Biology subjects

Cohen, I.

Publications and source records attributed to Cohen, I..

At least 19 recordsLinked to original sources

bioRxiv2026

Parrots imitate song and dance with mixed vocal-gestural neural signals

Humans shrug when saying "I don't know" and nod when saying "yes," yet it remains unclear how the brain coordinates vocal and gestural motor systems for learned, multimodal communication. Here we find that budgerigar parrots precisely imitate the fine temporal alignment between song and affiliative headbob gestures. Distinct colonies developed unique vocal-gestural motifs, which reorganized into new shared forms following social re-pairing. Neural recordings from the central nucleus of the anterior arcopallium (AAC), the cortical output of the parrot song system, revealed intermixed representations of vocalizations and head kinematics, including mixed selectivity at the level of single neurons. These findings show that socially learned multimodal communication is implemented by the joint representation of vocal and gestural motor signals within single neurons, revealing neural mechanisms that may extend to frontal cortical regions controlling speech and gesture in humans.

neuroscience↗

bioRxiv2026

Directionally tuned signals in mouse visual and subicular cortex during passive rotation

Head-direction (HD) cells integrate visual and vestibular inputs and provide an internal compass which is essential for navigation, but how the directional activity in the subicular complex (SUB) and in the visual cortex (VIS) depends on the visual scene has not been compared directly. Here, we recorded simultaneously from the two regions with Neuropixels probes, while rotating head-fixed mice across all azimuthal directions, in controlled visual conditions, and in darkness. We found many directionally tuned units in both SUB and VIS. The preferred directions of SUB units were distributed uniformly and followed the rotation of a single prominent visual cue. The preferred directions of VIS units on the other hand were concentrated towards the visual cue. Heading was decoded with good accuracy from population activity from either region in cue rich visual conditions. In the presence of a single cue, decoding performance was higher in VIS. In darkness, the directional tuning was apparently lost at the single cell level, in both VIS and SUB. Importantly, even in darkness, the tuning-ordered structure of pairwise correlations was largely maintained in SUB, but not in VIS. This dissociation suggests that the SUB coherence reflects an internally organized attractor that can maintain its structure without vision or active movement, whereas VIS coherence largely reflects the external sensory structure. A wave-like distortion in decoded heading with respect to a visual cue suggests that a single salient landmark can shape the HD signal. Taken together, visual and head direction signals allow for an internal compass with continuity in the absence of landmarks, and recalibration as landmarks are reinstated.

neuroscience↗

bioRxiv2026

Shear Strain Stiffening in Cartilage is Governed by a Mechanical Phase Transition

Large shear deformation in cartilage can lead to tissue failure and injury, which are often precursors to diseases such as post-traumatic osteoarthritis. Under shear, cartilage strain-stiffens prior to failure, which makes stiffening an important indicator of changes to the loading of the extracellular matrix that gives rise to this tissue's properties. While a variety of stiffening mechanisms ranging from uncrimping to fiber-alignment have been explored, whether such mechanisms apply to the depth dependent shear strain stiffening in articular cartilage remains poorly understood. Here, we present experiments and theory that support the idea that the strain-stiffening behavior is caused by a mechanical phase transition from a random isotropic network whose mechanics arise primarily from bending-dominated modes to one where the mechanics arise from stretching-dominated modes. Indeed, consistent with network model predictions, we find that stress-strain data for all depths can be collapsed onto a single universal curve that diverges at a depth-dependent critical strain. These results show that increasing the local concentration of collagen, which constitutes the primary load-bearing network in cartilage, decreases the critical strain at which the strain-stiffening transition occurs, while increasing the low-strain elastic modulus. Furthermore, we demonstrate that bulk compression leads to a higher critical strain and decreased low-strain elastic modulus. Network simulations capture this rich behavior, and indicate that under compression the network collapses, which allows for larger strains before the transition from bending-dominated to stretching-dominated mechanics occurs. Collectively, these findings shed light on the roles that tissue composition and axial strain play in the mechanisms that organize how articular cartilage stiffens during the lead-up to injury.

