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1.
Sci Rep ; 14(1): 12852, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834578

RESUMO

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.


Assuntos
Pulvinar , Movimentos Sacádicos , Animais , Pulvinar/fisiologia , Movimentos Sacádicos/fisiologia , Masculino , Percepção Espacial/fisiologia , Percepção Visual/fisiologia , Estimulação Luminosa , Macaca mulatta , Atenção/fisiologia
2.
Environ Microbiol ; 26(6): e16664, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830671

RESUMO

Milk is a complex biochemical fluid that includes macronutrients and microbiota, which, together, are known to facilitate infant growth, mediate the colonization of infant microbiomes, and promote immune development. Examining factors that shape milk microbiomes and milk-nutrient interplay across host taxa is critical to resolving the evolution of the milk environment. Using a comparative approach across four cercopithecine primate species housed at three facilities under similar management conditions, we test for the respective influences of the local environment (housing facility) and host species on milk (a) macronutrients (fat, sugar, and protein), (b) microbiomes (16S rRNA), and (c) predicted microbial functions. We found that milk macronutrients were structured according to host species, while milk microbiomes and predicted function were strongly shaped by the local environment and, to a lesser extent, host species. The milk microbiomes of rhesus macaques (Macaca mulatta) at two different facilities more closely resembled those of heterospecific facility-mates compared to conspecifics at a different facility. We found similar, facility-driven patterns of microbial functions linked to physiology and immune modulation, suggesting that milk microbiomes may influence infant health and development. These results provide novel insight into the complexity of milk and its potential impact on infants across species and environments.


Assuntos
Microbiota , Leite , Nutrientes , RNA Ribossômico 16S , Animais , Leite/microbiologia , Nutrientes/metabolismo , RNA Ribossômico 16S/genética , Macaca mulatta/microbiologia , Feminino , Cercopithecidae/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Evolução Biológica
3.
J Biomed Sci ; 31(1): 58, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824576

RESUMO

BACKGROUND: A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques. METHODS: We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires. RESULTS: RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose. CONCLUSIONS: These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.


Assuntos
Doença de Chagas , Macaca mulatta , Vacinas Protozoárias , Receptores de Antígenos de Linfócitos T , Animais , Doença de Chagas/imunologia , Doença de Chagas/prevenção & controle , Receptores de Antígenos de Linfócitos T/imunologia , Vacinas Protozoárias/imunologia , Trypanosoma cruzi/imunologia , Imunoglobulinas/imunologia
4.
J Vis ; 24(6): 6, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38843389

RESUMO

Infant primates see poorly, and most perceptual functions mature steadily beyond early infancy. Behavioral studies on human and macaque infants show that global form perception, as measured by the ability to integrate contour information into a coherent percept, improves dramatically throughout the first several years after birth. However, it is unknown when sensitivity to curvature and shape emerges in early life or how it develops. We studied the development of shape sensitivity in 18 macaques, aged 2 months to 10 years. Using radial frequency stimuli, circular targets whose radii are modulated sinusoidally, we tested monkeys' ability to radial frequency stimuli from circles as a function of the depth and frequency of sinusoidal modulation. We implemented a new four-choice oddity task and compared the resulting data with that from a traditional two-alternative forced choice task. We found that radial frequency pattern perception was measurable at the youngest age tested (2 months). Behavioral performance at all radial frequencies improved with age. Performance was better for higher radial frequencies, suggesting the developing visual system prioritizes processing of fine visual details that are ecologically relevant. By using two complementary methods, we were able to capture a comprehensive developmental trajectory for shape perception.


Assuntos
Percepção de Forma , Macaca mulatta , Reconhecimento Visual de Modelos , Estimulação Luminosa , Animais , Percepção de Forma/fisiologia , Estimulação Luminosa/métodos , Reconhecimento Visual de Modelos/fisiologia , Masculino , Feminino
5.
BMC Neurol ; 24(1): 191, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849737

