Primate optogenetics El-Shamayleh, Yasmine; Horwitz, Gregory D.
Proceedings of the National Academy of Sciences - PNAS,
12/2019, Letnik:
116, Številka:
52
Journal Article
Recenzirano
Odprti dostop
Monkeys are a premier model organism for neuroscience research. Activity in the central nervous systems of monkeys can be recorded and manipulated while they perform complex perceptual, motor, or ...cognitive tasks. Conventional techniques for manipulating neural activity in monkeys are too coarse to address many of the outstanding questions in primate neuroscience, but optogenetics holds the promise to overcome this hurdle. In this article, we review the progress that has been made in primate optogenetics over the past 5 years. We emphasize the use of gene regulatory sequences in viral vectors to target specific neuronal types, and we present data on vectors that we engineered to target parvalbumin-expressing neurons. We conclude with a discussion of the utility of optogenetics for treating sensorimotor hearing loss and Parkinson’s disease, areas of translational neuroscience in which monkeys provide unique leverage for basic science and medicine.
Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the
family are nonpathogenic. To date, no approved vaccines, ...antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPV
) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPV
was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVAC
, was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses.
Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.
Abstract
Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates ...experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.
The small molecule remdesivir (GS-5734) showed therapeutic efficacy in a nonhuman primate model of Marburg disease with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.
Primates, including humans, can typically recognize objects in visual images at a glance despite naturally occurring identity-preserving image transformations (e.g., changes in viewpoint). A primary ...neuroscience goal is to uncover neuron-level mechanistic models that quantitatively explain this behavior by predicting primate performance for each and every image. Here, we applied this stringent behavioral prediction test to the leading mechanistic models of primate vision (specifically, deep, convolutional, artificial neural networks; ANNs) by directly comparing their behavioral signatures against those of humans and rhesus macaque monkeys. Using high-throughput data collection systems for human and monkey psychophysics, we collected more than one million behavioral trials from 1472 anonymous humans and five male macaque monkeys for 2400 images over 276 binary object discrimination tasks. Consistent with previous work, we observed that state-of-the-art deep, feedforward convolutional ANNs trained for visual categorization (termed DCNN
models) accurately predicted primate patterns of object-level confusion. However, when we examined behavioral performance for individual images within each object discrimination task, we found that all tested DCNN
models were significantly nonpredictive of primate performance and that this prediction failure was not accounted for by simple image attributes nor rescued by simple model modifications. These results show that current DCNN
models cannot account for the image-level behavioral patterns of primates and that new ANN models are needed to more precisely capture the neural mechanisms underlying primate object vision. To this end, large-scale, high-resolution primate behavioral benchmarks such as those obtained here could serve as direct guides for discovering such models.
Recently, specific feedforward deep convolutional artificial neural networks (ANNs) models have dramatically advanced our quantitative understanding of the neural mechanisms underlying primate core object recognition. In this work, we tested the limits of those ANNs by systematically comparing the behavioral responses of these models with the behavioral responses of humans and monkeys at the resolution of individual images. Using these high-resolution metrics, we found that all tested ANN models significantly diverged from primate behavior. Going forward, these high-resolution, large-scale primate behavioral benchmarks could serve as direct guides for discovering better ANN models of the primate visual system.
From thought to action Andersen, Richard A.; Aflalo, Tyson; Kellis, Spencer
Proceedings of the National Academy of Sciences - PNAS,
12/2019, Letnik:
116, Številka:
52
Journal Article
Recenzirano
Odprti dostop
A dramatic example of translational monkey research is the development of neural prosthetics for assisting paralyzed patients. A neuroprosthesis consists of implanted electrodes that can record the ...intended movement of a paralyzed part of the body, a computer algorithm that decodes the intended movement, and an assistive device such as a robot limb or computer that is controlled by these intended movement signals. This type of neuroprosthetic system is also referred to as a brain–machine interface (BMI) since it interfaces the brain with an external machine. In this review, we will concentrate on BMIs in which microelectrode recording arrays are implanted in the posterior parietal cortex (PPC), a high-level cortical area in both humans and monkeys that represents intentions to move. This review will first discuss the basic science research performed in healthy monkeys that established PPC as a good source of intention signals. Next, it will describe the first PPC implants in human patients with tetraplegia from spinal cord injury. From these patients the goals of movements could be quickly decoded, and the rich number of action variables found in PPC indicates that it is an appropriate BMI site for a very wide range of neuroprosthetic applications. We will discuss research on learning to use BMIs in monkeys and humans and the advances that are still needed, requiring both monkey and human research to enable BMIs to be readily available in the clinic.
