Biology subjects

Morrison, J. H.

Publications and source records attributed to Morrison, J. H..

16 recordsLinked to original sources

bioRxiv2026

Progressive loss of independence in neuronal representations predicts cognitive decline

Intelligent behavior depends on the brains ability to represent multiple features of the environment simultaneously while keeping those representations independent1,2. Patients with Alzheimers disease often mix up objects, people, and events3-7, raising the possibility that disease mixes up the way that information is represented in the brain. Here we show that the independence of visual representations progressively breaks down during early stages of disease progression in a rhesus macaque model of Alzheimers disease and related dementias8-10. In visual area V4, representations of different visual features become progressively less independent, such that the representation of one feature is increasingly influenced by the value of another. We term this loss of independence neuronal feature confusion. This neuronal change predicts a specific behavioral consequence: because feature representations become less independent, preferences associated with one visual feature increasingly influence visually guided choices associated with other, independent features. Using an analogous image-selection task, we found the same behavioral signature in people with mild cognitive impairment, distinguishing them from age-matched controls. These results identify a specific and measurable alteration in neuronal population representations that predicts a behavioral change observed across species. More broadly, these findings demonstrate that neuronal population representations can guide the development of sensitive, non-invasive behavioral methods for early detection of functional changes associated with Alzheimers disease.

neuroscience↗

bioRxiv2026

Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease

Alzheimers disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.

neuroscience↗

bioRxiv2025

Separable global and local beta burst dynamics in motor cortex of primates

Sensorimotor beta band oscillations are known to modulate during normal movement control and abnormal beta modulation is linked to pathological bradykinesia. However, the functional differences between beta localized to one brain area versus beta synchronized across brain areas remains unclear. We monitored beta bursts in non-human primates, both neurotypical and stroke- impaired, during the performance of complex motor tasks. Across both groups of animals, we identified two distinct beta burst types: global bursts that tend to be synchronized across cortical and subcortical areas, and local bursts that tend to be confined to cortex. These two types exhibited distinct neural dynamics, with global bursts linked to reduced firing variability and overall slowed movements. In contrast, local bursts often occurred during the execution of complex behaviors, particularly during prehension. We found evidence for changes in the distribution of global and local bursts during recovery after stroke. In impaired animals early after stroke, global bursts predominated and were associated with reduced speed and impaired grasping. Notably, recovery of grasping was associated with a reduction in global bursts and an increase in local bursts, suggesting that local bursts may play an important role during prehension. Our findings reveal distinct roles of global and local beta bursts and indicate that the normalization of global and local burst timing tracks recovery of dexterity.

neuroscience↗

bioRxiv2025

Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B) varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity, and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimers Disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which is treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in the rhesus macaque SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendritic shafts and spines of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and to neurodegenerative forces. Scope StatementNMDAR are ionotropic receptors that contribute to neurotransmission and second messenger signaling events. NMDAR can induce a diverse array of neuronal events, in part due to variation in subunit composition and subcellular localization of receptor expression. Expression of the GluN2B subunit varies across the prefrontal cortex in humans. This subunit is highly expressed in the subgenual cingulate, an area associated with mood and emotion, and more moderately expressed in the dorsolateral prefrontal cortex, an area associated with cognitive processes. Extrasynaptic NMDAR, which often contain with the GluN2B subunit, have been linked to detrimental cellular events like neurodegeneration. Here, using high resolution electron microscopy in rhesus macaques, we found evidence that extrasynaptic NMDAR-GluN2B expression may be more prominent in subgenual cortex than in the dorsolateral prefrontal cortex. Conversely, synaptic NMDAR-GluN2B may be more prominent in the dorsolateral prefrontal cortex, consistent with their essential contribution to neuronal firing during working memory. These findings may help to illuminate the propensity of the subgenual cortex to tonic hyperactivity in major depression and its vulnerability to neurodegeneration in Alzheimers disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.

neuroscience↗

bioRxiv2025

ADAR1 haploinsufficiency and sustained viral RdRp dsRNA synthesis synergize to dysregulate RNA editing and cause multi-system interferonopathy

