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Briefly discusses the causes of unfavourable interactions between humans and free-living non-human primates, and alternatives to lethal methods of resolving these.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anesthetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, suggesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaqueV1 and V2 and simultaneouslymeasured behavioral judgments of texture. We generated stimuli along a continuumbetween naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior comparedwith V1. The firing of both V1 andV2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the secondmonkey. We conclude that neural responses supporting texture perception likely continue to develop downstreamof V2. Further, combined with neural data recordedwhile the same twomonkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and therefore unlikely to directly reflect the formation of perceptual decisions. [ABSTRACT FROM AUTHOR]

Nonhuman primate (NHP) studies that utilize simian immunodeficiency virus (SIV) to model human immunodeficiency virus (HIV-1) infection have proven to be powerful, highly informative research tools. However, there are substantial differences between SIV and HIV-1. Accordingly, there are numerous research questions for which SIV-based models are not well suited, including studies of certain aspects of basic HIV-1 biology, and pre-clinical evaluations of many proposed HIV-1 treatment, prevention, and vaccination strategies. To overcome these limitations of NHP models of HIV-1 infection, several groups have pursued the derivation of a minimally modified HIV-1 (mmHIV-1) capable of establishing pathogenic infection in macaques that authentically recapitulates key features of HIV-1 in humans. These efforts have focused on three complementary objectives: (1) engineering HIV-1 to circumvent species-specific cellular restriction factors that otherwise potently inhibit HIV-1 in macaques, (2) introduction of a C chemokine receptor type 5 (CCR5)-tropic envelope, ideally that can efficiently engage macaque CD4, and (3) correction of gene expression defects inadvertently introduced during viral genome manipulations. While some progress has been made toward development of mmHIV-1 variants for use in each of the three macaque species (pigtail, cynomolgus, and rhesus), model development progress has been most promising in pigtail macaques (PTMs), which do not express an HIV-1-restricting tripartite motif-containing protein 5 α (TRIM5α). In our work, we have derived a CCR5-tropic mmHIV-1 clone designated stHIV-A19 that comprises 94% HIV-1 genome sequence and replicates to high acute-phase titers in PTMs. In animals treated with a cell-depleting CD8α antibody at the time of infection, stHIV-A19 maintains chronically elevated plasma viral loads with progressive CD4+ T-cell loss and the development of acquired immune-deficiency syndrome (AIDS)-defining clinical endpoints. However, in the absence of CD8α+ cell depletion, no mmHIV-1 model has yet displayed high levels of chronic viremia or AIDS-like pathogenesis. Here, we review mmHIV-1 development approaches, the phenotypes, features, limitations, and potential utility of currently available mmHIV-1s, and propose future directions to further advance these models. [ABSTRACT FROM AUTHOR]

The frontal eye field (FEF) plays a well-established role in the control of visual attention. The strength of an FEF neuron’s response to a visual stimulus presented in its receptive field is enhanced if the stimulus captures spatial attention by virtue of its salience. A stimulus can be rendered salient by cognitive factors as well as by physical attributes. These include surprise. The aim of the present experiment was to determine whether surprise-induced salience would result in enhanced visual-response strength in the FEF. Toward this end, we monitored neuronal activity in two male monkeys while presenting first a visual cue predicting with high probability that the reward delivered at the end of the trial would be good or bad (large or small) and then a visual cue announcing the size of the impending reward with certainty. The second cue usually confirmed but occasionally violated the expectation set up by the first cue. Neurons responded more strongly to the second cue when it violated than when it confirmed expectation. The increase in the firing rate was accompanied by a decrease in spike-count correlation as expected from capture of attention. Although both good surprise and bad surprise induced enhanced firing, the effects appeared to arise from distinct mechanisms as indicated by the fact that the bad-surprise signal appeared at a longer latency than the good-surprise signal and by the fact that the strength of the two signals varied independently across neurons. [ABSTRACT FROM AUTHOR]

Abstract Heart rate (HR) and respiration rate (RR) play an important role in the study of complex behaviors and their physiological correlations in non-human primates (NHPs). However, collecting HR and RR information is often challenging, involving either invasive implants or tedious behavioral training, and there are currently few established simple and non-invasive techniques for HR and RR measurement in NHPs owing to their stress response or indocility. In this study, we employed a frequency-modulated continuous wave (FMCW) radar to design a novel contactless HR and RR monitoring system. The designed system can estimate HR and RR in real time by placing the FMCW radar on the cage and facing the chest of both awake and anesthetized macaques, the NHP investigated in this study. Experimental results show that the proposed method outperforms existing methods, with averaged absolute errors between the reference monitor and radar estimates of 0.77 beats per minute (bpm) and 1.29 respirations per minute (rpm) for HR and RR, respectively. In summary, we believe that the proposed non-invasive and contactless estimation method could be generalized as a HR and RR monitoring tool for NHPs. Furthermore, after modifying the radar signal-processing algorithms, it also shows promise for applications in other experimental animals for animal welfare, behavioral, neurological, and ethological research.

Abstract The dorsal pulvinar has been implicated in visuospatial attentional and perceptual confidence processing. Pulvinar lesions in humans and monkeys lead to spatial neglect symptoms, including an overt spatial saccade bias during free choices. However, it remains unclear whether disrupting the dorsal pulvinar during target selection that relies on a perceptual decision leads to a perceptual impairment or a more general spatial orienting and choice deficit. To address this question, we reversibly inactivated the unilateral dorsal pulvinar by injecting GABA-A agonist THIP while two macaque monkeys performed a color discrimination saccade task with varying perceptual difficulty. We used Signal Detection Theory and simulations to dissociate perceptual sensitivity (d-prime) and spatial selection bias (response criterion) effects. We expected a decrease in d-prime if dorsal pulvinar affects perceptual discrimination and a shift in response criterion if dorsal pulvinar is mainly involved in spatial orienting. After the inactivation, we observed response criterion shifts away from contralesional stimuli, especially when two competing stimuli in opposite hemifields were present. Notably, the d-prime and overall accuracy remained largely unaffected. Our results underline the critical contribution of the dorsal pulvinar to spatial orienting and action selection while showing it to be less important for visual perceptual discrimination.

