptomic analysis provides new insights into the early and late phases of RILI and highlights possible biomarkers and potential therapeutic targets of RILI. Activation of TGF-β and macrophage polarization appear to be key mechanisms involved in RILI.

Intramuscular Administration of Placenta-Derived Stromal Cells Enhances Survival of Rhesus Macaque Monkeys Exposed to Total Body Irradiation

Placenta-derived stromal cells named PLX-R18 have been shown in-vitro to secrete pro-hematopoiesis proteins, induce bone marrow migration, and promote colony formation. Murine in-vivo studies indicated that placental cells are capable of reducing lethality from the Hematopoietic Sub-syndrome of Acute Radiation Syndrome (HS-ARS).A NIAID-supported pilot study with non-human primate (NHP) rhesus macaque monkeys was conducted with the objective to characterize the effect of PLX-R18 on HS-ARS, including survival and hematological parameters in irradiated NHP. 62 male and female rhesus macaque monkeys were divided into irradiated and non-irradiated cohorts. Non-irradiated or irradiated NHPs were treated with three intramuscular doses of PLX-R18 at 1 and 5 days post irradiation, or with placebo control. All doses of PLX-R18 improved outcome of irradiated NHPs relative to placebo (dose of 4, 10 and 20M cells/kg increased survival by 33.3, 35.7 and 16.7% respectively).A tendency towards earlier recovery of blood lineages was evident in all doses tested, particularly, for the two lower doses. The 4 million cells/kg dose of PLX-R18 reduced the duration of critical neutropenia, thrombocytopenia, and anemia (NEUT< 0.1x10^9/L, PLT< 10x10^9/L, HGB< 65 g/L) by 1.5, 1.5, and 0.7 days respectively. Importantly, NHP results recapitulate findings from mouse studies with respect to non-irradiated animals in that hematological parameters are minimally affected.Taken together, all doses of PLX-R18 positively affected survival rates and multiple hematological parameters of HS-ARS in rhesus monkeys and had no negative effects in either irradiated or non-irradiated monkeys. This supports the intended development of PLX-R18 as a treatment for HS-ARS. DisclosuresSher:Pluristem LTD: Employment, Equity Ownership. Prezma:Pluristem LTD: Employment, Equity Ownership. Fuchs-Telem:Pluristem LTD: Employment, Equity Ownership. Shraga- Heled:Pluristem LTD: Employment, Equity Ownership. Authier:CiToxLAB: Employment. Chang:SRI International: Employment. Ascah:CiToxLAB: Employment. Bakke:SRI International: Employment. Gahagen:SRI International: Employment. Ofir:Pluristem LTD: Employment, Equity Ownership.

Attention reduces the burstiness of V1 neurons involved in attended target enhancement.

Attention-dependent reduction in the tendency for neurons to fire bursts (burstiness) is widely observed in the visual cortex. However, the underlying mechanism and the functional role of this phenomenon remain unclear. We recorded well-isolated single-unit activities in primary visual cortex (V1) from two primates (Macaca mulatta) while they performed a detection task engaging spatial attention with two levels of difficulty (hard/easy). We found that attention modulated burstiness of V1 neurons in a cell-type specific manner. For neurons whose net response enhanced with the increase of task difficulty (difficulty-enhanced neuron), representing their involvement in boosting the signal of the attended stimulus, attention led to a reduction in burstiness during hard task but not during easy task. In contrast, regardless of the level of task difficulty, attention-dependent reduction in burstiness was not observed in neurons that showed a net suppression in firing rate with the increase of task difficulty (difficulty-suppressed neuron), indicating their commitment in filtering out the interference of distractor. This differentiation in the effects of attentional modulation on burstiness among the cells with distinct functional roles in attention suggests that the reduction in burstiness by attention is linked to target enhancement and is not associated with distractor suppression.

A Special Cranial Nucleus (CSF-Contacting Nucleus) in Primates.