biophysics↗

bioRxiv2026

All Models are Wrong, Some are Annotated: Automating Metadata in Biomedical Repositories

ObjectiveHigh-quality metadata is essential for scientific discovery, yet sparse annotations in rapidly growing repositories leave many biologically relevant details uncaptured. We evaluated whether large language models (LLMs) can accurately infer ion channel and receptor subtype metadata from source code in a neuroscience repository. Materials and MethodsWe extracted 5,133 model files from ModelDB. A subset of 1,100 was manually annotated; 253 were held out for testing, and the remainder split into training (80%) and validation (20%) sets. LLM-based approaches (GPT-5.2 and GPT-mini) were evaluated under zero-shot and heuristic-augmented prompting. Performance was assessed at type and subtype levels using accuracy, precision, recall, and F1 score. A feature-engineered XGBoost model using text- and simulation-derived features served as a baseline. ResultsLLMs outperformed the XGBoost baseline. At the type level, GPT-mini with heuristic augmentation achieved the highest performance (accuracy 96.0%, F1 0.962). At the subtype level, both GPT-5.2+heuristics and GPT-mini+heuristics achieved identical accuracy (88.1%), with GPT-5.2+heuristics achieving the highest F1(0.878). Model outputs were consistent across runs and errors confined to related mechanistic families. Discussion and ConclusionLLMs demonstrate strong potential for metadata annotation directly from source code, outperforming feature-engineering approaches with minimal tuning. However, performance varied across subtypes, and errors often reflected ambiguity or bias toward more common labels. These findings suggest LLMs may serve as practical tools for scalable metadata generation in biomedical repositories, although careful evaluation and domain-specific validation remain important. While demonstrated in computational neuroscience, this approach may generalize to repository-agnostic metadata annotation in other scientific code repositories.

neuroscience↗

bioRxiv2026

The hippocampus as a small-world cognitive map

When a mouse perceives a hawks shadow, it may have only seconds to decide where to run, yet the safest refuge is often neither visible nor nearby. To survive, it must search its cognitive map quickly enough to choose among many possibilities, and accurately enough to avoid dead ends and hazards along the way, all while what counts as "safe" changes as paths, refuges, and threats shift with time. This scenario highlights a core design problem: cognitive maps must preserve fine local structure for reliable action, yet remain globally searchable so that distant, useful solutions can be found efficiently in both space and time. The hippocampus is thought to support such maps, with population activity representing world states and their transitions--yet how these maps are structured to solve this design problem is not well understood. Here, we used a novel geometry-aware autoencoder to model the structure of the cognitive map from longitudinal calcium imaging from thousands of hippocampal CA1 neurons in mice learning a memory-guided navigation task. We discovered that the hippocampal population code achieves both local fidelity and global searchability through small-world network structure in the space of neural representations that leverages two complementary mechanisms. At the population level, helical (rotation-plus-drift) dynamics of neural representations relative to past experience build new maps that preserve local information about nearby positions in space and time while remaining distinguishable from earlier representations. At the cellular level, neurons with coordinated multi-field activity create sparse, long-range shortcuts between distant representations. During synchronous population events in immobility, decoded activity often jumps to distant states in space, time, and task conditions, suggesting these shortcuts are engaged during offline processing. This functional organization, with implications for both neuroscience and artificial intelligence, sheds light on how hippocampal representations may be optimized for a fundamental challenge faced by intelligent systems: efficiently searching through accurate internal models of the world.

