Biology subjects

Do, M. T. H.

Publications and source records attributed to Do, M. T. H..

7 recordsLinked to original sources

bioRxiv2026

Divergence of Melanopsin's Intrinsic Properties and Downstream Actions

Opsins are light-activated receptors. A basic question is how the molecular properties of an opsin shape its effects on the organism. In mammals, melanopsin regulates perception, cognition, physiology, and mood. Because these actions are vital, an international standard has been formulated to express light in terms of melanopsin stimulation. Short wavelengths are absorbed best by melanopsin and should drive its effects most strongly. We report that melanopsin's cellular and behavioral effects show little or even opposite wavelength sensitivity in some regimes. This divergence stems from melanopsin's persistent activity, which generates adaptation. Wavelengths absorbed strongly by melanopsin produce high persistent activity and adaptation, giving net desensitization, whereas wavelengths absorbed weakly can produce sensitization instead. We provide a quantitative model that captures these transformations. This work indicates how the downstream actions of a molecule may diverge starkly from its intrinsic properties.

neuroscience↗

bioRxiv2026

High-fidelity backpropagation through primate foveal cones

Primate vision has exceptionally high spatial acuity and contrast sensitivity. This performance originates in specialized photoreceptors of the fovea. These cones transduce light into electrical signals in the outer segment, and convey these signals to the presynaptic terminal for transmission. Backpropagating signals are also possible, as the terminal receives inputs. Such signals could influence phototransduction itself. To test this idea, we recorded electrophysiologically from both ends of single cones dissociated from the macaque fovea. We found that backpropagation was effective despite the extreme slenderness and length of these cells. Backpropagation was also effective in a passive compartmental model, indicating that amplification by voltage-gated channels is not required. We then modeled foveal cones receiving terminal inputs from retinal networks. Despite faithful backpropagation of these inputs, they appear unlikely to influence phototransduction. Thus, even though foveal cones exhibit effective backpropagation, their encoding of visual information may remain compartmentalized. SIGNIFICANCE STATEMENTHumans, like other primates, see a fineness of detail that eludes other mammals. This capability is used for tasks like reading and recognizing faces. It is lost in leading forms of vision impairment, such as age-related macular degeneration. Investigating it therefore provides insight into the origin of exceptional sensory performance while strengthening the foundation for preserving and restoring sight. This study examines cells that initiate high-acuity vision, the foveal cones, which produce electrical signals from light and send them forward. It reveals that electrical signals also travel effectively in reverse, from the site of transmission to that of production, and how the production of light responses may be independent nonetheless.

neuroscience↗

bioRxiv2026

Minimal Mimics and Maps of Natural Light for Mammals

Light drives processes that include perception and the regulation of circadian rhythms, sleep, metabolism, and development. These processes are initiated by photopigment molecules, each preferentially absorbing particular wavelengths. Light of a given spectrum stimulates an animals set of photopigments in a specific profile. Natural skylight and its variations produce stimulation profiles that promote normal physiology. To mimic these profiles using artificial light, we consider the thermally stable, photoconvertible states of relevant photopigments: ground states of rhodopsin and cone photopigments, and three states of melanopsin. This gives a relatively high-dimensional representation of illumination. Nevertheless, we find that two wavelengths suffice to closely mimic the effects of natural light for mammals, including humans and mice. Adjusting the wavelength ratio allows mimicry of natural lights variations, such as those from twilight to noon. Ratio adjustments also compensate for lights filtering by elements like the eyes optics and laboratory cages. Adding a third wavelength makes natural light mimicry nearly perfect. By contrast, common artificial lighting--designed for low-dimensional, human color space--stimulates photopigments in unnatural proportions. We conclude by providing species-specific maps of photopigment stimulation profiles under natural and artificial illumination, which make our observations intuitive while providing insight into the diverse visual ecologies of mammals. SIGNIFICANCE STATEMENTHumans sense light for vital processes like sight and physiological regulation. These processes are normal under natural skylight, where they evolved. However, much of modern life is spent in artificial light, which is unlike natural light in many of its biological effects. This disparity has been linked to disorders that range from cardiovascular disease to cancer. This manuscript introduces simple forms of artificial lighting that replicate the effects of natural skylight on photoreceptors of humans and other species. It also demonstrates how the biological effects of natural and artificial lights can be captured in simple maps, facilitating the choice and further design of illumination that is beneficial.