The progressive degradation in the trabecular meshwork (TM) is related to age-related ocular diseases like primary open-angle glaucoma. However, the molecular basis and biological significance of the aging process in TM have not been fully elucidated. Here, we established a dynamic single-cell transcriptomic landscape of aged macaque TM, wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM aging. Furthermore, we divided TM cells into 13 clusters and performed an in-depth analysis on cluster 0, which had the highest aging score and the most significant changes in cell proportions between the two groups. Ultimately, we found that the APOE gene was an important differentially expressed gene in cluster 0 during the aging process, highlighting the close relationship between cell migration and extracellular matrix regulation, and TM function. Our work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components, thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal range. Our work provides valuable insights for future clinical diagnosis and treatment of glaucoma. [ABSTRACT FROM AUTHOR]

Heart rate (HR) and respiration rate (RR) play an important role in the study of complex behaviors and their physiological correlations in non-human primates (NHPs). However, collecting HR and RR information is often challenging, involving either invasive implants or tedious behavioral training, and there are currently few established simple and non-invasive techniques for HR and RR measurement in NHPs owing to their stress response or indocility. In this study, we employed a frequency-modulated continuous wave (FMCW) radar to design a novel contactless HR and RR monitoring system. The designed system can estimate HR and RR in real time by placing the FMCW radar on the cage and facing the chest of both awake and anesthetized macaques, the NHP investigated in this study. Experimental results show that the proposed method outperforms existing methods, with averaged absolute errors between the reference monitor and radar estimates of 0.77 beats per minute (bpm) and 1.29 respirations per minute (rpm) for HR and RR, respectively. In summary, we believe that the proposed non-invasive and contactless estimation method could be generalized as a HR and RR monitoring tool for NHPs. Furthermore, after modifying the radar signal-processing algorithms, it also shows promise for applications in other experimental animals for animal welfare, behavioral, neurological, and ethological research. [ABSTRACT FROM AUTHOR]

Cytoarchitecture, the organization of cells within organs and tissues, serves as a crucial anatomical foundation for the delineation of various regions. It enables the segmentation of the cortex into distinct areas with unique structural and functional characteristics. While traditional 2D atlases have focused on cytoarchitectonic mapping of cortical regions through individual sections, the intricate cortical gyri and sulci demands a 3D perspective for unambiguous interpretation. In this study, we employed fluorescent micro-optical sectioning tomography to acquire architectural datasets of the entire macaque brain at a resolution of 0.65 µm × 0.65 µm × 3 µm. With these volumetric data, the cortical laminar textures were remarkably presented in appropriate view planes. Additionally, we established a stereo coordinate system to represent the cytoarchitectonic information as surface-based tomograms. Utilizing these cytoarchitectonic features, we were able to three-dimensionally parcel the macaque cortex into multiple regions exhibiting contrasting architectural patterns. The whole-brain analysis was also conducted on mice that clearly revealed the presence of barrel cortex and reflected biological reasonability of this method. Leveraging these high-resolution continuous datasets, our method offers a robust tool for exploring the organizational logic and pathological mechanisms of the brain's 3D anatomical structure. [ABSTRACT FROM AUTHOR]

The dorsal pulvinar has been implicated in visuospatial attentional and perceptual confidence processing. Pulvinar lesions in humans and monkeys lead to spatial neglect symptoms, including an overt spatial saccade bias during free choices. However, it remains unclear whether disrupting the dorsal pulvinar during target selection that relies on a perceptual decision leads to a perceptual impairment or a more general spatial orienting and choice deficit. To address this question, we reversibly inactivated the unilateral dorsal pulvinar by injecting GABA-A agonist THIP while two macaque monkeys performed a color discrimination saccade task with varying perceptual difficulty. We used Signal Detection Theory and simulations to dissociate perceptual sensitivity (d-prime) and spatial selection bias (response criterion) effects. We expected a decrease in d-prime if dorsal pulvinar affects perceptual discrimination and a shift in response criterion if dorsal pulvinar is mainly involved in spatial orienting. After the inactivation, we observed response criterion shifts away from contralesional stimuli, especially when two competing stimuli in opposite hemifields were present. Notably, the d-prime and overall accuracy remained largely unaffected. Our results underline the critical contribution of the dorsal pulvinar to spatial orienting and action selection while showing it to be less important for visual perceptual discrimination. [ABSTRACT FROM AUTHOR]

BackgroundEpidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.MethodsIn this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.Results[18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.ConclusionsThese findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

Abstract Necrophilic behavior (attempted copulation with corpses) has been scarcely reported in non-human primates, especially in the wild. Here is the first case of necrophilic behavior observed in wild stump-tailed macaques in Thailand. Six groups of total N > 460 individuals have been identified and habituated. The corpse of an adult female was found and directly observed for 2 days and by camera trap for 3 days. The cause of death could not be identified, but no prominent physical injury was detected. Within 3 days of the observation, three different males attempted copulation with the corpse. Noteworthy for this observation was that not only males in the group of the dead female but also males from different groups interacted with the corpse. Taken together, these observations suggest that some cues emanating from the corpse coupled with a nonresistant/passive orientation may have triggered these responses in the males. Given that necrophiliac responses have been scarcely reported in non-human primates, our findings provide new insight into these behaviors and to comparative thanatology in general.

IntroductionRhesus macaques are natural hosts to multiple viruses including rhesus cytomegalovirus (RhCMV), rhesus rhadinovirus (RRV), and Simian Foamy Virus (SFV). While viral infections are ubiquitous, viral transmissions to uninfected animals are incompletely defined. Management procedures of macaque colonies include cohorts that are Specific Pathogen Free (SPF). Greater understanding of viral transmission would augment SPF protocols. Moreover, vaccine/challenge studies of human viruses would be enhanced by leveraging transmission of macaque viruses to recapitulate expected challenges of human vaccine trials.Materials and methodsThis study characterizes viral transmissions to uninfected animals following inadvertent introduction of RhCMV/RRV/SFV-infected adults to a cohort of uninfected juveniles. Following co-housing with virus-positive adults, juveniles were serially evaluated for viral infection.ResultsHorizontal viral transmission was rapid and absolute, reaching 100% penetrance between 19 and 78 weeks.ConclusionsThis study provides insights into viral natural histories with implications for colony management and modeling vaccine-mediated immune protection studies.