neuroscience↗

bioRxiv2026

Wounding-Induced Redirection of Sugar Transport Fuels Tissue Repair

Wounding triggers growth programs to restore damaged tissues, creating a local surge in metabolic demand. How resource recruitment is modified to meet this demand is unclear. Here, we show that regeneration of dissected root tips is dependent on photosynthetic sucrose in a dose-dependent manner, although sucrose itself is excluded from the injury site. High-resolution tracking of Glifon, a novel live glucose reporter, reveals that glucose accumulates near the cut. Glucose accumulation required the apoplasmic sugar transport components CELL WALL INVERTASE (CWINV) and SUGAR TRANSPORTER PROTEINS (STP), which were rapidly induced by wounding. Loss of CWINV or STP function compromised root repair, particularly under limited sucrose availability, whereas increased STP13 gene dosage enhanced repair rates. Similar sugar transport genes were activated in other wounding contexts and promoted wound-induced adventitious root initiation. We propose that injury elicits a proactive local shift in sugar flow to promote resource recruitment and sustain tissue repair. Significance StatementPlants grow under constant physical assault and have evolved mechanisms to repair damaged organs. Wound repair increases demand for sugars to fuel cell division and growth, but unlike animals, plants cannot dilate blood vessels and rely on fixed phloem tubes. Our work shows how plants solve this problem. We uncover a circuit that blocks entry of the transported sugar sucrose into the wound site, converting it to glucose in the cell wall space, which is then rapidly imported into injury-adjacent cells. This wound-induced mechanism precedes repair, creating a proactive "sugar sink" that draws carbohydrates toward the damaged zone. Boosting this mechanism increases wound repair rates, suggesting this mechanism allows plants to control resource distribution, balancing growth and wound repair.

plant biology↗

bioRxiv2025

How tp1, an indirect wing steering muscle, stabilizes Drosophila's flight

Flapping flight is inherently unstable, requiring Drosophila to fine-tune their wing motions on a milliseconds timescale. Pioneering studies have shown that the direct steering muscles, which attach to the wing hinge, are important for generating these rapid flight reflexes. Recent connectome data, however, reveal that indirect steering muscles or tension muscles, which alter the mechanics of the thorax, receive some of the same synaptic inputs from the sensory apparatus as the direct steering muscles. This discovery suggests that the indirect steering muscles may also be important for flight control. Here, we show that the indirect tergopleural muscles indeed contribute substantially to stabilization, particularly for large pitch perturbations. We find that for small perturbations (less than 1000 deg/s), flies modulate their wing stroke amplitude to generate lift-based corrective torques, a strategy that has been previously documented. For larger perturbations, however, we observe that Drosophila engage an additional wing degree of freedom--the wing pitch angle--to leverage additional lift and drag forces during the corrective maneuver. Quasi-steady aerodynamic simulations reveal that this strategy minimizes power consumption, anaolgous to how some mammals (including humans) adjust their steady-state gaits in a near energy-optimal manner. Using optogenetics and a control theory framework we demonstrate that the tergopleural muscle is activated by a proportional gain component of a nonlinear PI controller responsible for determining the wing pitch angle during large perturbations. A simplified torsional-spring model for the wing hinge captures the changes in the wing pitch dynamics observed during correction maneuvers by using the tergopleural muscle to adjust the rest angle of the wing. These findings provide a striking example of reflex strategy selection in time-critical behaviors and underscores the vital role of indirect steering muscles in flight stabilization.

neuroscience↗

bioRxiv2025

A multi-muscular, redundant strategy for free-flight roll stability

Whether recovering after a gust of wind, or rapidly saccading away from an oncoming predator, fruit flies show remarkable aerial dexterity about their body roll axis. Here, we investigated the detailed wing kinematic changes during free-flight roll motion and probed the neuromuscular basis for such changes. Consistent with previous work, we observed that flies manipulated the stroke amplitude difference between their wings to control their roll angle. Here, we show that flies are capable of achieving such changes by altering the stroke amplitude of either or both of their wings. Further we found that during corrections flies can also take advantage of an aerodynamically significant change in the angle of attack of their uppermost wing. Curiously, these corrective wing changes cannot be eliminated when motor neurons hypothesized to be used during roll maneuvers (i1, i2, b1, b2, and b3) are individually inhibited. However, free-flight optogenetic manipulations and quasi-steady aerodynamic calculations show that each of these motor neurons individually can effect kinematic changes consistent with a roll correction. Combining this evidence with an analysis of haltere inputs found in the BANC connectome, we propose that the observed robustness could be the result of two sets of muscular redundancies that receive shared inputs from haltere sensory afferents: one set, containing b1 and b2, is able to increase the stroke amplitude of the lower wing; while the other set, containing i1, i2, and b3, is able to decrease the stroke amplitude and wing pitch angle of the upper wing. Because of the redundancy in the input sensory information and output wing motion in the muscles in each cluster, the fly is able to perform roll stability maneuvers even when one of the constituent motor neurons is inhibited. This framework proposes new ways fast aerial maneuverability can be implemented when dealing with the flys most unstable rotational degree of freedom.

