Biology subjects

Drummond, N.

Publications and source records attributed to Drummond, N..

7 recordsLinked to original sources

bioRxiv2026

A human developmental and adult brain atlas benchmarks dopaminergic stem cell models and cell therapy candidates

Parkinsons disease (PD) is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons1. Stem cell-derived mDA neurons hold promise for disease modelling2,3 and are currently in clinical trials for cell replacement therapy4-6. However, systematic benchmarking has been limited by the lack of a unified high-resolution reference and methods that quantify incomplete or mixed lineage specification in vitro7. We establish a single-cell and spatial atlas of the human developing diencephalon-midbrain-hindbrain axis resolving 93 cell subtypes, including 39 lacking prior single-cell characterization and 4 entirely novel populations. Using this atlas as a reference, we integrate 19 hPSC-derived mDA datasets, both published2,8-25 and unpublished, to build the Human Dopaminergic Neural Atlas (HDNA) spanning 2D, 3D, and graft models, including those used in clinical trials. To classify cells and quantify lineage fidelity, we develop CapybaraBrain, a marker-driven non-negative decomposition framework that assigns each cell continuous identity scores across all 93 developmental programs, enabling systematic discrimination of discrete, transitioning, and cross-lineage hybrid states26. We uncover a pervasive landscape of off-target populations reflecting relaxed transcriptional boundaries in vitro, including a previously unrecognized TH-PITX2 midbrain neuronal population, and we validate atlas-predicted latent lineage plasticity through inducible genetic fate mapping in mouse models. We further define maturation-associated transcriptional programs by harmonizing adult mDA subtype atlases, revealing that dopaminergic identity and maturation are partially decoupled across protocols. Finally, projecting PD patient-derived tri-cultures onto the HDNA uncovers genotype- and cell-type-specific transcriptional dysregulation. Together, these integrated atlases and computational framework establish a unified standard for benchmarking differentiation fidelity, exposing off-target states, and guiding next-generation PD models and cell therapies.

Developmental Biology↗

bioRxiv2026

A high throughput platform for measuring and predicting vitrification behavior in multicomponent aqueous solutions

Cryopreservation depends critically on suppression of ice formation by cryoprotective agents (CPAs), but limited data is available on the CPA concentration required for vitrification (Cv). Here, we introduce a high-throughput 384-well platform that integrates automated liquid handling, randomized plate layouts, and a binary-search strategy to rapidly determine Cv across hundreds of formulations. Relative to conventional methods, this approach increases throughput by [~]50-fold, compressing a year of measurements into one week, while markedly reducing manual labor. Across [~]200 CPA compositions, we demonstrate that environmental boundary conditions strongly influence vitrification behavior: plates sealed with silicone mats exhibited lower Cv than open plates, indicating that sealed configurations promote vitrification. Further, the data reveal a decrease in Cv with increasing CPA molecular weight, consistent with enhanced ice suppression by larger molecules. We also present a simple mixture model that accurately predicts Cv for a broad range of CPA formulations, including mixtures containing up to seven CPAs (R{superscript 2} [≥] 0.93), and use this model to evaluate published CPA toxicity data to identify formulations that operate near their vitrification threshold while maintaining relatively low toxicity. Together, these results establish a framework for rapid Cv determination, predictive modeling of vitrification behavior, and rational design of CPA formulations.

bioengineering↗

bioRxiv2026

A multi-input optic glomerulus mediates opposing behavioral responses to visual objects

Prey, predators or conspecifics are first detected as visual objects in many seeing animals. Vision guides behavioral actions towards or away from these objects. An error in this visual perception could prove fatal. How object information is untangled to avoid errors remains unclear. Here we show that LC10d visual projection neurons in Drosophila melanogaster mediate avoidance of visual objects in the absence of a chemosensory profile. LC10d neurons are broadly tuned to objects and project to the same retinorecipient brain region that receives inputs from LC10a neurons, which are required for tracking. The descending neurons DNa10 are directly downstream of the anterior-facing LC10d sub-population and mediate LC10d-dependent avoidance. Our work demonstrates the use of two similar neuron types and chunking of the visual field into zones as strategies to disentangle similar sets of visual cues requiring nearly opposite behavioral responses.

neuroscience↗

bioRxiv2025

Population Morphology Implies a Common Developmental Blueprint for Drosophila Motion Detectors