Necrophilic behavior (attempted copulation with corpses) has been scarcely reported in non-human primates, especially in the wild. Here is the first case of necrophilic behavior observed in wild stump-tailed macaques in Thailand. Six groups of total N > 460 individuals have been identified and habituated. The corpse of an adult female was found and directly observed for 2 days and by camera trap for 3 days. The cause of death could not be identified, but no prominent physical injury was detected. Within 3 days of the observation, three different males attempted copulation with the corpse. Noteworthy for this observation was that not only males in the group of the dead female but also males from different groups interacted with the corpse. Taken together, these observations suggest that some cues emanating from the corpse coupled with a nonresistant/passive orientation may have triggered these responses in the males. Given that necrophiliac responses have been scarcely reported in non-human primates, our findings provide new insight into these behaviors and to comparative thanatology in general. [ABSTRACT FROM AUTHOR]

Simple Summary: Monkeys in urban spaces are often labeled as 'pests' by people who share spaces with them, mainly driven by their behavior to adapt and survive in a human-dominated environment. In Malaysia, there has been an increase in complaints about urban monkeys, which drives management strategies mainly to reduce human populations that impact the animals' welfare and conservation. Understanding the dynamics between monkeys, people, and the urban ecosystem is the first step to identifying the drivers of the complaints. This study investigates the types of ecological activities of the long-tailed macaque (Macaca fascicularis) at an urban tourism site and how human activity influences it. Monkeys were impacted negatively by the presence of humans. Less affiliative interactions were performed when human traffic was high; for example, less social behavior was seen in the group. The monkeys also used anthropogenic structures predominantly when people were present and would spend time on natural structures when people were not. This study supports evidence that monkeys alter behaviors to adapt to living in urban spaces. A structured management plan needs to consider these dynamics to manage complaints. The increasing overlap of resources between human and long-tailed macaque (Macaca fascicularis) (LTM) populations have escalated human–primate conflict. In Malaysia, LTMs are labeled as a 'pest' species due to the macaques' opportunistic nature. This study investigates the activity budget of LTMs in an urban tourism site and how human activities influence it. Observational data were collected from LTMs daily for a period of four months. The observed behaviors were compared across differing levels of human interaction, between different times of day, and between high, medium, and low human traffic zones. LTMs exhibited varying ecological behavior patterns when observed across zones of differing human traffic, e.g., higher inactivity when human presence is high. More concerning is the impact on these animals' welfare and group dynamics as the increase in interactions with humans takes place; we noted increased inactivity and reduced intra-group interaction. This study highlights the connection that LTMs make between human activity and sources of anthropogenic food. Only through understanding LTM interaction can the cause for human–primate conflict be better understood, and thus, more sustainable mitigation strategies can be generated. [ABSTRACT FROM AUTHOR]

Non-human primates (NHPs) are pivotal animal models for translating novel cell replacement therapies into clinical applications, including validating the safety and efficacy of induced pluripotent stem cell (iPSC)-derived products. Preclinical development and the testing of cell-based therapies ideally comprise xenogeneic (human stem cells into NHPs) and allogenic (NHP stem cells into NHPs) transplantation studies. For the allogeneic approach, it is necessary to generate NHP-iPSCs with generally equivalent quality to the human counterparts that will be used later on in patients. Here, we report the generation and characterization of transgene- and feeder-free cynomolgus monkey (Macaca fascicularis) iPSCs (Cyno-iPSCs). These novel cell lines have been generated according to a previously developed protocol for the generation of rhesus macaque, baboon, and human iPSC lines. Beyond their generation, we demonstrate the potential of the novel Cyno-iPSCs to differentiate into two clinically relevant cell types, i.e., cardiomyocytes and neurons. Overall, we provide a resource of novel iPSCs from the most frequently used NHP species in the regulatory testing of biologics and classical pharmaceutics to expand our panel of iPSC lines from NHP species with high relevance in preclinical testing and translational research. [ABSTRACT FROM AUTHOR]

Simple Summary: Although alopecia is prevalent among captive rhesus macaques, its cause is not well understood. Poor coat quality may raise concerns because it can be a byproduct of conditions such as stress, autoimmune disease, hormonal imbalance, infection, or poor nutrition. Despite lack of consensus as to the cause(s) of alopecia, multiple studies in captive primates have found two commonalities: alopecia fluctuates seasonally, and pregnant females tend to have more alopecia than males or nonpregnant females. Most studies have focused on loss of hair, rather than if and when hair is regrown, but alopecia can result from disruption to any phase of the hair follicle's cycle of shedding and regrowth. To better understand how season and pregnancy affect the hair follicle cycle and alopecia, we documented the severity of alopecia and the presence of hair regrowth in outdoor group-housed rhesus for one year. We found a seasonal pattern of alopecia and regrowth in all animals, and that females in their third trimester showed less regrowth, which prevented a decrease in alopecia. Regrowth for females resumed on average 1–2 months postpartum. Hair shedding and regrowth follows a seasonal pattern in rhesus, and conditions in late-term pregnancy suppress hair regrowth into early postpartum. Several studies have examined the etiology of alopecia, or hair loss, in rhesus macaques. While outcomes differ across studies, some commonalities have emerged. Females, particularly pregnant females, show more alopecia than males, and alopecia follows a seasonal pattern. Much research has explored causes of hair loss; however, alopecia can result from lack of hair growth in addition to hair loss. To better understand how sex, reproductive state, and season affect alopecia, we followed 241 rhesus macaques (Macaca mulatta) in outdoor breeding groups over one year, recording both alopecia severity and presence of hair regrowth. We found that both alopecia and hair regrowth followed a seasonal pattern; alopecia was highest in spring and lowest in late summer, while regrowth started in spring and peaked in late summer. Reproductive state also correlated with both alopecia and hair growth. Females in their third trimester had the highest average level of alopecia and the lowest amount of hair regrowth. Regrowth resumed postpartum, regardless of whether females were rearing an infant. Results indicate that the seasonal pattern of alopecia is due in part to the seasonal limitations on hair regrowth, and that breeding, which also occurs seasonally in rhesus macaques, may further suppress hair regrowth. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19. Seven days after infection, SARS-CoV-2 was detected in the olfactory cortex and interconnected regions and was accompanied by robust neuroinflammation and neuronal damage exacerbated in aged, diabetic animals. Our study provides an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.

Midget and parasol ganglion cells (GCs) represent the major output channels from the primate eye to the brain. On-type midget and parasol GCs exhibit a higher background spike rate and thus can respond more linearly to contrast changes than their Off-type counterparts. Here, we show that a calcium-permeable AMPA receptor (CP-AMPAR) antagonist blocks background spiking and sustained light-evoked firing in On-type GCs while preserving transient light responses. These effects are selective for On-GCs and are occluded by a gap-junction blocker suggesting involvement of AII amacrine cells (AII-ACs). Direct recordings from AII-ACs, cobalt uptake experiments, and analyses of transcriptomic data confirm that CP-AMPARs are expressed by primate AII-ACs. Overall, our data demonstrate that under some background light levels, CP-AMPARs at the rod bipolar to AII-AC synapse drive sustained signaling in On-type GCs and thus contribute to the more linear contrast signaling of the primate On- versus Off-pathway.

