Now a study led by Dr. David S. Williams, professor of ophthalmology and neurobiology at the David Geffen School of Medicine at UCLA, in collaboration with researchers at the University of California, Santa Barbara and Harvard, reports that the answer for primates is the opposite of what is seen in many other vertebrates. Working with retinal tissue near the fovea of Rhesus monkeys (Macaca mulatta), the team found that the majority of disk membranes in primate cones are closed, self-contained structures, much like the disks found in rod photoreceptors, the cells responsible for vision in dim light. The work, published in the Journal of Neuroscience, represents the first quantitative assessment of the relative proportion of open and closed disk membranes in a mammalian cone, and it settles a debate that has lingered since the earliest electron micrographs of the retina were first interpreted.

The significance of the question is easier to appreciate when one considers what the disks actually do. Phototransduction, the molecular cascade that turns a single photon into an electrical signal, takes place on these membranes. Light-sensitive opsin proteins and the G protein transducin are embedded in the disk membrane, and the second messenger cyclic GMP, along with calcium ions, diffuses in the compartments defined by the disk geometry. Whether the interior of a disk communicates freely with the space outside the cell or is sealed off changes the diffusion pathways available to these signaling molecules, the surface area available for protein trafficking, and the way in which the cell renews its light-sensitive machinery. Structure, in other words, is not a cosmetic detail; it constrains the entire operating logic of the photoreceptor.

Historically, the debate arose because different experimental approaches yielded apparently conflicting pictures. Early transmission electron microscopy of retinal sections produced images that some investigators interpreted as showing continuity between the disk rim and the plasma membrane, while others saw sealed, independent sacs. Preparation artifacts, the extreme fragility of photoreceptor outer segments, and the sheer difficulty of cutting and imaging tissue thin enough to resolve the relevant membranes all conspired to keep the question open. In non-mammalian cones, serial sectioning and physiological measurements converged on the conclusion that the disks are generally open, continuous evaginations of the plasma membrane, and many researchers assumed that mammalian cones would follow the same plan. Without quantitative data from primate tissue, however, the assumption remained exactly that: an assumption.

The UCLA-led team attacked the problem with two independent methods, each capable of addressing the question from a different direction. The first was electron tomography, a technique that goes beyond conventional two-dimensional electron micrographs by reconstructing three-dimensional volumes of tissue from a series of images taken at different tilt angles. Rather than inferring membrane topology from a single thin slice, tomography allows investigators to trace membranes through the volume and determine whether a given disk is sealed or whether it opens onto the extracellular space. Applied to the cone outer segments of the foveal region in Rhesus monkey retina, this approach provided direct structural evidence about the patency, or openness, of individual disk membranes.

The second approach was electrophysiological. If cone disks were open to the extracellular space, the electrical properties of the cell would reflect that continuity in measurable ways, because the membrane area accessible to ion channels and to the diffusion of charged signaling molecules would be organized differently than in a cell with sealed disks. By recording from primate cone photoreceptors and analyzing the electrical signatures of the outer segment, the researchers obtained functional evidence that could be compared directly against the structural data. The power of the study lies in this convergence: two methods with entirely different sources of potential error pointed to the same conclusion, and that conclusion contradicted the pattern established in non-mammalian vertebrates.

Through both approaches, the researchers found that the majority of disk membranes in primate cones are closed, independent structures. This is the configuration familiar from rod photoreceptors, whose disks are well established to be enclosed sacs that are periodically shed at the tip of the outer segment and renewed through new membrane synthesis at the base. The finding means that primate cones, despite their distinct morphology and their role in high-acuity color vision, share with rods the fundamental design principle of sealed disk membranes. It also means that textbooks and models of cone function, many of which have implicitly carried the open-disk assumption into discussions of mammalian and human vision, will need to be revised.

