Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log10, and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches.

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.

Gene expression in the primate orbitofrontal cortex related to anxious temperament.

Anxiety disorders are among the most prevalent psychiatric disorders, causing significant suffering and disability. Relative to other psychiatric disorders, anxiety disorders tend to emerge early in life, supporting the importance of developmental mechanisms in their emergence and maintenance. Behavioral inhibition (BI) is a temperament that emerges early in life and, when stable and extreme, is linked to an increased risk for the later development of anxiety disorders and other stress-related psychopathology. Understanding the neural systems and molecular mechanisms underlying this dispositional risk could provide insight into treatment targets for anxiety disorders. Nonhuman primates (NHPs) have an anxiety-related temperament, called anxious temperament (AT), that is remarkably similar to BI in humans, facilitating the design of highly translational models for studying the early risk for stress-related psychopathology. Because of the recent evolutionary divergence between humans and NHPs, many of the anxiety-related brain regions that contribute to psychopathology are highly similar in terms of their structure and function, particularly with respect to the prefrontal cortex. The orbitofrontal cortex plays a critical role in the flexible encoding and regulation of threat responses, in part through connections with subcortical structures like the amygdala. Here, we explore individual differences in the transcriptional profile of cells within the region, using laser capture microdissection and single nuclear sequencing, providing insight into the molecules underlying individual differences in AT-related function of the pOFC, with a particular focus on previously implicated cellular systems, including neurotrophins and glucocorticoid signaling.

Propagating spatiotemporal activity patterns across macaque motor cortex carry kinematic information.

Propagating spatiotemporal neural patterns are widely evident across sensory, motor, and association cortical areas. However, it remains unclear whether any characteristics of neural propagation carry information about specific behavioral details. Here, we provide the first evidence for a link between the direction of cortical propagation and specific behavioral features of an upcoming movement on a trial-by-trial basis. We recorded local field potentials (LFPs) from multielectrode arrays implanted in the primary motor cortex of two rhesus macaque monkeys while they performed a 2D reach task. Propagating patterns were extracted from the information-rich high-gamma band (200 to 400 Hz) envelopes in the LFP amplitude. We found that the exact direction of propagating patterns varied systematically according to initial movement direction, enabling kinematic predictions. Furthermore, characteristics of these propagation patterns provided additional predictive capability beyond the LFP amplitude themselves, which suggests the value of including mesoscopic spatiotemporal characteristics in refining brain-machine interfaces.

Neuronal Activity in the Gustatory Cortex during Economic Choice.

An economic choice entails computing and comparing the values of individual offers. Offer values are represented in the orbitofrontal cortex (OFC)-an area that participates in value comparison-but it is unknown where offer values are computed in the first place. One possibility is that this computation takes place in OFC. Alternatively, offer values might be computed upstream of OFC. For choices between edible goods, a primary candidate is the gustatory region of the anterior insula (gustatory cortex, GC). Here we recorded from the GC of male rhesus monkeys choosing between different juice types. As a population, neurons in GC represented the flavor, the quantity, and the subjective value of the juice chosen by the animal. These variables were represented by distinct groups of cells and with different time courses. Specifically, chosen value signals emerged shortly after offer presentation, while neurons encoding the chosen juice and the chosen quantity peaked after juice delivery. Surprisingly, neurons in GC did not represent individual offer values in a systematic way. In a computational sense, the variables encoded in GC follow the process of value comparison. Thus our results argue against the hypothesis that offer values are computed in GC. At the same time, signals representing the subjective value of the expected reward indicate that responses in GC are not purely sensory. Thus neuronal responses in GC appear consummatory in nature.

Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates.

Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and the highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore, to better understand the impact of COVID-19 on the brain, we used mass-spectrometry-based proteomics with a data-independent acquisition mode to investigate cerebrospinal fluid (CSF) proteins collected from two different nonhuman primates, Rhesus Macaque and African Green Monkeys, for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe central nervous system (CNS) pathology. Our results indicated that CSF proteome changes after infection resolution corresponded with bronchial virus abundance during early infection and revealed substantial differences between the infected nonhuman primates and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals exhibited highly scattered data distributions compared to their corresponding controls indicating the heterogeneity of the CSF proteome change and the host response to the viral infection. Dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis, and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping these dysregulated proteins to the Human Brain Protein Atlas found that they tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It, therefore, appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.

Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.

Low-cost, portable, easy-to-use kiosks to facilitate home-cage testing of nonhuman primates during vision-based behavioral tasks.

Nonhuman primates (NHPs), especially rhesus macaques, have significantly contributed to our understanding of the neural computations underlying human vision. Besides the established homologies in the visual brain areas between these species and our ability to probe detailed neural mechanisms in monkeys at multiple scales, NHPs' ability to perform human-like visual behavior makes them an extremely appealing animal model of human vision. Traditionally, such behavioral studies have been conducted in controlled laboratory settings, offering experimenters tight control over variables like luminance, eye movements, and auditory interference. However, in-lab experiments have several constraints, including limited experimental time, the need for dedicated human experimenters, additional lab space requirements, invasive surgeries for headpost implants, and extra time and training for chairing and head restraints. To overcome these limitations, we propose adopting home-cage behavioral training and testing of NHPs, enabling the administration of many vision-based behavioral tasks simultaneously across multiple monkeys with reduced human personnel requirements, no NHP head restraint, and monkeys' unrestricted access to experiments. In this article, we present a portable, low-cost, easy-to-use kiosk system developed to conduct home-cage vision-based behavioral tasks in NHPs. We provide details of its operation and build to enable more open-source development of this technology. Furthermore, we present validation results using behavioral measurements performed in the lab and in NHP home cages, demonstrating the system's reliability and potential to enhance the efficiency and flexibility of NHP behavioral research.NEW & NOTEWORTHY Training nonhuman primates (NHPs) for vision-based behavioral tasks in a laboratory setting is a time-consuming process and comes with many limitations. To overcome these challenges, we have developed an affordable, open-source, wireless, touchscreen training system that can be placed in the NHPs' housing environment. This system enables NHPs to work at their own pace. It provides a platform to implement continuous behavioral training protocols without major experimenter intervention and eliminates the need for other standard practices like NHP chair training, collar placement, and head restraints. Hence, these kiosks ultimately contribute to animal welfare and therefore better-quality neuroscience in the long run. In addition, NHPs quickly learn complex behavioral tasks using this system, making it a promising tool for wireless electrophysiological research in naturalistic, unrestricted environments to probe the relation between brain and behavior.

Perinatal Western-style diet exposure associated with decreased microglial counts throughout the arcuate nucleus of the hypothalamus in Japanese macaques.

Perinatal exposure to a high-fat, high-sugar Western-style diet (WSD) is associated with altered neural circuitry in the melanocortin system. This association may have an underlying inflammatory component, as consumption of a WSD during pregnancy can lead to an elevated inflammatory environment. Our group previously demonstrated that prenatal WSD exposure was associated with increased markers of inflammation in the placenta and fetal hypothalamus in Japanese macaques. In this follow-up study, we sought to determine whether this heightened inflammatory state persisted into the postnatal period, as prenatal exposure to inflammation has been shown to reprogram offspring immune function and long-term neuroinflammation would present a potential means for prolonged disruptions to microglia-mediated neuronal circuit formation. Neuroinflammation was approximated in 1-yr-old offspring by counting resident microglia and peripherally derived macrophages in the region of the hypothalamus examined in the fetal study, the arcuate nucleus (ARC). Microglia and macrophages were immunofluorescently stained with their shared marker, ionized calcium-binding adapter molecule 1 (Iba1), and quantified in 11 regions along the rostral-caudal axis of the ARC. A mixed-effects model revealed main effects of perinatal diet (P = 0.011) and spatial location (P = 0.003) on Iba1-stained cell count. Perinatal WSD exposure was associated with a slight decrease in the number of Iba1-stained cells, and cells were more densely located in the center of the ARC. These findings suggest that the heightened inflammatory state experienced in utero does not persist postnatally. This inflammatory response trajectory could have important implications for understanding how neurodevelopmental disorders progress.NEW & NOTEWORTHY Prenatal Western-style diet exposure is associated with increased microglial activity in utero. However, we found a potentially neuroprotective reduction in microglia count during early postnatal development. This trajectory could inform the timing of disruptions to microglia-mediated neuronal circuit formation. Additionally, this is the first study in juvenile macaques to characterize the distribution of microglia along the rostral-caudal axis of the arcuate nucleus of the hypothalamus. Nearby neuronal populations may be greater targets during inflammatory insults.