RESUMO

BACKGROUND: Depression is a complex mood disorder whose pathogenesis involves multiple cell types and molecular pathways. The prefrontal cortex, as a key brain region for emotional regulation, plays a crucial role in depression. Microglia, as immune cells of the central nervous system, have been closely linked to the development and progression of depression through their dysfunctional states. This study aims to utilize single-cell RNA-seq technology to reveal the pathogenic mechanism of YAP1 in prefrontal cortex microglia in depression. METHODS: Firstly, we performed cell type identification and differential analysis on normal and depressed prefrontal cortex tissues by mining single-cell RNA-seq datasets from public databases. Focusing on microglia, we conducted sub-clustering, differential gene KEGG enrichment analysis, intercellular interaction analysis, and pseudotime analysis. Additionally, a cross-species analysis was performed to explore the similarities and differences between human and rhesus monkey prefrontal cortex microglia. To validate our findings, we combined bulk RNA-Seq and WGCNA analysis to reveal key genes associated with depression and verified the relationship between YAP1 and depression using clinical samples. RESULTS: Our study found significant changes in the proportion and transcriptional profiles of microglia in depressed prefrontal cortex tissues. Further analysis revealed multiple subpopulations of microglia and their associated differential genes and signaling pathways related to depression. YAP1 was identified as a key molecule contributing to the development of depression and was significantly elevated in depression patients. Moreover, the expression level of YAP1 was positively correlated with HAMD scores, suggesting its potential as a biomarker for predicting the onset of depression. CONCLUSION: This study utilized single-cell RNA-seq technology to reveal the pathogenic mechanism of YAP1 in prefrontal cortex microglia in depression, providing a new perspective for a deeper understanding of the pathophysiology of depression and identifying potential targets for developing novel treatment strategies.


Assuntos
Macaca mulatta , Microglia , Córtex Pré-Frontal , Análise de Célula Única , Proteínas de Sinalização YAP , Córtex Pré-Frontal/metabolismo , Microglia/metabolismo , Proteínas de Sinalização YAP/metabolismo , Humanos , Animais , Análise de Célula Única/métodos , RNA-Seq , Depressão/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Masculino , Feminino , Análise da Expressão Gênica de Célula Única
6.
Drug Alcohol Depend ; 260: 111347, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38833794

RESUMO

BACKGROUND: One possible reason for the lack of FDA-approved pharmacotherapies to treat cocaine use disorder (CUD) is that, although cocaine is typically used in combination with alcohol, it is studied in isolation in preclinical studies. A better understanding of the cocaine-alcohol interactions that promote polysubstance use (PSU) will improve animal models of CUD and hasten pharmacotherapy development. We used a rhesus monkey model of cocaine-alcohol PSU to investigate one possible mechanism: that alcohol is used to mitigate negative effects associated with termination of cocaine use. METHODS: In 6 adult male rhesus monkeys, the relationship between self-administered cocaine intake and oral ethanol intake 2hours later was examined during self-administration of cocaine (0.0003-0.3mg/kg per injection, i.v.) under a fixed-ratio 30 schedule (FR30) or a progressive-ratio (PR) schedule. Next, ethanol consumption was measured 0-120minutes after experimenter-administered cocaine (0.3-1.7mg/kg, i.v.). RESULTS: Self-administered cocaine intake under both FR30 and PR schedules was unrelated to oral ethanol intakes 2hours later. When cocaine was administered non-contingently, cocaine decreased ethanol intake as well as intake of a non-alcoholic solution in monkeys who never consumed ethanol (n=4) in a time- and dose-dependent manner. CONCLUSIONS: Taken together, the results do not provide evidence for cocaine-induced increases in ethanol consumption. By extension, the results do not support the hypothesis that cocaine users drink alcohol to counteract negative effects that occur after terminating use. This finding implies either that such effects do not exist or that such effects exist but are unaffected by ethanol.


Assuntos
Consumo de Bebidas Alcoólicas , Cocaína , Macaca mulatta , Autoadministração , Animais , Masculino , Cocaína/administração & dosagem , Etanol/administração & dosagem , Esquema de Reforço , Relação Dose-Resposta a Droga , Transtornos Relacionados ao Uso de Cocaína
7.
Sci Rep ; 14(1): 13571, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866887

RESUMO

The identification and validation of radiation biomarkers is critical for assessing the radiation dose received in exposed individuals and for developing radiation medical countermeasures that can be used to treat acute radiation syndrome (ARS). Additionally, a fundamental understanding of the effects of radiation injury could further aid in the identification and development of therapeutic targets for mitigating radiation damage. In this study, blood samples were collected from fourteen male nonhuman primates (NHPs) that were exposed to 7.2 Gy ionizing radiation at various time points (seven days prior to irradiation; 1, 13, and 25 days post-irradiation; and immediately prior to the euthanasia of moribund (preterminal) animals). Plasma was isolated from these samples and was analyzed using a liquid chromatography tandem mass spectrometry approach in an effort to determine the effects of radiation on plasma proteomic profiles. The primary objective was to determine if the radiation-induced expression of specific proteins could serve as an early predictor for health decline leading to a preterminal phenotype. Our results suggest that radiation induced a complex temporal response in which some features exhibit upregulation while others trend downward. These statistically significantly altered features varied from pre-irradiation levels by as much as tenfold. Specifically, we found the expression of integrin alpha and thrombospondin correlated in peripheral blood with the preterminal stage. The differential expression of these proteins implicates dysregulation of biological processes such as hemostasis, inflammation, and immune response that could be leveraged for mitigating radiation-induced adverse effects.