The implications extend into several areas of cell biology and physiology. Disk membrane renewal is one of the most remarkable housekeeping operations in the body: photoreceptors constantly rebuild their light-sensitive stacks, and in rods this involves the daily shedding and phagocytosis of aged disk packets by the retinal pigment epithelium. Whether cones renew their disks through a comparable process has been debated in its own right, and the closed architecture documented in this study provides a structural framework for understanding how such renewal could proceed in primate cones. Similarly, models of phototransduction depend on assumptions about the compartments in which cyclic GMP and calcium diffuse; sealed disks create a distinct intradiskal space whose ionic composition can be regulated separately from the extracellular environment, altering the dynamics of adaptation, the process by which photoreceptors adjust their sensitivity across enormous ranges of light intensity.

Because the tissue examined came from the region near the fovea, the part of the primate retina responsible for our sharpest, most detailed vision, the findings speak directly to human visual physiology. The Rhesus macaque is a well-established model for human retinal structure and function, and the cone-dominant foveal region is precisely where the stakes of the structural question are highest. Understanding that the disks in these cells are closed brings the structural biology of primate cones into alignment with the electrophysiological models that have been refined over decades, and it offers a corrected foundation for studying retinal diseases that target cones, including the macular degenerations that rob millions of people of central vision. The authors declare no competing financial interests, and the research was published as a peer-reviewed contribution to the Journal of Neuroscience under the title describing the ultrastructural and electrophysiological determination of monkey cone outer segment membrane patency.

What makes the study a striking example of basic science at its best is that it resolves, with modern tools, a question posed at the dawn of retinal ultrastructure. The combination of three-dimensional electron tomography with complementary electrophysiology provided the quantitative rigor that earlier generations of microscopists could not achieve, and the answer it delivered, that primate cone disks are closed like those of rods, reshapes how scientists will model phototransduction, disk renewal, and cone physiology in humans. After sixty years of uncertainty, the architecture of the cells that give primates their remarkable color vision is finally clear, and that clarity opens the door to a deeper understanding of how the eye builds sight from stacks of membrane only nanometers thick.

Subject of Research: Structural patency of disk membranes in primate cone photoreceptors

Article Title: Study from the Stein Eye Institute answers long-debated structural question of primate cone photoreceptors

Article References: Study from the Stein Eye Institute answers long-debated structural question of primate cone photoreceptors. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cone photoreceptors, retina, disk membranes, electron tomography, electrophysiology, phototransduction, Rhesus macaque, fovea, vision science, UCLA, Journal of Neuroscience, photoreceptor structure

The research, conducted by Ramona Siebert, Nick Taubert, Martin A. Giese, and Peter Thier at the University of Tübingen, trained two rhesus macaques to categorize videos of four distinct facial expression types: neutral faces, lip-smacking, silent bared-teeth displays, and open-mouth threat displays. These categories span the social spectrum of macaque communication, from affiliative gestures that signal benign intent to aggressive displays that warn of possible attack. The animals watched dynamic, naturalistic video clips rather than static photographs, an important design choice because real facial expressions unfold in time and involve coordinated movements of many facial structures at once.

Once the monkeys had learned the task, the researchers tested whether the animals could generalize their classifications to videos they had never seen before, featuring novel individuals. The macaques succeeded, demonstrating that they had not merely memorized specific clips or individual faces but had extracted something general about each expression category. Performance, however, was not perfect, and the pattern of errors proved to be one of the most informative aspects of the study. Misclassifications did not simply track how visually similar two expression categories looked, which suggested that something more interesting than raw visual resemblance was shaping the monkeys’ judgments.

To understand what drove those errors, the team developed a novel automated approach that combined deep learning-based motion tracking with the Macaque Facial Action Coding System, a standardized framework for decomposing macaque faces into discrete action units such as lip movements, brow raises, and ear positions. This pipeline allowed the researchers to objectively quantify the facial movements in every video clip, replacing subjective human coding with measurable, reproducible descriptors. The analysis revealed that the monkeys’ category boundaries could not be reduced to visual similarity metrics alone, a result that challenges simple feature-matching accounts of expression perception.