Sensing of viral double-stranded RNA by MDA5 triggers abundant but transient interferon-stimulated gene (ISGs) expression. If dsRNA synthesis is made persistent by transgenically expressing a picornaviral RNA-dependent RNA polymerase (RdRp) in mice, lifelong MDA5-MAVS pathway activation and marked, global ISG upregulation result. This confers robust protection from viral diseases but in contrast to numerous other chronic MDA5 hyperactivation states, the mice suffer no autoimmune or other health consequences. Here we find they further confound expectations by being resistant to a strong autoimmunity (lupus) provocation. However, knockout of one allele of Adar breaks the autoinflammation-protected state of RdRptg mice and results in a severe disease that resembles interferonopathies caused by MDA5 gain-of-function protein mutations. Adar+/- mice are healthy but Adar+/- RdRptg mice have shortened lifespan, stunted growth, premature fur graying, poorly developed teeth, skeletal abnormalities, and extreme ISG elevations. A-to-I edits are both abnormally distributed and increased (numbers of genes and sites). These results, with a nucleic acid-triggered and MDA5-wild type model, illuminate the ADAR1-MDA5 axis in the regulation of innate immunity and establish that viral polymerase-sourced dsRNA can drive autoinflammatory disease pathogenesis. IMPORTANCERNA virus double-stranded RNAs are important pathogen associated molecular patterns that are sensed by the RIG-I like receptor MDA5, which triggers an acute innate immune response involving many ISGs. One key to a healthy innate immune system is that MDA5 not sense endogenous dsRNA. This is normally ensured by dsRNA duplex-disrupting ADAR1 editing of host dsRNAs. Picornavirus RdRptg mice have an unusual constitutive MDA5 activation state, with very high lifelong MDA5-mediated ISG expression that confers robust protection from diverse lethal viruses. Importantly, and in contrast to numerous other chronic MDA5 hyperactivation states, the mice develop no autoinflammatory consequences. If we delete one ADAR1 allele, however, which by itself is well tolerated, the mice develop a multisystem disease that resembles the human interferonopathy Singleton-Merten syndrome. In contrast to other MDA5/ADAR1 disease models, the MDA5 and ADAR1 proteins are both wild type in this dsRNA-driven model.

immunology↗

bioRxiv2023

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside other CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4 T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL57 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4 T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4 T cells in CNS immune surveillance and their decline during chronic SIV-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/555037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@191f9caorg.highwire.dtl.DTLVardef@a67d2dorg.highwire.dtl.DTLVardef@645443org.highwire.dtl.DTLVardef@d81fd6_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefUtilizing single-cell and spatial transcriptomics on adult rhesus brain, we uncover a unique CCR7+ CD4 T cell subset resembling central memory T cells (TCM) within brain and border tissues, including skull bone marrow. Our findings show decreased frequencies of this subset during SIV- induced chronic neuroinflammation, emphasizing responsiveness of CCR7+ CD4 T cells to CNS disruptions. HighlightsO_LICCR7+ CD4 T cells survey border and parenchymal CNS compartments during homeostasis; reduced presence of CCR7+ CD4 T cells in cerebrospinal fluid leads to immune activation, implying a role in neuroimmune homeostasis. C_LIO_LICNS CCR7+ CD4 T cells exhibit phenotypic and functional features of central memory T cells (TCM) including production of interleukin 2 and the capacity for rapid recall proliferation. Furthermore, CCR7+ CD4 T cells reside in the skull bone marrow. C_LIO_LICCR7+ CD4 T cells are markedly decreased within the brain parenchyma during chronic viral neuroinflammation. C_LI

neuroscience↗

bioRxiv2023

CD4 T cell Responses in the CNS during SIV infection

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS) - known as Neuro-HIV-persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Despite viral suppression with ART, acute infection led to significant depletion of CNS CD4 T cells, persisting into the chronic phase. These findings underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our results offer insights for potential T cell-focused interventions while also underscoring the challenges in eradicating HIV from the CNS, even with effective ART. AUTHOR SUMMARYAntiretroviral therapy (ART) has improved health outcomes of people living with HIV. However, there are still challenges, especially in the central nervous system (CNS), where ongoing inflammation can lead to neurological disorders. Our study focused on understanding the role of CD4 T cells in the brain during HIV infection and treatment. We used a model with SIV-infected rhesus monkeys to study the AIDS virus in the brain and surrounding tissues. We discovered that a subset of CD4 T cells, which are vulnerable to HIV, are present throughout the CNS. During the early stages of infection, we noticed high levels of the virus in both the brain and nearby tissues. By examining these CD4 T cells at a single-cell level, we found that they actively respond to the virus by activating specific antiviral effector functions to fight it. Although ART controlled virus replication in the brain, CD4 T cells were continuously depleted, indicative of immune perturbations. Overall, our study helps us understand the role of CD4 T cells within the CNS during both acute and chronic HIV infection. This knowledge could help us develop new ways to target the virus in the CNS and devise treatments for complications related to Neuro-HIV.