Over the past few decades, a large number of studies have identified herpesvirus sequences from many mammalian species around the world. Among the different nonhuman primate species tested so far for ...cytomegaloviruses (CMVs), only a few were from the New World. Seeking to identify CMV homologues in New World monkeys (NWMs), we carried out molecular screening of 244 blood DNA samples from 20 NWM species from Central and South America. Our aim was to reach a better understanding of their evolutionary processes within the Platyrrhini parvorder. Using PCR amplification with degenerate consensus primers targeting highly conserved amino acid motifs encoded by the herpesvirus DNA polymerase gene, we characterized novel viral sequences from 12 species belonging to seven genera representative of the three NWM families. BLAST searches, pairwise nucleotide and amino acid sequence comparisons, and phylogenetic analyses confirmed that they all belonged to the
genus. Previously determined host taxa allowed us to demonstrate a good correlation between the distinct monophyletic clades of viruses and those of the infected primates at the genus level. In addition, the evolutionary branching points that separate NWM CMVs were congruent with the divergence dates of their hosts at the genus level. These results significantly expand our knowledge of the host range of this viral genus and strongly support the occurrence of cospeciation between these viruses and their hosts. In this respect, we propose that NWM CMV DNA polymerase gene sequences may serve as reliable molecular markers with which to infer Platyrrhini phylogenetics.
Investigating evolutionary processes between viruses and nonhuman primates has led to the discovery of a large number of herpesviruses. No study published so far on primate cytomegaloviruses has extensively studied New World monkeys (NWMs) at the subspecies, species, genus, and family levels. The present study sought to identify cytomegalovirus homologues in NWMs and to decipher their evolutionary relationships. This led us to characterize novel viruses from 12 of the 20 primate species tested, which are representative of the three NWM families. The identification of distinct viruses in these primates not only significantly expands our knowledge of the host range of this viral genus but also sheds light on its evolutionary history. Phylogenetic analyses and molecular dating of the sequences obtained support a virus-host coevolution.
Advances in neuroimaging and neuroanatomy have yielded major insights concerning fundamental principles of cortical organization and evolution, thus speaking to how well different species serve as ...models for human brain function in health and disease. Here, we focus on cortical folding, parcellation, and connectivity in mice, marmosets, macaques, and humans. Cortical folding patterns vary dramatically across species, and individual variability in cortical folding increases with cortical surface area. Such issues are best analyzed using surface-based approaches that respect the topology of the cortical sheet. Many aspects of cortical organization can be revealed using 1 type of information (modality) at a time, such as maps of cortical myelin content. However, accurate delineation of the entire mosaic of cortical areas requires a multimodal approach using information about function, architecture, connectivity, and topographic organization. Comparisons across the 4 aforementioned species reveal dramatic differences in the total number and arrangement of cortical areas, particularly between rodents and primates. Hemispheric variability and bilateral asymmetry are most pronounced in humans, which we evaluated using a high-quality multimodal parcellation of hundreds of individuals. Asymmetries include modest differences in areal size but not in areal identity. Analyses of cortical connectivity using anatomical tracers reveal highly distributed connectivity and a wide range of connection weights in monkeys and mice; indirect measures using functional MRI suggest a similar pattern in humans. Altogether, a multifaceted but integrated approach to exploring cortical organization in primate and nonprimate species provides complementary advantages and perspectives.
Extracellular vesicles (EVs) are small, membrane-bound particles released by cells, playing a pivotal role in intercellular communication. These vesicles carry a diverse range of bioactive molecules, ...including proteins, lipids, and nucleic acids, which are critical in mediating various physiological and pathological processes. These properties have led to their use as therapeutic agents in a variety of fields. However, because EVs are administered in concentrations and their various components can be distributed throughout the body upon degradation, they may have undesirable pharmacodynamic properties that may be relevant to patient safety.
In this study, we performed a telemetry study in cynomolgus monkeys to determine the cardiovascular risk of mesenchymal stem cell (MSC)-derived EVs. Heart rate, blood pressure and electrocardiogram (ECG) were measured using a telemetry system before dosing (0 h) and at 1, 3, 6, 24 and 48 h after a single intravenous administration of extracellular vesicles at a dose of 2×1010 particles/head in a transmitter-loaded cynomolgus monkey. No statistically significant changes in heart rate, systolic blood pressure, diastolic blood pressure and mean blood pressure were observed in MSC-derived EVs compared to vehicle controls at any time point. Electrocardiogram measurements showed no significant differences in PR, QRS, RR, QT and QTcF intervals compared to the vehicle control at any time point, and no abnormalities in electrocardiogram waveforms were observed in the animals. In conclusion, MSC-derived EVs did not appear to have an effect on cardiovascular function in cynomolgus monkeys.
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