Some expressions, it turned out, were far easier for the monkeys than others. Open-mouth threat displays were readily categorized correctly and reliably distinguished from lip-smacking, and they also produced the strongest arousal responses, as measured by pupil dilation. Pupillometry has become a valuable tool in animal cognition research because pupil size is modulated by autonomic arousal, providing a physiological readout of how salient or emotionally charged a stimulus is. The combination of accurate categorization and heightened arousal suggests that threat displays carry particular functional significance for macaques, commanding both perceptual precision and an emotional response.

Silent bared-teeth displays told a very different story. Categorization of these expressions varied substantially across stimulus identities, meaning that the same expression type produced different judgments depending on who was making it. The researchers found that this variability was influenced by the signaler’s body weight, gaze direction, and coordinated movements of the eyebrows and ears. In macaque societies, the bared-teeth display can serve multiple functions, from signaling submission to facilitating affiliation, and the new findings hint that monkeys may interpret such displays in a context-dependent way, factoring in who is signaling and what the rest of the face and body are doing.

To probe these mechanisms further, the team turned to synthetic stimuli. Using morphed avatar faces, they generated expressions whose component intensities could be precisely controlled. The monkeys categorized these avatar expressions according to the intensity of the expression components, demonstrating graded perception rather than all-or-nothing category boundaries. This is a significant result because it shows that macaque expression perception is not a rigid sorting process but a graded one, in which the strength of facial actions maps continuously onto perceptual judgments, much as human observers perceive emotional intensity along a continuum.

The avatar experiments also allowed the researchers to dissect which ingredients of a facial expression are actually necessary for recognition. Manipulations revealed that categorization was robust against the lack of coherent motion and against the lack of facial realism, so long as a basic level of texture was present. In other words, the monkeys did not need a fully lifelike, smoothly moving face to classify an expression; a sufficiently textured but simplified avatar sufficed. This finding has practical implications for laboratory research, since it validates the use of synthetic faces in primate studies and suggests that the perceptual system extracts expression-relevant structure even from impoverished stimuli.

One boundary of the monkeys’ abilities emerged clearly: human facial expressions elicited no systematic categorizations and no differential arousal. Despite the superficial resemblance between some human and macaque expressions, the macaques did not treat human faces as meaningful within their classification framework. This cross-species result underscores that expression perception in these animals is tuned to conspecific signals, shaped by the specific morphology, dynamics, and social functions of macaque facial behavior rather than by a generic facial expression detector.

Taken together, the study paints a picture of facial expression perception in rhesus monkeys as functionally meaningful, context-dependent, and holistic. Expressions are not fixed categories defined by mouth movements alone; they are social signals whose interpretation is shaped by all components of facial behavior and by characteristics of the signaler, including body weight and gaze. The methodological contribution may prove as influential as the behavioral one: by fusing deep learning motion tracking with an established action coding system, the researchers have created a toolset for quantifying facial behavior objectively, opening the door to comparable studies across laboratories and species. For a field that has long relied on human judgment to define what a monkey’s face means, the message is clear that the monkeys themselves may be reading far more than we assumed.

Subject of Research: Dynamic facial expression perception and categorization in rhesus macaques using naturalistic videos and synthetic avatars

Article Title: Behavioral characterization of dynamic facial expression perception in rhesus monkeys (Macaca mulatta) using naturalistic and synthetic stimuli

Article References: Siebert, R., Taubert, N., Giese, M. A., & Thier, P. (2026). Behavioral characterization of dynamic facial expression perception in rhesus monkeys (Macaca mulatta) using naturalistic and synthetic stimuli. Animal Cognition. https://doi.org/10.1007/s10071-026-02109-6

Image Credits: AI Generated

DOI: 10.1007/s10071-026-02109-6

Keywords: rhesus macaque, facial expression, animal cognition, social signaling, pupillometry, deep learning, facial action coding system, avatars, graded perception, threat display, lip-smacking, Tübingen