Late adolescence is a period of dynamic change in the brain as humans learn to navigate increasingly complex environments. In particular, prefrontal cortical (PFC) regions undergo extensive remodeling as the brain is fine-tuned to orchestrate cognitive control over attention, reasoning, and emotions. Late adolescence also presents a uniquely vulnerable period as neurodevelopmental illnesses, such as schizophrenia, become evident and worsen into young adulthood. Challenges in early development, including prenatal exposure to infection, may set the stage for a cascade of maladaptive events that ultimately result in aberrant PFC connectivity and function before symptoms emerge. A growing body of research suggests that activation of the mother's immune system during pregnancy may act as a disease primer, in combination with other environmental and genetic factors, contributing to an increased risk of neurodevelopmental disorders, including schizophrenia. Animal models provide an invaluable opportunity to examine the course of brain and behavioral changes in offspring exposed to maternal immune activation (MIA). Although the vast majority of MIA research has been carried out in rodents, here we highlight the translational utility of the nonhuman primate (NHP) as a model species more closely related to humans in PFC structure and function. In this review, we consider the protracted period of brain and behavioral maturation in the NHP, describe emerging findings from MIA NHP offspring in the context of rodent preclinical models, and lastly explore the translational relevance of the NHP MIA model to expand understanding of the etiology and developmental course of PFC pathology in schizophrenia.

Abstract Background Recent studies have shown that umbilical cord mesenchymal stem cells have an anti-aging effect in ovaries, but the cellular and molecular mechanisms of HA-MSC ovarian anti-aging remain to be studied. Therefore, we conducted a 10X Genomics single-nucleus transcriptome sequencing experiment on the ovaries of macaque monkeys after HA-MSC treatment. Methods The results of cell subgroup classification were visualized by 10X Genomics single nuclear transcriptome sequencing. The aging model of hGCs was established, and the migration ability of the cells was determined after coculture of HA-MSCs and aging hGCs. The genes screened by single nuclear transcriptional sequencing were verified in vitro by qPCR. Results Compared with the aging model group, the number of cell receptor pairs in each subgroup of the HA-MSC-treated group increased overall. Treatment with 200 μmol/L H2O2 for 48 h was used as the optimum condition for the induction of hGC senescence. After coculture of noncontact HA-MSCs with senescent hGCs, it was found that HA-MSCs can reverse the cell structure, proliferation ability, senescence condition, expression level of senescence-related genes, and expression level of key genes regulating the senescence pathway in normal hGCs. Conclusions HA-MSC therapy can improve the tissue structure and secretion function of the ovary through multiple cellular and molecular mechanisms to resist ovarian aging. In vitro validation experiments further supported the results of single-cell sequencing, which provides evidence supporting a new option for stem cell treatment of ovarian senescence.

Nonhuman primate (NHP) studies that utilize simian immunodeficiency virus (SIV) to model human immunodeficiency virus (HIV-1) infection have proven to be powerful, highly informative research tools. However, there are substantial differences between SIV and HIV-1. Accordingly, there are numerous research questions for which SIV-based models are not well suited, including studies of certain aspects of basic HIV-1 biology, and pre-clinical evaluations of many proposed HIV-1 treatment, prevention, and vaccination strategies. To overcome these limitations of NHP models of HIV-1 infection, several groups have pursued the derivation of a minimally modified HIV-1 (mmHIV-1) capable of establishing pathogenic infection in macaques that authentically recapitulates key features of HIV-1 in humans. These efforts have focused on three complementary objectives: (1) engineering HIV-1 to circumvent species-specific cellular restriction factors that otherwise potently inhibit HIV-1 in macaques, (2) introduction of a C chemokine receptor type 5 (CCR5)-tropic envelope, ideally that can efficiently engage macaque CD4, and (3) correction of gene expression defects inadvertently introduced during viral genome manipulations. While some progress has been made toward development of mmHIV-1 variants for use in each of the three macaque species (pigtail, cynomolgus, and rhesus), model development progress has been most promising in pigtail macaques (PTMs), which do not express an HIV-1-restricting tripartite motif-containing protein 5 α (TRIM5α). In our work, we have derived a CCR5-tropic mmHIV-1 clone designated stHIV-A19 that comprises 94% HIV-1 genome sequence and replicates to high acute-phase titers in PTMs. In animals treated with a cell-depleting CD8α antibody at the time of infection, stHIV-A19 maintains chronically elevated plasma viral loads with progressive CD4+ T-cell loss and the development of acquired immune-deficiency syndrome (AIDS)-defining clinical endpoints. However, in the absence of CD8α+ cell depletion, no mmHIV-1 model has yet displayed high levels of chronic viremia or AIDS-like pathogenesis. Here, we review mmHIV-1 development approaches, the phenotypes, features, limitations, and potential utility of currently available mmHIV-1s, and propose future directions to further advance these models.

A major goal of modern neuroscience is to understand the functions of the varied neuronal types that comprise the mammalian brain. Toward this end, some types of neurons can be targeted and manipulated with enhancer-bearing AAV vectors. These vectors hold great promise to advance basic and translational neuroscience, but to realize this potential, their selectivitymust be characterized. In this study, we investigated the selectivity of AAV vectors carrying an enhancer of the murine Dlx5 and Dlx6 genes. Vectors were injected into the visual cortex of two macaque monkeys, the frontal cortex of two others, and the somatosensory/motor cortex of three rats. Post-mortem immunostaining revealed that parvalbumin-expressing neurons were transduced efficiently in all cases but calretinin-expressing neurons were not. We speculate that this specificity is a consequence of differential activity of this DLX5/6 enhancer in adult neurons of different developmental lineages. [ABSTRACT FROM AUTHOR]