animal behavior and cognition↗

bioRxiv2025

Partial Inhibition of Viral Replication Machinery Enhances Recombination in Herpes Simplex Viruses

Herpes simplex viruses (HSV-1 and HSV-2) are widespread human pathogens, most commonly causing oral and genital lesions. These DNA viruses use recombination as a major driver of evolution. Intragenomic and intergenomic recombination events can be detected both in vivo and in vitro. As viral recombination is tightly linked to replication, deciphering mechanisms that specifically effect recombination remains a challenge. Here, we employed a triple-fluorescent color recombination assay to identify homology mediated and non-canonical recombination events between co-infecting HSV-1 strains. We developed a deep learning model that detects and classifies progeny plaques according to their colors. This setup enabled us to perturb the infection process using small molecule inhibitors targeting either viral or host proteins. We identified that inhibitors that reduce infectious viral progeny, increased viral homology mediated recombination. The antiviral drugs, including acyclovir, also increased recombination between HSV-1 and HSV-2 and aberrations in the progeny viral genomes. Taken together our results indicate that commonly used anti-herpes drugs increase intraspecies and interspecies recombination rates and genetic rearrangements. SignificanceHerpes simplex viruses cause significant morbidity in all human populations. Current therapies rely primarily on antivirals that target viral replication. Viral recombination plays a key role in replication and evolution of these dsDNA viruses. To better characterize the viral recombination process, we introduce a fluorescence-based HSV-1 recombination assay coupled with deep learning-based plaque classification, enabling high-throughput quantification of recombination rates. We found that clinically relevant moderate concentrations of commonly used antiviral replication inhibitors, enhance homology-mediated intraspecies recombination, HSV-1/HSV-2 interspecies recombination, as well as the accumulation of defective genomes. We conclude that partial inhibition of the herpes replication complex can promote viral diversification, with potential implications for HSV evolution and drug resistance.

microbiology↗

bioRxiv2025

De novo biosynthesis of cannabinoid and its analogs in Yarrowia lipolytica

Cannabis sativa has long been a cornerstone of both medicinal and cultural practices, with its therapeutic use spanning over 2,700 years. Central to its therapeutic effects are cannabinoids, which interact with the endocannabinoid system to influence various physiological processes such as anxiety, pain, and inflammation. Despite its benefits, cannabinoid production faces challenges and scarcity from plant extraction. This work leverages Yarrowia lipolytica as a platform for cannabinoid biosynthesis. By optimizing precursor supply, engineering biomolecular condensate-like dual prenyltransferase expression and expanding endogenous metabolism with a noncanonical polyketide synthase, we achieved the de novo biosynthesis of various cannabinoid and its analogs. Our engineered Y. lipolytica produced [~]3.5 mg/L of cannabigerolic acid, 18.8 mg/L of orsellinic acid, and 0.5 mg/L of cannabigerorcinic acid. Additionally, CBGA titer reached 15.7 mg/L with olivetolic acid supplement. This work demonstrates Y. lipolyticas versatility as a promising host for cannabinoid and its analogs production, which opens avenues for further research and medicinal applications.

synthetic biology↗

bioRxiv2024

Genome-wide Association Study of Rice Vegetative Biomass under Different Inorganic Nitrogen Forms: Ammonium or Nitrate