The team used NULISAseq, a next-generation sequencing-based targeted proteomic platform developed by Alamar Biosciences that offers attomolar sensitivity and broad dynamic range while requiring only tiny sample volumes. The CNS Disease Panel 120 quantified roughly 130 protein targets spanning neuronal, glial, vascular, immune, and metabolic pathways. The macaques, aged between 5.97 and 33.58 years, were stratified into adult, pre-geriatric, and geriatric groups corresponding broadly to human adulthood, late midlife, and advanced age. Twelve human cerebrospinal fluid samples from the Stanford Alzheimer’s Disease Research Center, including aged controls, APOE4 carriers, and Alzheimer’s patients, were run in parallel to anchor the cross-species comparison.

The first headline finding is an asymmetry between compartments. In plasma, nearly 38 percent of measured proteins showed significant monotonic associations with chronological age, and the differences were overwhelmingly positive, meaning protein concentrations rose with age, consistent with increased production or impaired clearance. In cerebrospinal fluid, by contrast, only about 19 percent of proteins tracked with age, and the changes were more bidirectional, with some proteins rising and others falling. Effect sizes were substantial in both fluids, with upper-quartile eta-squared values approaching 0.5, indicating that age explains a large share of the variance for a subset of analytes. Principal component analysis reinforced the split: the dominant axis of plasma variance was significantly associated with age, sex, birthplace, and body weight, whereas the dominant cerebrospinal fluid axis was not tied to age at all, with age-related variance distributed across higher-order components.

Encouragingly for translational research, the canonical markers of neurosenescence behaved in macaques much as they do in humans. Neurofilament light and heavy chains, well-established indicators of axonal injury, rose robustly with age in both fluids, and levels in older macaques overlapped substantially with human reference values. The astrocytic proteins GFAP and CHI3L1, also known as YKL-40, increased with age in both compartments. Microglial markers told a more compartmentalized story: CHIT1 and TREM2 climbed with age in cerebrospinal fluid, with CHIT1 showing a particularly large effect size of 0.450, while plasma levels changed little. Absolute TREM2 concentrations in macaque cerebrospinal fluid were lower than in human samples, hinting at species differences in microglial biology or in how the human-optimized antibodies recognize the macaque protein.

Among synaptic proteins, the neuronal pentraxins NPTX1, NPTX2, and NPTXR declined consistently in the cerebrospinal fluid of older animals, a pattern that echoes findings from human aging and Alzheimer’s cohorts. Crucially, markers of acute neuronal injury such as ENO2, UCHL1, FABP3, and S100B did not rise in parallel, arguing that the pentraxin drop reflects synaptic remodeling rather than wholesale neuronal breakdown. The study also uncovered a possible upstream driver: cerebrospinal pleiotrophin, a growth factor involved in neurite outgrowth and synaptic stabilization, fell markedly with age and remained correlated with all three pentraxins even after adjusting for chronological age. The authors are careful to note that this PTN-pentraxin axis is a correlation, not a demonstrated cause, but it offers a biologically coherent framework for future mechanistic work.

Perhaps the most intriguing result concerns the blood-brain barrier and choroid plexus. Folate receptor 1, or FOLR1, which shuttles folate across the blood-cerebrospinal fluid barrier, and IGFBP7, a cellular senescence marker enriched in the choroid plexus, showed non-linear age patterns with striking inter-individual variance among geriatric animals. Unsupervised clustering revealed that this variance corresponds to two proteomic states: geriatric animals with relatively preserved FOLR1 and IGFBP7 levels, and those with depleted levels. The two states differed across broader biological modules as well, with the high-FOLR1/high-IGFBP7 group showing higher pentraxin and amyloid- and tau-related signals, and the low group showing enrichment of vascular and immune proteins. In plasma, the same clustering analysis produced only weak, unstable partitions, suggesting that structured molecular subtypes, reminiscent of the ageotypes described in human longitudinal studies, emerge specifically within the aging central nervous system.