The ventrolateral prefrontal cortex (VLPFC) shows robust activation during the perception of faces and voices. However, little is known about what categorical features of social stimuli drive neural activity in this region. Since perception of identity and expression are critical social functions, we examined whether neural responses to naturalistic stimuli were driven by these two categorical features in the prefrontal cortex. We recorded single neurons in the VLPFC, while two male rhesus macaques (Macaca mulatta) viewed short audiovisual videos of unfamiliar conspecifics making expressions of aggressive, affiliative, and neutral valence. Of the 285 neurons responsive to the audiovisual stimuli, 111 neurons had a main effect (two-way ANOVA) of identity, expression, or their interaction in their stimulus-related firing rates; however, decoding of expression and identity using single-unit firing rates rendered poor accuracy. Interestingly, when decoding from pseudo-populations of recorded neurons, the accuracy for both expression and identity increased with population size, suggesting that the population transmitted information relevant to both variables. Principal components analysis of mean population activity across time revealed that population responses to the same identity followed similar trajectories in the response space, facilitating segregation from other identities. Our results suggest that identity is a critical feature of social stimuli that dictates the structure of population activity in the VLPFC, during the perception of vocalizations and their corresponding facial expressions. These findings enhance our understanding of the role of the VLPFC in social behavior. [ABSTRACT FROM AUTHOR]

The functional organization of the primate insula has been studied using a variety of techniques focussing on regional differences in either architecture, connectivity, or function. These complementary methods offered insights into the complex organization of the insula and proposed distinct parcellation schemes at varying levels of detail and complexity. The advent of imaging techniques that allow noninvasive assessment of structural and functional connectivity, has popularized data-driven connectivity-based parcellation methods to investigate the organization of the human insula. Yet, it remains unclear if the subdivisions derived from these data-driven clustering methods reflect meaningful descriptions of the functional specialization of the insula. In this study, we employed hierarchical clustering to examine the cluster parcellations of the macaque insula. As our aim was exploratory, we examined parcellations consisting of two up to ten clusters. Three different cluster validation methods (fingerprinting, silhouette, elbow) converged on a four-cluster solution as the most optimal representation of our data. Examining functional response properties of these clusters, in addition to their brain-wide functional connectivity suggested a functional specialization related to processing gustatory, somato-motor, vestibular and social visual cues. However, a more detailed functional differentiation aligning with previous functional investigations of insula subfields became evident at higher cluster numbers beyond the proposed optimal four clusters. Overall, our findings demonstrate that resting-state-based hierarchical clustering can provide a meaningful description of the insula's functional organization at some level of detail. Nonetheless, cluster parcellations derived from this method are best combined with data obtained through other modalities, to provide a more comprehensive and detailed account of the insula's complex functional organization. [ABSTRACT FROM AUTHOR]

During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial features are in the causal chain that steers the eyes. However, there is no physiological evidence to support a mechanistic link between face-encoding neurons in high-level visual areas and the oculomotor system. In this study, we targeted the middle face patches of the inferior temporal (IT) cortex in two macaque monkeys using an functional magnetic resonance imaging (fMRI) localizer. We then utilized muscimol microinjection to unilaterally suppress IT neural activity inside and outside the face patches and recorded eye movements while the animals free viewing natural scenes. Inactivation of the face-selective neurons altered the pattern of eye movements on faces: The monkeys found faces in the scene but neglected the eye contralateral to the inactivation hemisphere. These findings reveal the causal contribution of the high-level visual cortex in eye movements. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that umbilical cord mesenchymal stem cells have an anti-aging effect in ovaries, but the cellular and molecular mechanisms of HA-MSC ovarian anti-aging remain to be studied. Therefore, we conducted a 10X Genomics single-nucleus transcriptome sequencing experiment on the ovaries of macaque monkeys after HA-MSC treatment. Methods: The results of cell subgroup classification were visualized by 10X Genomics single nuclear transcriptome sequencing. The aging model of hGCs was established, and the migration ability of the cells was determined after coculture of HA-MSCs and aging hGCs. The genes screened by single nuclear transcriptional sequencing were verified in vitro by qPCR. Results: Compared with the aging model group, the number of cell receptor pairs in each subgroup of the HA-MSC-treated group increased overall. Treatment with 200 μmol/L H2O2 for 48 h was used as the optimum condition for the induction of hGC senescence. After coculture of noncontact HA-MSCs with senescent hGCs, it was found that HA-MSCs can reverse the cell structure, proliferation ability, senescence condition, expression level of senescence-related genes, and expression level of key genes regulating the senescence pathway in normal hGCs. Conclusions: HA-MSC therapy can improve the tissue structure and secretion function of the ovary through multiple cellular and molecular mechanisms to resist ovarian aging. In vitro validation experiments further supported the results of single-cell sequencing, which provides evidence supporting a new option for stem cell treatment of ovarian senescence. [ABSTRACT FROM AUTHOR]

Introduction: It is becoming clearer that the microbiota helps drive responses to vaccines; however, little is known about the underlying mechanism. In this study, we aimed to identify microbial features that are associated with vaccine immunogenicity in infant rhesus macaques. Methods: We analyzed 16S rRNA gene sequencing data of 215 fecal samples collected at multiple timepoints from 64 nursery-reared infant macaques that received various HIV vaccine regimens. PERMANOVA tests were performed to determine factors affecting composition of the gut microbiota throughout the first eight months of life in these monkeys. We used DESeq2 to identify differentially abundant bacterial taxa, PICRUSt2 to impute metagenomic information, and mass spectrophotometry to determine levels of fecal shortchain fatty acids and bile acids. Results: Composition of the early-life gut microbial communities in nurseryreared rhesus macaques from the same animal care facility was driven by age, birth year, and vaccination status. We identified a Sutterella and a Rodentibacter species that positively correlated with vaccine-elicited antibody responses, with the Sutterella species exhibiting more robust findings. Analysis of Sutterellarelated metagenomic data revealed five metabolic pathways that significantly correlated with improved antibody responses following HIV vaccination. Given these pathways have been associated with short-chain fatty acids and bile acids, we quantified the fecal concentration of these metabolites and found several that correlated with higher levels of HIV immunogen-elicited plasma IgG. Discussion: Our findings highlight an intricate bidirectional relationship between the microbiota and vaccines, where multiple aspects of the vaccination regimen modulate the microbiota and specific microbial features facilitate vaccine responses. An improved understanding of this microbiota-vaccine interplay will help develop more effective vaccines, particularly those that are tailored for early life. [ABSTRACT FROM AUTHOR]

Primates rely on two eyes to perceive depth, while maintaining stable vision when either one eye or both eyes are open. Although psychophysical and modeling studies have investigated how monocular signals are combined to form binocular vision, the underlying neuronal mechanisms, particularly in V1 where most neurons exhibit binocularity with varying eye preferences, remain poorly understood. Here, we used two-photon calcium imaging to compare the monocular and binocular responses of thousands of simultaneously recorded V1 superficial-layer neurons in three awake macaques. During monocular stimulation, neurons preferring the stimulated eye exhibited significantly stronger responses compared to those preferring both eyes. However, during binocular stimulation, the responses of neurons preferring either eye were suppressed on the average, while those preferring both eyes were enhanced, resulting in similar neuronal responses irrespective of their eye preferences, and an overall response level similar to that with monocular viewing. A neuronally realistic model of binocular combination, which incorporates ocular dominance-dependent divisive interocular inhibition and binocular summation, is proposed to account for these findings.