neuroscience↗

bioRxiv2025

Retinal Origins of Circadian Photoregulation's Specialized Dynamic Range and Temporal Integration

The day-night cycle drives profound environmental changes, which animals anticipate using the circadian clock. The clock synchronizes with this cycle by extracting features of light that indicate solar elevation. It uses a specialized dynamic range to sense relevant photon rates and precise, extended temporal integration to encode total photon counts. This feature selectivity is distinct from that of visual perception and is thought to arise in the brain. We have found it within the retina's M1 melanopsin photoreceptors, which signal light to the clock. M1s have heterogeneous intrinsic and synaptic drives, and collectively account for the dynamic range of circadian photoregulation. Both individually and as a population, M1s approach the level of temporal integration observed behaviorally. M1s and behavior match closely when the pupillary light reflex, another M1-driven function, dynamically shapes retinal illumination. Thus, the earliest steps of photoreception are tuned to signifiers of Earth's rotation.

neuroscience↗

bioRxiv2024

Molecular and spatial analysis of ganglion cells on retinal flatmounts: diversity, topography, and perivascularity

Diverse retinal ganglion cells (RGCs) transmit distinct visual features from the eye to the brain. Recent studies have categorized RGCs into 45 types in mice based on transcriptomic profiles, showing strong alignment with morphological and electrophysiological properties. However, little is known about how these types are spatially arranged on the two-dimensional retinal surface--an organization that influences visual encoding--and how their local microenvironments impact development and neurodegenerative responses. To address this gap, we optimized a workflow combining imaging-based spatial transcriptomics (MERFISH) and immunohistochemical co-staining on thin flatmount retinal sections. We used computational methods to register en face somata distributions of all molecularly defined RGC types. More than 75% (34/45) of types exhibited non-uniform distributions, likely reflecting adaptations of the retinas anatomy to the animals visual environment. By analyzing the local neighborhoods of each cell, we identified perivascular RGCs located near blood vessels. Seven RGC types are enriched in the perivascular niche, including members of intrinsically photosensitive RGC (ipRGC) and direction-selective RGC (DSGC) subclasses. Orthologous human RGC counterparts of perivascular types - Melanopsin-enriched ipRGCs and ON DSGCs - were also proximal to blood vessels, suggesting their perivascularity may be evolutionarily conserved. Following optic nerve crush in mice, the perivascular M1-ipRGCs and ON DSGCs showed preferential survival, suggesting that proximity to blood vessels may render cell-extrinsic neuroprotection to RGCs through an mTOR-independent mechanism. Overall, our work offers a resource characterizing the spatial profiles of RGC types, enabling future studies of retinal development, physiology, and neurodegeneration at individual neuron type resolution across the two-dimensional space.

neuroscience↗

bioRxiv2024

Loss of SARM1 protects against retinal ganglion cell degeneration in Autosomal Dominant Optic Atrophy

Autosomal Dominant Optic Atrophy (ADOA), the most prevalent inherited optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. Here, we present a novel mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identify SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppresses all the degeneration phenotypes. Additionally, we show that SARM1 is located within the mitochondrial intermembrane space (IMS). These findings indicate that SARM1 is activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

neuroscience↗

bioRxiv2018

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

High acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible model organisms lack a fovea, its specialized function and dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate and validate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >65 cell types match between the two regions, but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved, but that projection neuron types and programs diverge, despite conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 6 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

neuroscience↗