SARS-CoV-2 in Captive Nonhuman Primates, Spain, 2020-2023.

We conducted a serologic and molecular study to assess exposure of captive nonhuman primates (NHPs) to SARS-CoV-2 in Spain during the 2020-2023 COVID-19 pandemic. We found limited exposure of NHPs to SARS-CoV-2. Biosafety measures must be strictly maintained to avoid SARS-CoV-2 reverse-zoonotic transmission in the human-NHP interface.

Multiple infusions of ex vivo-expanded regulatory T cells promote CD163+ myeloid cells and kidney allograft survival in non-lymphodepleted non-human primates.

Clinical verification of adoptively transferred regulatory T cell (Treg) efficacy in transplantation remains challenging. Here, we examined the influence of autologous ex vivo-expanded polyclonal Tregs on kidney graft survival in a clinically relevant non-human primate model. Peripheral blood Tregs were isolated and expanded using artificial antigen presenting cells. Immunosuppression was comprised of tapered tacrolimus and CTLA4 immunoglobulin, in five animals each without or with Treg infusions. Escalating Treg doses were administered 6, 10, 13, 16, 20, 23, 27 and 30 days after transplant. Infused Tregs were monitored for Treg signature, anti-apoptotic (Bcl-2) and proliferation (Ki67) marker expression. Treg infusions prolonged median graft survival time significantly from 35 to 70 days. Treg marker (Ki67 and Bcl-2) expression by infused Tregs diminished after their infusion but remained comparable to that of circulating native Tregs. No major changes in circulating donor-reactive T cell responses or total Treg percentages, or in graft-infiltrating T cell subsets were observed with Treg infusion. However, Treg infusion was associated with significant increases in CD163 expression by circulating HLA-DR+ myeloid cells and elevated levels of circulating soluble CD163. Further, graft-infiltrating CD163+ cells were increased with Treg infusion. Thus, multiple Treg infusions were associated with M2-like myeloid cell enhancement that may mediate immunomodulatory, anti-inflammatory and graft reparative effects.

Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production.

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

Lymph-Node-Based CD3+ CD20+ Cells Emerge from Membrane Exchange between T Follicular Helper Cells and B Cells and Increase Their Frequency following Simian Immunodeficiency Virus Infection.

CD4+ T follicular helper (TFH) cells are key targets for human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication and contribute to the virus reservoir under antiretroviral therapy (ART). Here, we describe a novel CD3+ CD20+ double-positive (DP) lymphocyte subset, resident in secondary lymphoid organs of humans and rhesus macaques (RMs), that appear predominantly after membrane exchange between TFH and B cells. DP lymphocytes are enriched in cells displaying a TFH phenotype (CD4+ PD1hi CXCR5hi), function (interleukin 21 positive [IL-21+]), and gene expression profile. Importantly, expression of CD40L upon brief in vitro mitogen stimulation identifies, by specific gene-expression signatures, DP cells of TFH-cell origin versus those of B-cell origin. Analysis of 56 RMs showed that DP cells (i) significantly increase following SIV infection, (ii) are reduced after 12 months of ART in comparison to pre-ART levels, and (iii) expand to a significantly higher frequency following ART interruption. Quantification of total SIV-gag DNA on sorted DP cells from chronically infected RMs showed that these cells are susceptible to SIV infection. These data reinforce earlier observations that CD20+ T cells are infected and expanded by HIV infection, while suggesting that these cells phenotypically overlap activated CD4+ TFH cells that acquire CD20 expression via trogocytosis and can be targeted as part of therapeutic strategies aimed at HIV remission. IMPORTANCE The HIV reservoir is largely composed of latently infected memory CD4+ T cells that persist during antiretroviral therapy and constitute a major barrier toward HIV eradication. In particular, CD4+ T follicular helper cells have been demonstrated as key targets for viral replication and persistence under ART. In lymph nodes from HIV-infected humans and SIV-infected rhesus macaques, we show that CD3+ CD20+ lymphocytes emerge after membrane exchange between T cells and B cells and are enriched in phenotypic, functional, and gene expression profiles found in T follicular helper cells. Furthermore, in SIV-infected rhesus macaques, these cells expand following experimental infection and after interruption of ART and harbor SIV DNA at levels similar to those found in CD4+ T cells; thus, CD3+ CD20+ lymphocytes are susceptible to SIV infection and can contribute to SIV persistence.

Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

Determining the safety of the tobacco cembranoid (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R): A translational study in nonhuman primates.

The tobacco cembranoid known as (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (4R) has been shown to offer neuroprotection against conditions such as brain ischemia, systemic inflammation, Parkinson's disease, and organophosphate toxicity in rodents. Previous safety studies conducted on male and female Sprague Dawley rats revealed no significant side effects following a single injection of 4R at varying concentrations (6, 24, or 98 mg/kg of body weight). This study aimed to assess the potential of 4R for clinical trials in neurotherapy in male nonhuman primates. Ten macaques (Macacca mulatta) were randomly separated into two groups of 5 and then intravenously injected with 4R or vehicle for 11 consecutive days at a dose of 1.4 mg/kg. Throughout the study, we monitored brain activity by electroencephalogram, somatosensory evoked potentials, and transcranial motor evoked potentials on days 0, 4, 8, and 12 and found no significant changes. The spontaneous behavior of the primates remained unaffected by the treatment. Minor hematological and blood composition variations were also detected in the experimental animals but lacked clinical significance. In conclusion, our results reinforce the notion that 4R is non-toxic in nonhuman primates under the conditions of this study.

Reconstruction of large scalp defect in a brown howler monkey (Alouatta guariba clamitans): A case report.

This case report describes different repair techniques used to reconstruct a large scalp defect in a brown howler monkey (Alouatta guariba clamitans) hit by a vehicle. Three reconstructive procedures were performed in two surgical stages. The repair techniques had successful outcomes on the patient's rehabilitation.

Mammalian models of status epilepticus - Their value and limitations.

Status epilepticus (SE) is a medical and neurologic emergency that may lead to permanent brain damage, morbidity, or death. Animal models of SE are particularly important to study the pathophysiology of SE and mechanisms of SE resistance to antiseizure medications with the aim to develop new, more effective treatments. In addition to rodents (rats or mice), larger mammalian species such as dogs, pigs, and nonhuman primates are used. This short review describes and discusses the value and limitations of the most frequently used mammalian models of SE. Issues that are discussed include (1) differences between chemical and electrical SE models; (2) the role of genetic background and environment on SE in rodents; (3) the use of rodent models (a) to study the pathophysiology of SE and mechanisms of SE resistance; (b) to study developmental aspects of SE; (c) to study the efficacy of new treatments, including drug combinations, for refractory SE; (d) to study the long-term consequences of SE and identify biomarkers; (e) to develop treatments that prevent or modify epilepsy; (e) to study the pharmacology of spontaneous seizures; (4) the limitations of animal models of induced SE; and (5) the advantages (and limitations) of naturally (spontaneously) occurring SE in epileptic dogs and nonhuman primates. Overall, mammalian models of SE have significantly increased our understanding of the pathophysiology and drug resistance of SE and identified potential targets for new, more effective treatments. This paper was presented at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in April 2024.

A paleo-neurologic investigation of the social brain hypothesis in frontotemporal dementia.

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.

Microstimulation in the primary visual cortex: activity patterns and their relation to visual responses and evoked saccades.

Intracortical microstimulation (ICMS) in the primary visual cortex (V1) can generate the visual perception of a small point of light, termed phosphene, and evoke saccades directed to the receptive field of the stimulated neurons. Although ICMS is widely used, a direct measurement of the spatio-temporal patterns of neural activity evoked by ICMS and their relation to the neural responses evoked by visual stimuli or how they relate to ICMS-evoked saccades are still missing. To investigate this, we combined ICMS with voltage-sensitive dye imaging in V1 of behaving monkeys and measured neural activity at a high spatial (meso-scale) and temporal resolution. We then compared the population response evoked by small visual stimuli to those evoked by microstimulation. Both stimulation types evoked population activity that spread over few millimeters in V1 and propagated to extrastriate areas. However, the population responses evoked by ICMS have shown faster dynamics for the activation transients and the horizontal propagation of activity revealed a wave-like propagation. Finally, neural activity in the ICMS condition was higher for trials with evoked saccades as compared with trials without saccades. Our results uncover the spatio-temporal patterns evoked by ICMS and their relation to visual processing and saccade generation.

Liver injury in cynomolgus monkeys following intravenous and intrathecal scAAV9 gene therapy delivery.

Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to ∼2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context.