neuroscience↗

bioRxiv2021

A Lentiviral Envelope Signal Sequence is a Tetherin Antagonizing Protein

Signal sequences are N-terminal peptides, generally less than 30 amino acids in length, that direct translocation of proteins into the endoplasmic reticulum and secretory pathway. The envelope glycoprotein (Env) of the nonprimate lentivirus Feline immunodeficiency virus (FIV) contains the longest signal sequence of all eukaryotic, prokaryotic and viral proteins (175 amino acids). The reason is unknown. Tetherin is a dual membrane-anchored host protein that inhibits the release of enveloped viruses from cells. Primate lentiviruses have evolved three antagonists: the small accessory proteins Vpu and Nef, and in the case of HIV-2, Env. Here we identify the FIV Env signal sequence (Fess) as the FIV tetherin antagonist. A short deletion in the central portion of Fess had no effect on viral replication in the absence of tetherin but severely impaired virion budding in its presence. Fess is necessary and sufficient, acting as an autonomous accessory protein with the rest of Env dispensable. In contrast to primate lentivirus tetherin antagonists, it functions by stringently blocking the incorporation of this restriction factor into viral particles rather than by degrading it or downregulating it from the plasma membrane.

microbiology↗

bioRxiv2021

Vivarium: an interface and engine for integrative multiscale modeling in computational biology

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSThis paper introduces Vivarium - software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models, and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists. ResultsVivarium is a Pythonic software for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs, and run with Vivariums simulation engine. Vivariums utility is demonstrated by building composite models that combine several modeling frameworks: agent based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics, and spatial diffusion. This demonstrates just the beginning of what is possible - future efforts can integrate many more types of models and at many more biological scales. AvailabilityThe models, simulation pipelines, and notebooks developed for this paper are available at the vivarium-notebooks repository: https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available at https://github.com/vivarium-collective/vivarium-core, and has been released on PyPI. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely-available Vivarium processes and composites, including the processes used in Section 3. Supplementary materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces.

systems biology↗

bioRxiv2021

Whole-Colony Modeling of Escherichia coli

Bacterial behavior is the outcome of both molecular mechanisms within each cell and interactions between cells in the context of their environment. Whereas whole-cell models simulate a single cells behavior using molecular mechanisms, agent-based models simulate many agents independently acting and interacting to generate complex collective phenomena. To synthesize agent-based and whole-cell modeling, we used a novel model integration software, called Vivarium, to construct an agent-based model of E. coli colonies where each agent is represented by a current source code snapshot from the E. coli Whole-Cell Modeling Project and interacts with other cells in a shared spatial environment. The result is the first "whole-colony" computational model that mechanistically links expression of individual proteins to a population-level phenotype. Simulated colonies exhibit heterogeneous effects on their environments, heterogeneous gene expression, and media-dependent growth. Extending the cellular model with mechanisms of antibiotic susceptibility and resistance, our model also suggested that variation in the expression level of the betalactamase AmpC, and not of the multi-drug efflux pump AcrAB-TolC, was the key mechanistic driver of survival in the presence of nitrocefin. We see this as a significant step forward in the creation of more comprehensive multi-scale models, and it broadens the range of phenomena that can be modeled in mechanistic terms. Author summaryThis work combines several models of molecular and physical processes that impact the physiology and behavior of the common microbe Escherichia coli into a multiscale model. Colonies comprised of multiple individual cells are simulated as they grow and divide--each with complex internal mechanisms, and with physical interactions and molecular diffusion in their environments. The integrative modeling methodology supports the addition of new submodels. The flexibility of this methodology is demonstrated by adding models of antibiotic resistance and simulating the colonys response to antibiotic treatment.

systems biology↗

bioRxiv2020

Neuroanatomical abnormalities in a nonhuman primate model of congenital Zika virus infection