Assuntos
Raios gama , Macaca mulatta , Proteômica , Animais , Raios gama/efeitos adversos , Masculino , Proteômica/métodos , Biomarcadores/sangue , Irradiação Corporal Total/efeitos adversos , Síndrome Aguda da Radiação/sangue , Síndrome Aguda da Radiação/etiologia , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Proteoma/análise , Proteoma/metabolismo
8.
Sci Transl Med ; 16(751): eadk6152, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865482

RESUMO

Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney from GGTA1 (α1,3-galactosyltransferase) knockout pigs expressing the human CD55 transgene (1KO.1TG) and were maintained on an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen. These recipients developed de novo xenoreactive antibodies and experienced xenograft rejection with evidence of thrombotic microangiopathy and antibody-mediated rejection (AMR). In comparison, three highly allosensitized rhesus macaques receiving a kidney from GGTA1, CMAH (cytidine monophospho-N-acetylneuraminic acid hydroxylase), and b4GNT2/b4GALNT2 (ß-1,4-N-acetyl-galactosaminyltransferase 2) knockout pigs expressing seven human transgenes including human CD46, CD55, CD47, THBD (thrombomodulin), PROCR (protein C receptor), TNFAIP3 (tumor necrosis factor-α-induced protein 3), and HMOX1 (heme oxygenase 1) (3KO.7TG) experienced significantly prolonged graft survival and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients who received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR.


Assuntos
Animais Geneticamente Modificados , Galactosiltransferases , Técnicas de Inativação de Genes , Rejeição de Enxerto , Sobrevivência de Enxerto , Transgenes , Transplante Heterólogo , Animais , Sobrevivência de Enxerto/imunologia , Humanos , Suínos , Galactosiltransferases/genética , Galactosiltransferases/deficiência , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Macaca mulatta , Transplante de Rim
9.
J Neuroimmune Pharmacol ; 19(1): 28, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38862787

RESUMO

Despite antiretroviral therapy (ART), HIV-associated peripheral neuropathy remains one of the most prevalent neurologic manifestations of HIV infection. The spinal cord is an essential component of sensory pathways, but spinal cord sampling and evaluation in people with HIV has been very limited, especially in those on ART. The SIV/macaque model allows for assessment of the spinal cord at key time points throughout infection with and without ART. In this study, RNA was isolated from the spinal cord of uninfected, SIV+, and SIV + ART animals to track alterations in gene expression using global RNA-seq. Next, the SeqSeek platform was used to map changes in gene expression to specific cell types. Pathway analysis of differentially expressed genes demonstrated that highly upregulated genes in SIV-infected spinal cord aligned with interferon and viral response pathways. Additionally, this upregulated gene set significantly overlapped with those expressed in myeloid-derived cells including microglia. Downregulated genes were involved in cholesterol and collagen biosynthesis, and TGF-b regulation of extracellular matrix. In contrast, enriched pathways identified in SIV + ART animals included neurotransmitter receptors and post synaptic signaling regulators, and transmission across chemical synapses. SeqSeek analysis showed that upregulated genes were primarily expressed by neurons rather than glia. These findings indicate that pathways activated in the spinal cord of SIV + ART macaques are predominantly involved in neuronal signaling rather than proinflammatory pathways. This study provides the basis for further evaluation of mechanisms of SIV infection + ART within the spinal cord with a focus on therapeutic interventions to maintain synaptodendritic homeostasis.