Primate cerebral cortex is highly convoluted with much of the cortical surface buried in sulcal folds. The origins of cortical folding and its functional relevance have been a major focus of systems and cognitive neuroscience, especially when considering stereotyped patterns of cortical folding that are shared across individuals within a primate species and across multiple species. However, foundational questions regarding organizing principles shared across species remain unanswered. Taking a cross-species comparative approach with a careful consideration of historical observations, we investigate cortical folding relative to primary visual cortex (area V1). We identify two macroanatomical structures-the retrocalcarine and external calcarine sulci-in 24 humans and 6 macaque monkeys. We show that within species, these sulci are identifiable in all individuals, fall on a similar part of the V1 retinotopic map, and thus, serve as anatomical landmarks predictive of functional organization. Yet, across species, the underlying eccentricity representations corresponding to these macroanatomical structures differ strikingly across humans and macaques. Thus, the correspondence between retinotopic representation and cortical folding for an evolutionarily old structure like V1 is species-specific and suggests potential differences in developmental and experiential constraints across primates.

Abstract Spinal cord injury (SCI) animal models have been widely created and utilized for repair therapy research, but more suitable experimental animals and accurate modeling methodologies are required to achieve the desired results. In this experiment, we constructed an innovative dorsal 1/4 spinal cord transection macaque model that had fewer severe problems, facilitating postoperative care and recovery. In essence, given that monkeys and humans share similar genetics and physiology, the efficacy of this strategy in a nonhuman primate SCI model basically serves as a good basis for its prospective therapeutic use in human SCI.

A major goal of modern neuroscience is to understand the functions of the varied neuronal types that comprise the mammalian brain. Toward this end, some types of neurons can be targeted and manipulated with enhancer-bearing AAV vectors. These vectors hold great promise to advance basic and translational neuroscience, but to realize this potential, their selectivity must be characterized. In this study, we investigated the selectivity of AAV vectors carrying an enhancer of the murine Dlx5 and Dlx6 genes. Vectors were injected into the visual cortex of two macaque monkeys, the frontal cortex of two others, and the somatosensory/motor cortex of three rats. Post-mortem immunostaining revealed that parvalbumin-expressing neurons were transduced efficiently in all cases but calretinin-expressing neurons were not. We speculate that this specificity is a consequence of differential activity of this DLX5/6 enhancer in adult neurons of different developmental lineages.

The functional organization of the primate insula has been studied using a variety of techniques focussing on regional differences in either architecture, connectivity, or function. These complementary methods offered insights into the complex organization of the insula and proposed distinct parcellation schemes at varying levels of detail and complexity. The advent of imaging techniques that allow non-invasive assessment of structural and functional connectivity, has popularized data-driven connectivity-based parcellation methods to investigate the organization of the human insula. Yet, it remains unclear if the subdivisions derived from these data-driven clustering methods reflect meaningful descriptions of the functional specialization of the insula. In this study, we employed hierarchical clustering to examine the cluster parcellations of the macaque insula. As our aim was exploratory, we examined parcellations consisting of two up to ten clusters. Three different cluster validation methods (fingerprinting, silhouette, elbow) converged on a four-cluster solution as the most optimal representation of our data. Examining functional response properties of these clusters, in addition to their brain-wide functional connectivity suggested a functional specialization related to processing gustatory, somato-motor, vestibular and social visual cues. However, a more detailed functional differentiation aligning with previous functional investigations of insula subfields became evident at higher cluster numbers beyond the proposed optimal four clusters. Overall, our findings demonstrate that resting-state-based hierarchical clustering can provide a meaningful description of the insula’s functional organization at some level of detail. Nonetheless, cluster parcellations derived from this method are best combined with data obtained through other modalities, to provide a more comprehensive and detailed account of the insula’s complex functional organization.

To probe the presence of mirror neurons in the human brain, cross-modal fMRI adaptation has been suggested as a suitable technique. The rationale behind this suggestion is that this technique allows making more accurate inferences about neural response properties underlying fMRI voxel activations, beyond merely showing shared voxels that are active during both action observation and execution. However, the validity of using cross-modal fMRI adaptation to demonstrate the presence of mirror neurons in parietal and premotor brain regions has been questioned given the inconsistent and weak results obtained in human studies. A better understanding of cross-modal fMRI adaptation effects in the macaque brain is required as the rationale for using this approach is based on several assumptions related to macaque mirror neuron response properties that still need validation. Here, we conducted a cross-modal fMRI adaptation study in macaque monkeys, using the same action execution and action observation tasks that successfully yielded mirror neuron region cross-modal action decoding in a previous monkey MVPA study. We scanned two male rhesus monkeys while they first executed a sequence of either reach-and-grasp or reach-and-touch hand actions and then observed a video of a human actor performing these motor acts. Both whole-brain and region-of-interest analyses failed to demonstrate cross-modal fMRI adaptation effects in parietal and premotor mirror neuron regions. Our results, in line with previous findings in non-human primates, show that cross-modal motor-to-visual fMRI adaptation is not easily detected in monkey brain regions known to house mirror neurons. Thus, our results advocate caution in using cross-modal fMRI adaptation as a method to infer whether mirror neurons can be found in the primate brain. [ABSTRACT FROM AUTHOR]

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results: Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. [ABSTRACT FROM AUTHOR]