BackgroundThere is a unique nucleus (CSF-contacting nucleus) in the brain of rat. It has been demonstrated in our previous research. The extraordinary feature of this nucleus is that it is not connected to any parenchymal organ but to the CSF. In primates, however, the presence or absence of this nucleus has not been proven. Confirmation of the presence of this nucleus in primates will provide the structural basis for brain-CSF communication and help to understand the neurohumoral regulatory mechanisms in humans.MethodsThe tracer cholera toxin B subunit conjugated to horseradish peroxidase (CB-HRP) was injected into the CSF in the lateral ventricle (LV) of primate rhesus monkeys. After 48 h, the monkeys were perfused and the brain was dissected out, and sectioned for CB-HRP staining. The CB-HRP positive structures were observed under confocal and electron microscopy. The three-dimensional (3D) structure of the CB-HRP positive neurons cluster was reconstructed by computer software.Results(1) CB-HRP labeling is confined within the ventricle, but not leakage into the brain parenchyma. (2) From the midbrain inferior colliculus superior border plane ventral to the aqueduct to the upper part of the fourth ventricle (4V) floor, a large number of CB-HRP positive neurons are consistently located, form a cluster, and are symmetrically located on both sides of the midline. (3) 3D reconstruction shows that the CB-HRP positive neurons cluster in the monkey brain occupies certain space. The rostral part is large and caudal part is thin appearing a “rivet”-like shape. (4) Under electron microscopy, the CB-HRP positive neurons show different types of synaptic connections with the non-CSF-contacting structures in the brain. Some of the processes stretch directly into the ventricle cavity.ConclusionSame as we did in rats, the CSF-contacting nucleus is also existed in the primate brain parenchyma. We also recommend listing it as the XIII pair of cranial nucleus, which is specialized in the communications between the brain and the CSF. It is significant to the completing of innervation in the organism.

Abstract P6-14-13: New approach to nipple reconstruction: In vivo evaluation of acellular nipple-areolar complex grafts

Abstract There are over 3M breast cancer survivors in the US, many of whom have undergone breast reconstructive surgery. With one-third of early stage and two-thirds of late-stage breast cancer patients opting for mastectomies without a standard, viable method to reliably reconstruct a permanent and natural nipple-areolar complex (NAC). NAC reconstruction is of key psychological importance for these patients, decreasing feelings of distress and increasing body image and self-esteem. Current NAC reconstruction options include rubber prostheses, 3D tattoos, and surgical techniques to create NAC-like structures from a patient’s own skin tissue. These approaches produce NACs that either lack physical depth or fail to maintain a protrusion. The objectives of the non-human primate 6 week engraftment studies with our decellularized human nipple areolar complex (hNAC) grafts were 1) to determine the biocompatibility of the hNAC graft and 2) to measure host-mediated recellularization of the hNAC graft on a nearest-to-human model species. If the hNAC graft maintains cell-derived insoluble matrix components yet is devoid of host cells, intracellular material, and pathogenic organisms, then the hNAC graft will not elicit an adverse humoral response and will show both good biocompatibility and recellularization. The methods employed for our studies involved surgical engraftment of the hNAC graft along the dorsal midline of three adult male non-human primates (rhesus macaque). The number of hNAC grafts engrafted for each NHP was 12 for one NHP and 18 for the other two. Gross animal weight, complete blood count data, and metabolite data were collected weekly from periods before, during (span of 6-weeks), and after hNAC engraftment for each animal. In addition, hNACs were surgically removed at defined weekly time points during the study for histological analysis of recellularization. All data was compiled for each study and statistically analyzed separately and combined. Statistical analyses included unpaired, parametric comparisons of systemic indicators (i.e. weight, complete blood count, metabolites) at each period of the study and of re-epithelialization and neovascular content for individual hNAC grafts during host-mediated recellularization over time. The results from this NHP study demonstrate good evidence of biocompatibility of the hNAC on non-human primates. Gross body weight remained unchanged for all NHPs and complete blood counts (e.g. red blood cells, white blood cells, platelets) and metabolites remained mostly within normal ranges for all NHPs. The hNAC grafts did not effect liver, kidney, or pancreas function. The hNAC grafts showed good recellularization during the study with significant increases measured for re-epithelialization and neovascularization. Histological analysis further revealed functioning microvasculature within grafts as early as 3-weeks post-engraftment. These data suggest that the hNAC graft is biocompatible and capable of recellularization. The presence of de novo epithelia and vasculature within the hNAC grafts collectively support recellularization and regeneration of a hNAC. Citation Format: David Graham, William Heim, Vincent Caronna, Abigail Chaffin, Brooke Grasperge, Scott Sullivan, Bruce A Bunnell, Nicholas C Pashos. New approach to nipple reconstruction: In vivo evaluation of acellular nipple-areolar complex grafts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-14-13.