Assuntos
Neuroglia , Neurônios , Síndrome de Imunodeficiência Adquirida dos Símios , Medula Espinal , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/virologia , Neuroglia/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/virologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/virologia , Antirretrovirais/uso terapêutico , Antirretrovirais/farmacologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Macaca mulatta , Expressão Gênica/efeitos dos fármacos , Masculino , Regulação da Expressão Gênica/efeitos dos fármacos
10.
Cereb Cortex ; 34(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38864574

RESUMO

The amygdala is present in a diverse range of vertebrate species, such as lizards, rodents, and primates; however, its structure and connectivity differs across species. The increased connections to visual sensory areas in primate species suggests that understanding the visual selectivity of the amygdala in detail is critical to revealing the principles underlying its function in primate cognition. Therefore, we designed a high-resolution, contrast-agent enhanced, event-related fMRI experiment, and scanned 3 adult rhesus macaques, while they viewed 96 naturalistic stimuli. Half of these stimuli were social (defined by the presence of a conspecific), the other half were nonsocial. We also nested manipulations of emotional valence (positive, neutral, and negative) and visual category (faces, nonfaces, animate, and inanimate) within the stimulus set. The results reveal widespread effects of emotional valence, with the amygdala responding more on average to inanimate objects and animals than faces, bodies, or social agents in this experimental context. These findings suggest that the amygdala makes a contribution to primate vision that goes beyond an auxiliary role in face or social perception. Furthermore, the results highlight the importance of stimulus selection and experimental design when probing the function of the amygdala and other visually responsive brain regions.


Assuntos
Tonsila do Cerebelo , Macaca mulatta , Imageamento por Ressonância Magnética , Estimulação Luminosa , Animais , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/diagnóstico por imagem , Masculino , Estimulação Luminosa/métodos , Emoções/fisiologia , Mapeamento Encefálico , Percepção Visual/fisiologia , Feminino , Reconhecimento Visual de Modelos/fisiologia
11.
Nat Commun ; 15(1): 4802, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839745

RESUMO

Staying engaged is necessary to maintain goal-directed behaviors. Despite this, engagement exhibits continuous, intrinsic fluctuations. Even in experimental settings, animals, unlike most humans, repeatedly and spontaneously move between periods of complete task engagement and disengagement. We, therefore, looked at behavior in male macaques (macaca mulatta) in four tasks while recording fMRI signals. We identified consistent autocorrelation in task disengagement. This made it possible to build models capturing task-independent engagement. We identified task general patterns of neural activity linked to impending sudden task disengagement in mid-cingulate gyrus. By contrast, activity centered in perigenual anterior cingulate cortex (pgACC) was associated with maintenance of performance across tasks. Importantly, we carefully controlled for task-specific factors such as the reward history and other motivational effects, such as response vigor, in our analyses. Moreover, we showed pgACC activity had a causal link to task engagement: transcranial ultrasound stimulation of pgACC changed task engagement patterns.


Assuntos
Giro do Cíngulo , Macaca mulatta , Imageamento por Ressonância Magnética , Recompensa , Animais , Masculino , Giro do Cíngulo/fisiologia , Giro do Cíngulo/diagnóstico por imagem , Lobo Frontal/fisiologia , Lobo Frontal/diagnóstico por imagem , Comportamento Animal/fisiologia , Mapeamento Encefálico , Motivação/fisiologia
12.
Curr Opin HIV AIDS ; 19(4): 201-211, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38841850

RESUMO

PURPOSE OF REVIEW: Highlighting opportunities/potential for immunotherapy by understanding dynamics of HIV control during pediatric HIV infection with and without antiretroviral therapy (ART), as modeled in Simian immunodeficiency virus (SIV) and Simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and observed in clinical trials. This review outlines mode of transmission, pathogenesis of pediatric HIV, unique aspects of the infant immune system, infant macaque models and immunotherapies. RECENT FINDINGS: During the earliest stages of perinatal HIV infection, the infant immune system is characterized by a unique environment defined by immune tolerance and lack of HIV-specific T cell responses which contribute to disease progression. Moreover, primary lymphoid organs such as the thymus appear to play a distinct role in HIV pathogenesis in children living with HIV (CLWH). Key components of the immune system determine the degree of viral control, targets for strategies to induce viral control, and the response to immunotherapy. The pursuit of highly potent broadly neutralizing antibodies (bNAbs) and T cell vaccines has revolutionized the approach to HIV cure. Administration of HIV-1-specific bNAbs, targeting the highly variable envelope improves humoral immunity, and T cell vaccines induce or improve T cell responses such as the cytotoxic effects of HIV-1-specific CD8+ T cells, both of which are promising options towards virologic control and ART-free remission as evidenced by completed and ongoing clinical trials. SUMMARY: Understanding early events during HIV infection and disease progression in CLWH serves as a foundation for predicting or targeting later outcomes by harnessing the immune system's natural responses. The developing pediatric immune system offers multiple opportunities for specific long-term immunotherapies capable of improving quality of life during adolescence and adulthood.