Rice is the most important source of daily calories in human diets and second only to wheat as the most important protein source. Rice is generally exposed to high ammonium (NH4+) levels in the rhizosphere but may employ both NH4+ and nitrification-derived nitrate (NO3-) as major sources of nitrogen. However, the genetic basis underlying rice adaptation to different nitrogen forms remains poorly characterized. Here, we assessed biomass under either NH4+ or NO3- as a sole nitrogen source in 390 accessions from the USDA Rice Diversity Panel 1. Rice effectively used either form of nitrogen to support early growth. Tolerance to a high-NH4+ exposure was correlated with biomass under NO3- and lower NH4+ levels. Both genotype and nitrogen source strongly influenced biomass accumulation and partitioning between shoot and root. Root showed the greatest biomass variability and sensitivity to nitrogen source. Genome-wide analyses identified 176 single nucleotide polymorphism (SNP) markers associated with biomass across the full diversity panel and individual populations. The majority of the associations were unique to the individual nitrogen source. We compiled a list of candidate genes, including putative genes involved in nitrogen metabolism, located within 150 kb of 112 most significant SNPs, each with at least 3 adjacent markers detected under the same combination of population and nitrogen source. A flexible consumer, rice may employ distinct genetic mechanisms to use different nitrogen sources, making the species more resilient to fluctuations in soil nitrogen. These insights can guide matching rice genotypes with fertilizer management to improve nitrogen-use efficiency.

plant biology↗

bioRxiv2023

Restriction of intercellular communication is required for organ regeneration

The excision of the root tip, including the stem cell niche, triggers rapid regeneration from remnant cells in the stump. In plants, cell identity relies on positional information transported through cytoplasmatic bridges known as plasmodesmata. However, how such information is reset to allow the regeneration of lost identities is unknown. Here, we show that the movement of mobile signals is temporarily restricted near the incision site and that regeneration-induced members of the LATERAL ORGAN DOMAIN (LBD) plant-specific developmental regulators are necessary and sufficient for this restriction. Regeneration was disrupted in high-order lbd mutants but was restored by transient localized plasmodesmata closure. We propose that LBD-mediated modulation of intercellular connectivity is crucial for plant regeneration and may have widespread roles in de novo pattern formation. One Sentence SummaryPlant-specific DNA binding genes mediate a transient restriction of intercellular communication to allow root regeneration

plant biology↗

bioRxiv2023

Single-cell type analysis of wing premotor circuits in the ventral nerve cord of Drosophila melanogaster

To perform most behaviors, animals must send commands from higher-order processing centers in the brain to premotor circuits that reside in ganglia distinct from the brain, such as the mammalian spinal cord or insect ventral nerve cord. How these circuits are functionally organized to generate the great diversity of animal behavior remains unclear. An important first step in unraveling the organization of premotor circuits is to identify their constituent cell types and create tools to monitor and manipulate these with high specificity to assess their functions. This is possible in the tractable ventral nerve cord of the fly. To generate such a toolkit, we used a combinatorial genetic technique (split-GAL4) to create 195 sparse transgenic driver lines targeting 196 individual cell types in the ventral nerve cord. These included wing and haltere motoneurons, modulatory neurons, and interneurons. Using a combination of behavioral, developmental, and anatomical analyses, we systematically characterized the cell types targeted in our collection. In addition, we identified correspondences between the cells in this collection and a recent connectomic data set of the ventral nerve cord. Taken together, the resources and results presented here form a powerful toolkit for future investigations of neuronal circuits and connectivity of premotor circuits while linking them to behavioral outputs.

neuroscience↗

bioRxiv2023

An anterior forebrain pathway in parrots is necessary for individual signatures of learned vocalizations