Alveolar bone repair of rhesus monkeys by using BMP-2 gene and mesenchymal stem cells loaded three-dimensional printed bioglass scaffold

Over the past years, the study about bone tissue engineering in the field of regenerative medicine has been a main research topic. Using three-dimensional (3D) porous degradable scaffold complexed with mesenchymal stem cells (MSCs) and growth factor gene to improve bone tissue repair and regeneration has raised much interest. This study mainly evaluated the osteogenesis of alveolar bone defects of animal in the following experimental groups: sham-operated (SO), 3D printed bioglass (3D-BG), 3D-BG with BMP-2 gene loaded CS (3D-BG + BMP/CS) and 3D-BG with rhesus marrow bone MSCs and BMP/CS (3D-BG + BMP/CS + rBMSCs). Simulated human bone defect with critical size of 10 × 10 × 5 mm were established in quadrumana - rhesus monkeys, and in vivo osteogenesis was characterized by X-ray, micro-Computed Tomography (mCT) and history. Our results revealed that 3D-BG + rBMSCs + BMP/CS scaffold could improve bone healing best by showing its promote osteogenic properties in vivo. Considering the great bone repair capacity of 3D-BG + BMP/CS + rBMSCs in humanoid primate rhesus monkeys, it could be a promising therapeutic strategy for surgery trauma or accidents, especially for alveolar bones defects.

Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.

Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function. To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs). Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and 3H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison. MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of 3H-muscimol (Vd; R=0.94). Mean Vd of infused animals was 37.9 mm3±11.7 mm3 and mean Vd: Vi 7.6±2.3. Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.

SILAC-based quantitative proteomic analysis of the livers of spontaneous obese and diabetic rhesus monkeys.

Type 2 diabetes mellitus (T2DM) is a severe metabolic disorder that affects more than 10% of the population worldwide. Obesity is a major cause of insulin resistance and contributes to the development of T2DM. Liver is an essential metabolic organ that plays crucial roles in the pathogenesis of obesity and diabetes. However, the underlying mechanisms of liver in the transition of obesity to diabetes are not fully understood. The nonhuman primate rhesus monkey is an appropriate animal for research of human diseases. Here, we first screened and selected three individuals of spontaneously diabetic rhesus monkeys. Interestingly, the diabetic monkeys were obese with a high body mass index at the beginning, but gradually lost their body weight during one year of observation. Furthermore, we performed stable isotope labeling with amino acids in cell culture-based quantitative proteomics to identify proteins and signaling pathways with altered expression in the liver of obese and diabetic monkeys. In total, 3,509 proteins were identified and quantified, of which 185 proteins displayed an altered expression level. Gene ontology analysis revealed that the expression of proteins involved in fatty acids β-oxidation and galactose metabolism was increased in obese monkeys; while proteins involved in oxidative phosphorylation and branched chain amino acid (BCAA) degradation were upregulated in diabetic monkeys. In addition, we observed mild apoptosis in the liver of diabetic monkeys, suggesting liver injury at the late onset of diabetes. Taken together, our liver proteomics may reveal a distinct metabolic transition from fatty acids β-oxidation in obese monkey to BCAA degradation in diabetic monkeys.

A Distinctive Platform System to Study the Effects of a Vestibular Prosthesis on Nonhuman Primate Postural Control

The purpose of this paper is to describe novel experiments and methodologies utilizing a distinctive balance platform system to investigate postural responses for moderate to severe vestibular loss and invasive vestibular prosthesis-assisted nonhuman primates (rhesus monkeys). For several millions of vestibular loss sufferers in the U.S., daily living is severely affected in that common everyday tasks, such as getting out of bed at night, maintaining balance on a moving bus, or walking on an uneven surface, may cause a loss of stability leading to falls and injury. Aside from loss of balance, blurred vision and vertigo (perceived spinning sensation) are also debilitating in vestibular-impaired individuals. Although the need for vestibular rehabilitative solutions is apparent, postural responses for a broad range of peripheral vestibular function, and for various stationary and moving support conditions, have not been systematically investigated. For the investigation of implants and prostheses that are being developed toward implementation in humans, nonhuman primates are a key component. The measurement system used in this research was unique. Our platform system facilitated the study of rhesus monkey posture for stationary support surface conditions (quiet stance and head turns) and for dynamic support surface conditions (pseudorandom roll tilts of the support surface). Further, the platform system was used to systematically study postural responses that will serve as baseline measures for future vestibular-focused human and nonhuman primate posture studies.