Background and aims: Hepatitis B virus (HBV) infection affects 300 million individuals worldwide, representing a major factor for the development of hepatic complications. Although existing antivirals are effective in suppressing replication, eradication of HBV is not achieved. Therefore, a multi-faceted approach involving antivirals and immunomodulatory agents is required. Non-human primates are widely used in pre-clinical studies due to their close evolutionary relationship to humans. Nonetheless, it is fundamental to identify the differences in immune response between humans and these models. Thus, we performed a transcriptomic characterization and interspecies comparison of the early immune responses to HBV in human and cynomolgus macaques. Methods: We characterized early transcriptomic changes in human and cynomolgus B cells, T cells, myeloid and plasmacytoid dendritic cells (pDC) exposed to HBV ex vivo for 2 hours. Differentially-expressed genes were further compared to the profiles of HBV-infected patients using publicly-available single-cell data. Results: HBV induced a wide variety of transcriptional changes in all cell types, with common genes between species representing only a small proportion. In particular, interferon gamma signaling was repressed in human pDCs. At the gene level, interferon gamma inducible protein 16 (IFI16) was upregulated in macaque pDCs, while downregulated in humans. Moreover, IFI16 expression in pDCs from chronic HBV-infected patients anti-paralleled serum HBsAg levels. Conclusion: Our characterization of early transcriptomic changes induced by HBV in humans and cynomolgus macaques represents a useful resource for the identification of shared and divergent host responses, as well as potential immune targets against HBV. [ABSTRACT FROM AUTHOR]

The bed nucleus of the stria terminalis (BNST), as part of the extended amygdala, has become a region of increasing interest regarding its role in numerous human stress-related psychiatric diseases, including post-traumatic stress disorder and generalized anxiety disorder amongst others. The BNST is a sexually dimorphic and highly complex structure as already evident by its anatomy consisting of 11 to 18 distinct sub-nuclei in rodents. Located in the ventral forebrain, the BNST is anatomically and functionally connected to many other limbic structures, including the amygdala, hypothalamic nuclei, basal ganglia, and hippocampus. Given this extensive connectivity, the BNST is thought to play a central and critical role in the integration of information on hedonic-valence, mood, arousal states, processing emotional information, and in general shape motivated and stress/anxiety-related behavior. Regarding its role in regulating stress and anxiety behavior the anterolateral group of the BNST (BNSTALG) has been extensively studied and contains a wide variety of neurons that differ in their electrophysiological properties, morphology, spatial organization, neuropeptidergic content and input and output synaptic organization which shape their activity and function. In addition to this great diversity, further species-specific differences are evident on multiple levels. For example, classic studies performed in adult rat brain identified three distinct neuron types (Type I-III) based on their electrophysiological properties and ion channel expression. Whilst similar neurons have been identified in other animal species, such as mice and non-human primates such as macaques, cross-species comparisons have revealed intriguing differences such as their comparative prevalence in the BNSTALG as well as their electrophysiological and morphological properties, amongst other differences. Given this tremendous complexity on multiple levels, the comprehensive elucidation of the BNSTALG circuitry and its role in regulating stress/anxiety-related behavior is a major challenge. In the present Review we bring together and highlight the key differences in BNSTALG structure, functional connectivity, the electrophysiological and morphological properties, and neuropeptidergic profiles of BNSTALG neurons between species with the aim to facilitate future studies of this important nucleus in relation to human disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Across the last decades, animal welfare science has established that regular access to sensory, motor, and cognitive stimulation significantly improves captive animal's well-being. In primates, in particular, cognitive enrichment protocols have been crucial to alleviate boredom and, more generally, several symptoms of compromised wellbeing. Despite this, cognitive enrichment practices have not received the same level of attention as structural and social enrichment. Consequently, captive animals are usually given ample climbing or grooming opportunities but are less frequently provided with intellectual challenges. This is especially problematic for primates and other species with high cognitive abilities and demands. Following and in order to expand upon recent scientific and technological progress, we developed a multiple-choice interface for touchscreen devices tailored to rhesus macaques housed at the facility of the Cognitive Neuroscience Laboratory of the German Primate Center. The interface allows the animals to flexibly choose between three tasks on a trial-by-trial basis, allowing them to switch activities as desired. Generally, our animals showed consistent task preferences, across time of day and weekly sessions, while also displaying proficiency in doing so. We believe that with a multiple-choice approach, it is possible to increase animal wellbeing by providing captive animals more opportunities to control their own environment, simultaneously providing researchers with a reliable and scalable method for cognitive assessment and animal training. Research on the psychological and physiological well-being of captive animals has focused on investigating different types of social and structural enrichment. Consequently, cognitive enrichment has been understudied, despite the promising external validity, comparability, and applicability. As we aim to fill this gap, we developed an interactive, multiple-choice interface for cage-mounted touchscreen devices that rhesus monkeys (Macaca mulatta) can freely interact with, from within their home enclosure at the Cognitive Neuroscience Laboratory of the German Primate Center. The multiple-choice interface offers interchangeable activities that animals can choose and switch between. We found that all 16 captive rhesus macaques tested consistently engaged with the multiple-choice interface across 6 weekly sessions, with 11 of them exhibiting clear task preferences, and displaying proficiency in performing the selected tasks. Our approach does not require social separation or dietary restriction and is intended to increase animals' sense of competence and agency by providing them with more control over their environment. Thanks to the high level of automation, our multiple-choice interface can be easily incorporated as a standard cognitive enrichment practice across different facilities and institutes working with captive animals, particularly non-human primates. We believe that the multiple-choice interface is a sustainable, scalable, and pragmatic protocol for enhancing cognitive well-being and animal welfare in captivity. [ABSTRACT FROM AUTHOR]

Briefly discusses causes the issue of unfavourable interactions between people and free-living human-nonhuman primates, and alternatives to lethal methods of resolving these.

Microendoscopic calcium imaging with one-photon miniature microscopes enables unprecedented readout of neural circuit dynamics during active behavior in rodents. In this study, we describe successful application of this technology in the rhesus macaque, demonstrating plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from large populations of neurons simultaneously in bilateral dorsal premotor cortices during performance of a naturalistic motor reach task. Imaging is stable over several months, allowing us to longitudinally track individual neurons and monitor their relationship to motor behavior over time. We observe neuronal calcium dynamics selective for reach direction, which we could use to decode the animal's trial-by-trial motor behavior. This work establishes head-mounted microendoscopic calcium imaging in macaques as a powerful approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and it promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease.