Parrots have enormous vocal imitation capacities and produce individually unique vocal signatures. Like songbirds, parrots have a nucleated neural song system with distinct anterior (AFP) and posterior forebrain pathways (PFP). To test if song systems of parrots and songbirds, which diverged over 50 million years ago, have a similar functional organization, we first established a neuroscience-compatible call-and-response behavioral paradigm to elicit learned contact calls in budgerigars (Melopsittacus undulatus). Using variational autoencoder-based machine learning methods, we show that contact calls within affiliated groups converge but that individuals maintain unique acoustic features, or vocal signatures, even after call convergence. Next, we transiently inactivated the outputs of AFP to test if learned vocalizations can be produced by the PFP alone. As in songbirds, AFP inactivation had an immediate effect on vocalizations, consistent with a premotor role. But in contrast to songbirds, where the isolated PFP is sufficient to produce stereotyped and acoustically normal vocalizations, isolation of the budgerigar PFP caused a degradation of call acoustic structure, stereotypy, and individual uniqueness. Thus the contribution of AFP and the capacity of isolated PFP to produce learned vocalizations have diverged substantially between songbirds and parrots, likely driven by their distinct behavioral ecology and neural connectivity.

neuroscience↗

bioRxiv2023

Integration of thalamic and retrosplenial inputs in presubicular layer 3 gates cross-laminar bursting signal to upstream head direction circuit

Head-direction (HD) signals function as the brains internal compass. They are organized as an attractor, and anchor to the environment via visual landmarks. Here we examine how thalamic HD signals and visual information from the retrosplenial cortex combine in the presubiculum. We find that monosynaptic excitatory connections from anterior thalamic nucleus and from retrosplenial cortex converge on single layer 3 pyramidal neurons in the dorsal portion of mouse presubiculum. Independent dual wavelength photostimulation of these inputs in slices leads to action potential generation preferentially for near-coincident inputs, indicating that layer 3 neurons can transmit a visually matched HD signal to medial entorhinal cortex. Layer 4 neurons, which innervate the lateral mammillary nucleus, form a second step in the association of HD and landmark signals. They receive little direct input from thalamic and retrosplenial axons. We show that layer 4 cells are excited di-synaptically, transforming regular spiking activity into bursts of action potentials, and that their firing is enhanced by cholinergic agonists. Thus, a coherent sense of orientation involves projection specific translaminar processing in the presubiculum, where neuromodulation facilitates landmark updating of HD signals in the lateral mammillary nucleus.

neuroscience↗

bioRxiv2023

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFN{gamma}, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

immunology↗

bioRxiv2022

STRAINS: A Big Data Method for Classifying Cellular Response to Stimuli at the Tissue Scale

Cellular response to stimulation governs tissue scale processes ranging from growth and development to maintaining tissue health and initiating disease. To determine how cells coordinate their response to such stimuli, it is necessary to simultaneously track and measure the spatiotemporal distribution of their behaviors throughout the tissue. Here, we report on a novel SpatioTemporal Response Analysis IN Situ (STRAINS) tool that uses fluorescent micrographs, cell tracking, and machine learning to measure such behavioral distributions. STRAINS is broadly applicable to any tissue where fluorescence can be used to indicate changes in cell behavior. For illustration, we use STRAINS to simultaneously analyze the mechanotransduction response of 5000 chondrocytes--over 20 million data points--in cartilage during the 50 ms to 4 hours after the tissue was subjected to local mechanical injury, known to initiate osteoarthritis. We find that chondrocytes exhibit a range of mechanobiological responses indicating activation of distinct biochemical pathways with clear spatial patterns related to the induced local strains during impact. These results illustrate the power of this approach.

biophysics↗

bioRxiv2022

Neuromuscular embodiment of feedback control elements in Drosophila flight

While insects like Drosophila are flying, aerodynamic instabilities require that they make millisecond-timescale adjustments to their wing motion to stay aloft and on course. These stabilization reflexes can be modeled as a proportional-integral (PI) controller; however, it is unclear how such control might be instantiated in insects at the level of muscles and neurons. Here, we show that the b1 and b2 motor units--prominent components of the flys steering muscles system--modulate specific elements of the PI controller: the angular displacement (integral, I) and angular velocity (proportional, P), respectively. Moreover, these effects are observed only during the stabilization of pitch. Our results provide evidence for an organizational principle in which each muscle contributes to a specific functional role in flight control, a finding that highlights the power of using top-down behavioral modeling to guide bottom-up cellular manipulation studies.

animal behavior and cognition↗