Assuntos
Infecções por HIV , Imunoterapia , Humanos , Infecções por HIV/imunologia , Imunoterapia/métodos , Animais , Criança , Macaca mulatta , Modelos Animais de Doenças , Lactente , Vírus da Imunodeficiência Símia/imunologia , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem
13.
Sci Rep ; 14(1): 13315, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858439

RESUMO

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.


Assuntos
Suplementos Nutricionais , Protetores contra Radiação , Animais , Protetores contra Radiação/farmacologia , Vitamina E/farmacologia , Vitamina E/análogos & derivados , Síndrome Aguda da Radiação/prevenção & controle , Síndrome Aguda da Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/patologia , Cromanos/farmacologia , Masculino , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Macaca mulatta , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Fígado/patologia
14.
Commun Biol ; 7(1): 716, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858589

RESUMO

The awake mammalian brain is functionally organized in terms of large-scale distributed networks that are constantly interacting. Loss of consciousness might disrupt this temporal organization leaving patients unresponsive. We hypothesize that characterizing brain activity in terms of transient events may provide a signature of consciousness. For this, we analyze temporal dynamics of spatiotemporally overlapping functional networks obtained from fMRI transient activity across different anesthetics and levels of anesthesia. We first show a striking homology in spatial organization of networks between monkeys and humans, indicating cross-species similarities in resting-state fMRI structure. We then track how network organization shifts under different anesthesia conditions in macaque monkeys. While the spatial aspect of the networks is preserved, their temporal dynamics are highly affected by anesthesia. Networks express for longer durations and co-activate in an anesthetic-specific configuration. Additionally, hierarchical brain organization is disrupted with a consciousness-level-signature role of the default mode network. In conclusion, large-scale brain network temporal dynamics capture differences in anesthetic-specific consciousness-level, paving the way towards a clinical translation of these cortical signature.


Assuntos
Encéfalo , Estado de Consciência , Imageamento por Ressonância Magnética , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Animais , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Humanos , Anestesia , Masculino , Macaca mulatta , Adulto , Rede Nervosa/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Feminino , Mapeamento Encefálico/métodos
15.
Proc Natl Acad Sci U S A ; 121(25): e2405588121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38861607

RESUMO

Many animals can extract useful information from the vocalizations of other species. Neuroimaging studies have evidenced areas sensitive to conspecific vocalizations in the cerebral cortex of primates, but how these areas process heterospecific vocalizations remains unclear. Using fMRI-guided electrophysiology, we recorded the spiking activity of individual neurons in the anterior temporal voice patches of two macaques while they listened to complex sounds including vocalizations from several species. In addition to cells selective for conspecific macaque vocalizations, we identified an unsuspected subpopulation of neurons with strong selectivity for human voice, not merely explained by spectral or temporal structure of the sounds. The auditory representational geometry implemented by these neurons was strongly related to that measured in the human voice areas with neuroimaging and only weakly to low-level acoustical structure. These findings provide new insights into the neural mechanisms involved in auditory expertise and the evolution of communication systems in primates.


Assuntos
Percepção Auditiva , Imageamento por Ressonância Magnética , Neurônios , Vocalização Animal , Voz , Animais , Humanos , Neurônios/fisiologia , Voz/fisiologia , Imageamento por Ressonância Magnética/métodos , Vocalização Animal/fisiologia , Percepção Auditiva/fisiologia , Masculino , Macaca mulatta , Encéfalo/fisiologia , Estimulação Acústica , Mapeamento Encefálico/métodos
16.
Proc Natl Acad Sci U S A ; 121(25): e2400601121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38861608

RESUMO

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.


Assuntos
20-Hidroxiesteroide Desidrogenases , Decídua , Inflamação , Macaca mulatta , Parto , Progesterona , Células Estromais , Feminino , Animais , Progesterona/metabolismo , Progesterona/farmacologia , Decídua/metabolismo , Humanos , Camundongos , Células Estromais/metabolismo , Gravidez , Inflamação/metabolismo , 20-Hidroxiesteroide Desidrogenases/metabolismo , 20-Hidroxiesteroide Desidrogenases/genética , Interleucina-1beta/metabolismo , Córion/metabolismo
17.
Sci Adv ; 10(24): eadk3953, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875332

RESUMO

The human ability to perceive vivid memories as if they "float" before our eyes, even in the absence of actual visual stimuli, captivates the imagination. To determine the neural substrates underlying visual memories, we investigated the neuronal representation of working memory content in the primary visual cortex of monkeys. Our study revealed that neurons exhibit unique responses to different memory contents, using firing patterns distinct from those observed during the perception of external visual stimuli. Moreover, this neuronal representation evolves with alterations in the recalled content and extends beyond the retinotopic areas typically reserved for processing external visual input. These discoveries shed light on the visual encoding of memories and indicate avenues for understanding the remarkable power of the mind's eye.