The neurodegeneration module delivered the study’s starkest divergence from human patterns. Despite confirmed amyloid pathology in the aging brains, cerebrospinal levels of amyloid-beta 38, 40, and 42, brain-derived total tau, and phosphorylated tau species were essentially age invariant, and macaque Aβ42 never reached the depleted levels characteristic of human Alzheimer’s disease. Plasma told a different story: amyloid-beta species and the phosphorylated tau epitopes pTau-181 and pTau-217 rose with age, and plasma amyloid ratios shifted directionally as in human aging. Immunohistochemistry on 41 brains confirmed extensive parenchymal and vascular amyloid deposition in geriatric animals alongside only sparse tau pathology, far milder than in human Alzheimer’s cases. Notably, plasma correlations between CHI3L1, CHIT1, CXCL10, and brain amyloid burden survived correction for chronological age, whereas most cerebrospinal correlations did not, positioning plasma as the more informative window on central amyloid accumulation in this model.

Inflammaging, the chronic low-grade inflammation of aging, was also broadly concordant with humans. Plasma interleukin-6, IL18, IL16, IL33, and the chemokine CCL2 all increased with age, and plasma GDF15, an integrative marker of mitochondrial and cellular stress, showed one of the strongest age associations in the entire panel, with a Spearman correlation of 0.547. Cerebrospinal inflammatory changes were more selective, with IL18 rising strongly and other cytokines elevated only in subsets of geriatric animals. One notable exception emerged: C-reactive protein, which typically rises with age in human cohorts, actually declined with age in macaque plasma despite elevated interleukin-6, a species difference the authors flag for further study. Proteins of metabolic and proteostatic stress, including PARK7, PGK1, and SQSTM1, added further compartment-specific texture to the aging signature.

Inter-individual variability emerged as a unifying theme. Using standardized pairwise distances in high-dimensional biomarker space, the researchers showed that older macaques differed from one another far more than younger ones did, in both fluids, and a sliding-window analysis confirmed a significant positive association between chronological age and molecular dispersion. Yet the rise in dispersion was steeper and more linear in plasma, while cerebrospinal fluid variability increased more gradually and resolved into the partially reproducible subtypes described above. The authors suggest that peripheral aging in macaques is a distributed, multi-pathway process, whereas molecular aging in the brain may follow structured, divergent paths that are not strictly tied to years lived.

The study has honest limitations. The antibody panel was designed for human proteins, and although rhesus macaques share roughly 93 percent genomic sequence identity with humans, some immune-related targets went undetected in macaque fluids, reflecting either true biological divergence or limited antibody cross-reactivity. The cohort is cross-sectional, so temporal ordering cannot be established, and the naturalistic colony includes age-correlated declines in body condition and comorbidities that are themselves part of the aging phenotype. Even so, the work delivers what the field has lacked: a compartment-resolved, human-benchmarked proteomic atlas of primate brain aging. By showing that macaques faithfully reproduce human neurosenescence markers while remaining largely free of terminal neurodegeneration, the study positions these animals as an ideal platform for studying the permissive early phase of brain aging, and for de-risking biomarker-driven clinical trials before they reach patients.

Subject of Research: Proteomic biomarkers of brain aging and early neuropathology in rhesus macaques

Article Title: Plasma and cerebrospinal fluid proteomics reveal distinct patterns of senescence and neuropathology in aging rhesus macaques

Article References: Plasma and cerebrospinal fluid proteomics reveal distinct patterns of senescence and neuropathology in aging rhesus macaques. (n.d.). https://doi.org/10.1007/s11357-026-02555-7

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02555-7

Keywords: rhesus macaque, proteomics, cerebrospinal fluid, plasma biomarkers, neurosenescence, inflammaging, Alzheimer's disease, amyloid-beta, tau, NULISAseq, blood-brain barrier, GeroScience