Adapting between scotopic and photopic illumination involves switching the routing of retinal signals between rod and cone-dominated circuits. In the daytime, cone signals pass through parallel On and Off cone bipolar cells (CBCs), that are sensitive to increments and decrements in luminance, respectively. At night, rod signals are routed into these cone-pathways via a key glycinergic interneuron, the AII amacrine cell (AII-AC). AII-ACs also provide On-pathway-driven crossover inhibition to Off-CBCs under photopic conditions. In primates, it is not known whether all Off-bipolar cell types receive functional inputs from AII-ACs. Here, we show that select Off-CBC types receive significantly higher levels of On-pathway-driven glycinergic input than others. The rise and decay kinetics of the glycinergic events are consistent with involvement of the α1 glycine receptor (GlyR) subunit, a result supported by a higher level of GLRA1 transcript in these cells. The Off-bipolar types that receive glycinergic input have sustained physiological properties and include the flat midget bipolar (FMB) cells, which provide excitatory input to the Off-midget ganglion cells (GCs; parvocellular pathway). Our results suggest that only a subset of Off-bipolar cells have the requisite receptors to respond to AII-AC input. Taken together with results in mouse retina, our findings suggest a conserved motif whereby signal output from AII-ACs is preferentially routed into sustained Off-bipolar signaling pathways.

The increasing overlap of resources between human and long-tailed macaque (Macaca fascicularis) (LTM) populations have escalated human–primate conflict. In Malaysia, LTMs are labeled as a ‘pest’ species due to the macaques’ opportunistic nature. This study investigates the activity budget of LTMs in an urban tourism site and how human activities influence it. Observational data were collected from LTMs daily for a period of four months. The observed behaviors were compared across differing levels of human interaction, between different times of day, and between high, medium, and low human traffic zones. LTMs exhibited varying ecological behavior patterns when observed across zones of differing human traffic, e.g., higher inactivity when human presence is high. More concerning is the impact on these animals’ welfare and group dynamics as the increase in interactions with humans takes place; we noted increased inactivity and reduced intra-group interaction. This study highlights the connection that LTMs make between human activity and sources of anthropogenic food. Only through understanding LTM interaction can the cause for human–primate conflict be better understood, and thus, more sustainable mitigation strategies can be generated.

Non-human primates (NHPs) are pivotal animal models for translating novel cell replacement therapies into clinical applications, including validating the safety and efficacy of induced pluripotent stem cell (iPSC)-derived products. Preclinical development and the testing of cell-based therapies ideally comprise xenogeneic (human stem cells into NHPs) and allogenic (NHP stem cells into NHPs) transplantation studies. For the allogeneic approach, it is necessary to generate NHP-iPSCs with generally equivalent quality to the human counterparts that will be used later on in patients. Here, we report the generation and characterization of transgene- and feeder-free cynomolgus monkey (Macaca fascicularis) iPSCs (Cyno-iPSCs). These novel cell lines have been generated according to a previously developed protocol for the generation of rhesus macaque, baboon, and human iPSC lines. Beyond their generation, we demonstrate the potential of the novel Cyno-iPSCs to differentiate into two clinically relevant cell types, i.e., cardiomyocytes and neurons. Overall, we provide a resource of novel iPSCs from the most frequently used NHP species in the regulatory testing of biologics and classical pharmaceutics to expand our panel of iPSC lines from NHP species with high relevance in preclinical testing and translational research.

Myanmar is one of the world’s most biologically rich countries and has among the largest contiguous intact forest landscapes in southeast Asia. Yet many of its ecosystems are highly threatened and there is an urgent need for greater wildlife conservation action, particularly for its 20 primate species, over half of which are either Endangered or Critically Endangered on the IUCN Red List of Threatened Species. Of these 20 species, three survive in small, isolated populations, while for the remaining 17 there is insufficient population and distribution information to accurately target conservation management and monitoring. To begin to address this challenge, we conducted semi-structured interviews with senior academics and professionals working in primate conservation in Myanmar to assess current knowledge on the conservation status of each of the primate species found there, as well as conservation efforts underway. We also conducted a systematic literature review to generate data on publication metrics for Myanmar primatology. The principal finding is that the populations of nearly all of Myanmar’s 20 primate species are declining, and there are gaps in knowledge on species population dynamics which are hindering conservation action. We present an overview of primatology in Myanmar and address the challenges and recommendations for the future of primate conservation in Myanmar.

Selective attention implements preferential routing of attended stimuli, likely through increasing the influence of the respective synaptic inputs on higher-area neurons. As the inputs of competing stimuli converge onto postsynaptic neurons, presynaptic circuits might offer the best target for attentional top-down influences. If those influences enabled presynaptic circuits to selectively entrain postsynaptic neurons, this might explain selective routing. Indeed, when two visual stimuli induce two gamma rhythms in V1, only the gamma induced by the attended stimulus entrains gamma in V4. Here, we modelled induced responses with a Dynamic Causal Model for Cross-Spectral Densities and found that selective entrainment can be explained by attentional modulation of intrinsic V1 connections. Specifically, local inhibition was decreased in the granular input layer and increased in the supragranular output layer of the V1 circuit that processed the attended stimulus. Thus, presynaptic attentional influences and ensuing entrainment were sufficient to mediate selective routing.

Abstract Introduction Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights Inflammation is a key driver of sporadic Alzheimer's disease. GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium. Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys. GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Background and aimsHepatitis B virus (HBV) infection affects 300 million individuals worldwide, representing a major factor for the development of hepatic complications. Although existing antivirals are effective in suppressing replication, eradication of HBV is not achieved. Therefore, a multi-faceted approach involving antivirals and immunomodulatory agents is required. Non-human primates are widely used in pre-clinical studies due to their close evolutionary relationship to humans. Nonetheless, it is fundamental to identify the differences in immune response between humans and these models. Thus, we performed a transcriptomic characterization and interspecies comparison of the early immune responses to HBV in human and cynomolgus macaques.MethodsWe characterized early transcriptomic changes in human and cynomolgus B cells, T cells, myeloid and plasmacytoid dendritic cells (pDC) exposed to HBV ex vivo for 2 hours. Differentially-expressed genes were further compared to the profiles of HBV-infected patients using publicly-available single-cell data.ResultsHBV induced a wide variety of transcriptional changes in all cell types, with common genes between species representing only a small proportion. In particular, interferon gamma signaling was repressed in human pDCs. At the gene level, interferon gamma inducible protein 16 (IFI16) was upregulated in macaque pDCs, while downregulated in humans. Moreover, IFI16 expression in pDCs from chronic HBV-infected patients anti-paralleled serum HBsAg levels.ConclusionOur characterization of early transcriptomic changes induced by HBV in humans and cynomolgus macaques represents a useful resource for the identification of shared and divergent host responses, as well as potential immune targets against HBV.