Assuntos
Memória de Curto Prazo , Neurônios , Córtex Visual Primário , Percepção Visual , Animais , Neurônios/fisiologia , Memória de Curto Prazo/fisiologia , Córtex Visual Primário/fisiologia , Percepção Visual/fisiologia , Estimulação Luminosa , Macaca mulatta , Córtex Visual/fisiologia
18.
Nat Commun ; 15(1): 5093, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877003

RESUMO

The capacity of HIV-1 to replicate during optimal antiretroviral therapy (ART) is challenging to assess directly. To gain greater sensitivity to detect evolution on ART, we used a nonhuman primate (NHP) model providing precise control over the level of pre-ART evolution and more comprehensive analyses than are possible with clinical samples. We infected 21 rhesus macaques (RMs) with the barcoded virus SIVmac239M and initiated ART early to minimize baseline genetic diversity. RMs were treated for 285-1200 days. We used several tests of molecular evolution to compare 1352 near-full-length (nFL) SIV DNA single genome sequences from PBMCs, lymph nodes, and spleen obtained near the time of ART initiation and those present after long-term ART, none of which showed significant changes to the SIV DNA population during ART in any animal. To investigate the possibility of ongoing replication in unsampled putative tissue sanctuaries during ART, we discontinued treatment in four animals and confirmed that none of the 336 nFL SIV RNA sequences obtained from rebound plasma viremia showed evidence of evolution. The rigorous nature of our analyses reinforced the emerging consensus of a lack of appreciable ongoing replication on effective ART and validates the relevance of this NHP model for cure studies.


Assuntos
Antirretrovirais , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Replicação Viral , Animais , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/fisiologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Antirretrovirais/uso terapêutico , Evolução Molecular , RNA Viral/genética , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/virologia , DNA Viral/genética , Masculino
19.
Nat Commun ; 15(1): 5105, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877026

RESUMO

Spatial attention is critical for recognizing behaviorally relevant objects in a cluttered environment. How the deployment of spatial attention aids the hierarchical computations of object recognition remains unclear. We investigated this in the laminar cortical network of visual area V4, an area strongly modulated by attention. We found that deployment of attention strengthened unique dependencies in neural activity across cortical layers. On the other hand, shared dependencies were reduced within the excitatory population of a layer. Surprisingly, attention strengthened unique dependencies within a laminar population. Crucially, these modulation patterns were also observed during successful behavioral outcomes that are thought to be mediated by internal brain state fluctuations. Successful behavioral outcomes were also associated with phases of reduced neural excitability, suggesting a mechanism for enhanced information transfer during optimal states. Our results suggest common computation goals of optimal sensory states that are attained by either task demands or internal fluctuations.


Assuntos
Atenção , Macaca mulatta , Córtex Visual , Córtex Visual/fisiologia , Atenção/fisiologia , Masculino , Animais , Estimulação Luminosa , Percepção Visual/fisiologia , Neurônios/fisiologia
20.
J Vis ; 24(6): 12, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38884544

RESUMO

Neural population activity in sensory cortex informs our perceptual interpretation of the environment. Oftentimes, this population activity will support multiple alternative interpretations. The larger the spread of probability over different alternatives, the more uncertain the selected perceptual interpretation. We test the hypothesis that the reliability of perceptual interpretations can be revealed through simple transformations of sensory population activity. We recorded V1 population activity in fixating macaques while presenting oriented stimuli under different levels of nuisance variability and signal strength. We developed a decoding procedure to infer from V1 activity the most likely stimulus orientation as well as the certainty of this estimate. Our analysis shows that response magnitude, response dispersion, and variability in response gain all offer useful proxies for orientation certainty. Of these three metrics, the last one has the strongest association with the decoder's uncertainty estimates. These results clarify that the nature of neural population activity in sensory cortex provides downstream circuits with multiple options to assess the reliability of perceptual interpretations.


Assuntos
Macaca mulatta , Estimulação Luminosa , Córtex Visual , Animais , Córtex Visual/fisiologia , Estimulação Luminosa/métodos , Percepção Visual/fisiologia , Masculino , Orientação/fisiologia , Neurônios/fisiologia
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