T4 and T5 neurons are the first direction-selective neurons in the visual pathway. They are the most numerous cell types in the fly brain ([~] 6000 within each optic lobe) and, as a population, their compact dendritic arbours span the entire visual field. They are classified into four subtypes (a, b, c, and d). Each subtype encodes one of four orthogonal motion directions (up, down, forwards, backwards). Crucially, the dendrites of these neurons are oriented inversely to the functional direction of motion which they encode. This dendritic orientation is what ultimately determines their functional directional encoding. The development of these neurons is well characterised up to the point of neuropil innervation. However, the full population of these neurons innervate their target neuropil prior to the emergence of directionality within their dendrites. As it stands, development prior to the emergence of dendritic orientations, and the adult oriented dendrite are both well understood, but the key components relating to the emergence of orientation itself are missing. Recent whole-brain electron microscopy (EM) connectomes of Drosophila melanogaster provide an unprecedented level of resolution and completeness when considering the morphology of neurons. Utilising this, we isolate the dendritic arbour of every T4 and T5 neuron within a female adult Drosophila brain, made available through FAFB-FlyWire. In doing so we are able to rigorously quantify the morphology of these dendrites in order to understand their similarities and differences. In doing so we aim to shed light on the origins of dendritic directionality. We reason that either this emerges through a tightly controlled, subtype specific mechanism, or is the result of a subtype agnostic mechanism and external factors. In the former case, we would expect evidence of this in differences between the morphological structure of individual dendrites between T4 and T5, and their subtypes. Our analysis however reveals a high degree of structural similarity between T4 and T5, and within their subtypes. Particularly, the geometry of branching, section orientation, and tree-graph structure of these dendrites show only minor variability, with no consistent separation between T4 and T5, or their subtypes. These results indicate that, despite forming in different neuropils, and serving distinct motion directions, T4 and T5 dendrites follow closely aligned morphological patterns. This suggests a shared mechanism of directed outgrowth, as opposed to symmetry breaking emerging through neuron type or subtype specific mechanisms. Author summaryThe Dendrites of T4 and T5 neurons orient spatially in a direction inverse to the direction of motion which they encode. The development of these neurons is understood up to the point of neuropil innervation, however they remain unicolumnar. The window between the directed adult dendrite, and their unicolumnar neuropil innervation is not yet understood. In order to shed light on how directionality within these dendrites may emerge, we perform a rigorous quantification of the morphology of all T4 and T5 dendrites within a single female adult Drosophila brain using nm-resolution reconstructions available from recent electron microscopy. This allows for the characterisation of neuropil and directionally specific morphological similarities and differences within this population. Although insightful variability is observed at the level of spatial properties of these dendrites, their geometry and topology is highly conserved across T4 and T5 populations, and directions of outgrowth. From these analyses, we conclude that although these dendrites originate in differing brain regions, with differing input partners, and perform differing, subtype-specific, detection of motion directions, the underlying process of dendritic outgrowth and emergence of orientation is most likely shared across both T4 and T5 and their subtypes.

neuroscience↗

bioRxiv2020

Information flow, cell types and stereotypy in a full olfactory connectome

The hemibrain connectome provides large scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the Drosophila olfactory system, covering all first, second and lateral horn-associated third-order neurons. We develop a generally applicable strategy to extract information flow and layered organisation from connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. Leveraging a second data set we provide a first quantitative assessment of inter - versus intra-individual stereotypy. Comparing neurons across two brains (three hemispheres) reveals striking similarity in neuronal morphology across brains. Connectivity correlates with morphology and neurons of the same morphological type show similar connection variability within the same brain as across two brains.

neuroscience↗

bioRxiv2020

Memory deficits following hippocampal versus parahippocampal damage double-dissociate according to both process and material type

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes or material-types in recognition memory. We tested a rare patient (Patient MH) with a perirhinal lesion that appeared to spare the hippocampus, using two recognition memory paradigms, each run separately with faces, scenes and words. Replicating reports of a previous case, Patient MH showed impaired familiarity and preserved recollection, relative to controls, with no evidence for any effect of material-type. Moreover, when compared with other amnesic patients, who had hippocampal lesions that appeared to spare the perirhinal cortex, Patient MH showed greater impairment on familiarity and less on recollection, forming a double dissociation. However, when replacing this traditional, binary categorization of patients with a parametric analysis that related memory performance to continuous measures of brain damage across all patients, we found a different pattern: while hippocampal damage predicted recollection, it was parahippocampal instead of perirhinal (or entorhinal) cortex volume that predicted familiarity. Furthermore, there was no evidence that these brain-behavior relationships were moderated by material-type, nor by laterality of damage. Thus, while our data provide the most compelling support yet for dual-process models of recognition memory, in which recollection and familiarity depend on different MTL structures, they suggest that familiarity depends more strongly upon the parahippocampal rather than perirhinal cortex. More generally, our study reinforces the need to go beyond single-case and group studies, and instead examine continuous brain-behavior relationships across larger patient groups.

neuroscience↗

bioRxiv2020

Complete connectomic reconstruction of olfactory projection neurons in the fly brain

Nervous systems contain sensory neurons, local neurons, projection neurons and motor neurons. To understand how these building blocks form whole circuits, we must distil these broad classes into neuronal cell types and describe their network connectivity. Using an electron micrograph dataset for an entire Drosophila melanogaster brain, we reconstruct the first complete inventory of olfactory projections connecting the antennal lobe, the insect analogue of the mammalian olfactory bulb, to higher-order brain regions in an adult animal brain. We then connect this inventory to extant data in the literature, providing synaptic-resolution holotypes both for heavily investigated and previously unknown cell types. Projection neurons are approximately twice as numerous as reported by light level studies; cell types are stereotyped, but not identical, in cell and synapse numbers between brain hemispheres. The lateral horn, the insect analogue of the mammalian cortical amygdala, is the main target for this olfactory information and has been shown to guide innate behaviour. Here, we find new connectivity motifs, including: axo-axonic connectivity between projection neurons; feedback and lateral inhibition of these axons by local neurons; and the convergence of different inputs, including non-olfactory inputs and memory-related feedback onto lateral horn neurons. This differs from the configuration of the second most prominent target for olfactory projection neurons: the mushroom body calyx, the insect analogue of the mammalian piriform cortex and a centre for associative memory. Our work provides a complete neuroanatomical platform for future studies of the adult Drosophila olfactory system. HighlightsO_LIFirst complete parts list for second-order neurons of an adult olfactory system C_LIO_LIQuantification of left-right stereotypy in cell and synapse number C_LIO_LIAxo-axonic connections form hierarchical communities in the lateral horn C_LIO_LILocal neurons and memory-related feedback target projection neuron axons C_LI

neuroscience↗