Decreased Rhes mRNA levels in the brain of patients with Parkinson's disease and MPTP-treated macaques.

In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson’s disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.

Representation of Rapid Image Sequences in V4 Networks

Natural viewing often consists of sequences of brief fixations to image patches of different structure. Whether and how briefly presented sequential stimuli are encoded in a temporal-position manner is poorly understood. Here, we performed multiple-electrode recordings in the visual cortex (area V4) of nonhuman primates (Macaca mulatta) viewing a sequence of 7 briefly flashed natural images, and measured correlations between the cue-triggered population response in the presence and absence of the stimulus. Surprisingly, we found significant correlations for images occurring at the beginning and the end of a sequence, but not for those in the middle. The correlation strength increased with stimulus exposure and favored the image position in the sequence rather than image identity. These results challenge the commonly held view that images are represented in visual cortex exclusively based on their informational content, and indicate that, in the absence of sensory information, neuronal populations exhibit reactivation of stimulus-evoked responses in a way that reflects temporal position within a stimulus sequence.

Characterization of an Acellular Scaffold for a Tissue Engineering Approach to the Nipple-Areolar Complex Reconstruction

A significant number of patients undergo mastectomies and breast reconstructions every year using many surgical-based techniques to reconstruct the nipple-areolar complex (NAC). Described herein is a tissue engineering approach that may permit a human NAC onlay graft during breast reconstruction procedures. By applying decellularization, which is the removal of cellular components from tissue, to an intact whole donor NAC, the extracellular matrix (ECM) structure of the NAC is preserved. This creates a biologically derived scaffold for cells to repopulate and regenerate the NAC. A detergent-based decellularization method was used to derive whole NAC scaffolds from nonhuman primate rhesus macaque NAC tissue. Using both histological and quantitative analyses for the native and decellularized tissues, the derived ECM graft was assessed. The bioactivity of the scaffold was evaluated following cell culture with bone marrow-derived mesenchymal stem cells (BMSCs). The data presented here demonstrate that scaffolds are devoid of cells and retain ECM integrity and a high degree of bioactivity. The content of collagen and glycosaminoglycans were not significantly altered by the decellularization process, whereas the elastin content was significantly decreased. The proliferation and apoptosis of seeded BMSCs were found to be approximately 65 and <1.5%, respectively. This study characterizes the successful decellularization of NAC tissue as compared to native NACs based on structural protein composition, lubricating protein retention, the maintenance of adhesion molecules, and bioactivity when reseeded with cells. These histological and quantitative analyses provide the foundation for a novel approach to NAC reconstruction.

UNC-Emory Infant Atlases for Macaque Brain Image Analysis: Postnatal Brain Development through 12 Months.

Computational anatomical atlases have shown to be of immense value in neuroimaging as they provide age appropriate reference spaces alongside ancillary anatomical information for automated analysis such as subcortical structural definitions, cortical parcellations or white fiber tract regions. Standard workflows in neuroimaging necessitate such atlases to be appropriately selected for the subject population of interest. This is especially of importance in early postnatal brain development, where rapid changes in brain shape and appearance render neuroimaging workflows sensitive to the appropriate atlas choice. We present here a set of novel computation atlases for structural MRI and Diffusion Tensor Imaging as crucial resource for the analysis of MRI data from non-human primate rhesus monkey (Macaca mulatta) data in early postnatal brain development. Forty socially-housed infant macaques were scanned longitudinally at ages 2 weeks, 3, 6, and 12 months in order to create cross-sectional structural and DTI atlases via unbiased atlas building at each of these ages. Probabilistic spatial prior definitions for the major tissue classes were trained on each atlas with expert manual segmentations. In this article we present the development and use of these atlases with publicly available tools, as well as the atlases themselves, which are publicly disseminated to the scientific community.

Development of a Nonhuman Primate (Rhesus Macaque) Model of Uncontrolled Traumatic Liver Hemorrhage

Development of a Nonhuman Primate (Rhesus Macaque) Model of Uncontrolled Traumatic Liver Hemorrhage