Zika virus (ZIKV) infection of pregnant women can cause major congenital neuronal abnormalities. In the present study, we evaluated neuropathological consequences of fetal ZIKV exposure in rhesus macaques, a highly translatable animal model for human neural development. Quantitative neuroanatomical analyses of the nearly full-term brains of fetuses infected with ZIKV at gestational days 50, 64, and 90, and three procedure-matched sham-inoculated controls were carried out. Whole tissue sections across a complete cerebral hemisphere were evaluated using immunohistochemical and neuroanatomical staining techniques to detect virus localization, identify affected cell types and evaluate gross neuroanatomical abnormalities. None of the subjects were microcephalic. Immunohistochemical staining revealed the presence of ZIKV in the frontal lobe, which contained activated microglia and showed increased apoptosis of immature neurons. ZIKV-infected animals exhibited macrostructural changes within the occipital lobe, including a reduction in gyrification as well as a higher proportion of white matter. Finally, the ZIKV-infected subjects had abnormalities throughout the visual pathway, including disorganization within the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Regional differences tracked with the temporal patterns of the developing brain and likely reflect the neural progenitor cell tropism ZIKV exhibits - painting a picture of inflammatory processes related to viral infiltration sweeping through the cortex, followed by a wave of cell death resulting in morphological changes. These findings may help explain why some infants born with normal sized heads during the ZIKV epidemic manifest developmental challenges as they age, and ultimately may contribute to developing effective treatments and interventions. One sentence summaryMacaque fetuses infected with Zika virus show both macro- and micro-scale neuropathological abnormalities, including decreased gyrencephality, relative increases in cortical white matter, activation of glia, and increased apoptosis.

neuroscience↗

bioRxiv2020

Head-mounted microendoscopic calcium imaging in dorsal premotor cortex of behaving rhesus macaque

A major effort is now underway across the brain sciences to identify, characterize and manipulate mesoscale neural circuits in order to elucidate the mechanisms underlying sensory perception, cognition and behavior. Optical imaging technologies, in conjunction with genetically encoded sensors and actuators, serve as important tools toward these goals, allowing access to large-scale genetically defined neuronal populations. In particular, one-photon miniature microscopes, coupled with genetically encoded calcium indicators and microendoscopic gradient-refractive index (GRIN) lenses, enable unprecedented readout of neural circuit dynamics in cortical and deep subcortical brain regions during active behavior in rodents. This has already led to breakthrough discoveries across a wide array of rodent brain regions and behaviors. However, in order to study the neural circuit mechanisms underlying more complex and clinically relevant human behaviors and cognitive functions, it is crucial to translate this technology to non-human primates. Here, we describe the first successful application of this technology in the rhesus macaque. We identified a viral strategy for robust expression of GCaMP, optimized a surgical protocol for microendoscope GRIN lens insertion, and created a chronic cranial chamber and lens mounting system for imaging in gyral cortex. Using these methods, we demonstrate the ability to perform plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from over 100 genetically-targeted neurons simultaneously in dorsal premotor cortex while the macaque performs a naturalistic motor reach task with the head unrestrained and freely moving. The recorded population of neurons exhibited calcium dynamics selective to the direction of reach, which we show can be used to decode the animals trial-by-trial motor behavior. Recordings were stable over several months, allowing us to longitudinally track large populations of individual neurons and monitor their relationship to motor behavior over time. Finally, we demonstrate the ability to conduct simultaneous, multi-site imaging in bilateral dorsal premotor cortices, offering an opportunity to study distributed networks underlying complex behavior and cognition. Together, this work establishes head-mounted microendoscopic calcium imaging in macaque as a powerful new approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease. HighlightsFirst demonstration of head-mounted microendoscopic calcium imaging in behaving macaque. Surgical protocols developed for preparing the animal for calcium imaging, including virus injections to express GCaMP and chronic implantation of a GRIN lens to enable optical access to gyral cortex. Proof of concept plug-and-play calcium imaging in behaving macaques with months long stable recording capability allowing populations of individual neurons to be tracked longitudinally. Bilateral calcium imaging from dorsal premotor cortex exhibited dynamics selective to the animals direction of reach and allowed decoding of the animals motor behavior

neuroscience↗

bioRxiv2019

dsRNA-Seq: Identification of viral infection by purifying and sequencing dsRNA

RNA viruses are a major source of emerging and re-emerging infectious diseases around the world. We developed a method to identify RNA viruses that is based on the fact that all RNA viruses produce dsRNA while replicating. Purifying and sequencing dsRNA from total RNA isolated from infected tissue allowed us to recover replicating viral sequences. We refer to this approach as dsRNA-Seq. By assembling dsRNA sequences into contigs we identified full length RNA viruses of varying genome types infecting mammalian culture samples, identified a known viral disease agent in laboratory infected mice, and successfully detected naturally occurring RNA viral infections in reptiles. Here we show that dsRNA-Seq is a preferable method for identifying viruses in organisms that dont have sequenced genomes and/or commercially available rRNA depletion reagents. Similar to other metagenomic strategies, dsRNA-Seq has the potential to identify unknown viral disease agents that share little to no similarity to known viruses. However, the significant advantage of this method is the ability to identify replicated viral sequences, which is useful for distinguishing infectious viral agents from potential noninfectious viral particles or contaminants.

molecular biology↗

bioRxiv2018

Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

BackgroundSoluble oligomers of the A{beta} peptide (A{beta}Os) are toxins that target and disrupt synapses. Generation of A{beta}Os has been recently recognized as a probable initiating event in Alzheimers disease (AD), leading to cognitive impairment. There is a translational gap in AD studies, with promising drugs developed based on work in rodent models failing in AD patients in clinical trials. Additionally, although women have a two-fold greater lifetime risk of developing AD compared to men, females have not been a focus of preclinical studies. Thus, we sought to develop a model of A{beta}O toxicity in female rhesus monkeys, to take advantage of the more highly differentiated cortical structure in this species as well as the similarities in the endocrine system between rhesus monkeys and humans.\n\nMethodsRepeated intracerebroventricular (i.c.v) injections of A{beta}Os were performed in adult female rhesus monkeys. Controls were unoperated aged matched monkeys. High-resolution confocal microscopy and morphometric analysis of Alexa 568 (A568) filled neurons were used to evaluate synaptic, neuronal, and glial markers in the dorsolateral prefrontal cortex (dlPFC) and hippocampus after A{beta}O injections. Cerebrospinal fluid (CSF) and brain tissue were also collected and analyzed for biomarkers of AD pathology, including: phosphorylated Tau protein (pTau), total Tau, A{beta}1-42, A{beta}1-40 and TNF- levels.\n\nResultsHere, we report that A{beta}O injection into the lateral ventricle of the brain induces loss of 37% of thin spines in targeted dlPFC neurons, an area highly vulnerable in AD and aging. Further, A{beta}Os associate with the synaptic marker PSD95, inducing loss of more than 60% of local excitatory synapses. A{beta}Os induce a robust neuroinflammatory response in the hippocampus, far from the injection site, with numerous activated ameboid microglia and TNF- release. Finally, A{beta}Os increased CSF levels of A{beta}1-42, pTau Ser396 and pTau Ser199, but not A{beta}1-40 or total Tau.\n\nConclusionsThese initial findings from detailed quantitative analysis of effects of A{beta}O administration on synapses in a female nonhuman primate model are a very promising step toward understanding the mechanism of early AD pathogenesis in the primate brain, and may help develop an effective disease-modifying therapy of high relevance to womens health.

neuroscience↗

bioRxiv2018

Timing of Cyclic Estradiol Treatment Differentially Affects Cognition in Aged Female Rhesus Monkeys

Some evidence suggests that there may be a limited \"window of opportunity\" for beneficial effects of hormone therapy on physiology after menopause in women. We tested, in aged, surgically menopausal (ovariectomized) rhesus monkeys, whether the timing of cyclic estradiol (E2) treatment impacted its effect on cognitive function. Monkeys were assigned to one of four treatment conditions after ovariectomy: either vehicle or E2 treatment for the duration of the protocol, vehicle for the first 2 years of the protocol followed by E2 for the remainder (delayed treatment), or E2 for the first year of the protocol followed by vehicle for the remainder (withdrawn treatment). Delayed treatment addressed the hypothesis that E2 treatment initiated more than 2 years after ovariectomy would have a reduced effect on cognitive function. Withdrawn treatment mirrors current clinical advice to women to use hormone therapy in the initial post-menopausal period then discontinue it. Two periods of cognitive testing assessed treatment effects on cognition over time. E2 treatment predominantly affected a prefrontal cortex-dependent test of spatiotemporal working memory (delayed response). Monkeys with delayed E2 treatment improved in delayed response performance over time, whereas vehicle-treated monkeys declined. Monkeys with withdrawn E2 treatment maintained their performance across assessments, as did monkeys treated with E2 across the entire protocol. These findings suggest that a \"window of opportunity\" for hormone treatment after cessation of ovarian function, if present in nonhuman primates, lasts longer than 2 years. It also supports the notion that beneficial effects of hormone therapy may persist after discontinuation of treatment.

neuroscience↗

bioRxiv2017

An open resource for nonhuman primate imaging

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience.\n\nUnfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMate Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 13 independent data collections aggregated across 11 sites (total = 98 macaque monkeys). We also outline the unique pitfalls and challenges that should be considered in the analysis of the non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

neuroscience↗