Biology subjects

Hummel, T.

Publications and source records attributed to Hummel, T..

11 recordsLinked to original sources

bioRxiv2026

An extraglomerular relay circuit for multimodal integration within the Drosophila antennal lobe

The central integration of sensory information within and between brain hemispheres is critical for efficient behavioral responses, but at which level of information processing multimodal integration occurs is poorly understood. In olfactory systems an array of receptor-specific synaptic glomeruli with corresponding projection neurons (PNs) form separate sensory channels within each hemisphere, which run in parallel with other sensory modalities to converge at higher brain regions. We recently identified a small cluster of commissural pioneer neurons (cPINs) in the Drosophila olfactory system, which controls the formation of bilateral sensory circuits to support interhemispheric integration at the first synaptic layer. Here we show that cPINs also mediate the integration of sensory channels by relaying class-specific input within the antennal lobe. Functional studies showed that medial cPINs converge olfactory amine/ammonia input with a class of non-olfactory PNs to trigger attraction. During olfactory circuit formation, growing cPINs specify separate dendritic input/output domains, which merge into distinct glomeruli of different sensory modalities. Mutant analysis of the Wnt5 pathway revealed that cPINs display an initial PN-related growth pattern, which becomes redirected to organize lateral relay between sensory channels. These results identified a small cluster of olfactory interneurons as a central coordinator for fast convergence of sensory information, providing a mechanistic model of neural circuit evolution.

neuroscience↗

bioRxiv2026

Structural basis of CO2 valence coding in Drosophila

In the olfactory system, glomerular sensory channels of single receptor identity support reliable odor recognition for appropriate approach or avoidance behaviors. For many olfactory stimuli, the assigned sensory value is innate but modulated by the internal state and previous experiences. How context-dependent modulation of innate valence coding supports distinct behavioral responses is poorly understood. Here we show that CO2 sensory information in Drosophila, intrinsically aversive but modified by attractive food signals, diverges from the canonical glomerular channel already in the antennal lobe and is relayed via the polarized local interneuron LN23. LN23 relays sensory input via an extraglomerular CO2 pathway and manipulation of LN23 activity revealed a dominant role in CO2-induced avoidance behavior. The extraglomerular CO2 pathway projects to the posterior lateral protocerebrum (PLP) adjacent to the canonical Lateral Horn (LH) olfactory processing center and segregates into anatomically distinct valence channels. Connectome data together with functional characterization showed the convergence of parallel CO2 channels onto two interconnected third-order neurons. These neurons integrate additional sensory modalities via distinct mechanisms: while the glomerular CO2 pathway converges with food relay neurons onto separated dendritic domains of the PD5 interneuron in the LH, the extraglomerular pathways integrating CO2 information with antennal humidity and temperature modalities establish antagonistic inputs onto the PLP interneuron PV9. This early anatomical divergence of a defined olfactory channel followed by separated multi-modal integration provides a structural basis for context-dependent valence coding and appropriate behavioral responses.

neuroscience↗

bioRxiv2025

Olfactory Training Enhances Adult Neurogenesis of the Olfactory Epithelium Improving Odor Discriminability of the Olfactory Bulb

Olfaction enables us to detect chemicals in the environment, and its impairment affects one in four people worldwide. As the most common therapy, olfactory training involves repeated exposure to odorants restoring function in 30-50% of patients. However, the mechanisms underlying this therapy, and its partial efficacy, are unknown. By modelling olfactory training in mice, we found that odor exposure triggers quiescent neural stem cells of the olfactory epithelium to re-enter the cell cycle, enhancing neurogenesis and survival of olfactory sensory neurons. Coupling neuronal activity with stem cells proliferation, these effects scaled with odor concentration and were replicated without odorants upon chemogenetic activation of olfactory sensory neurons. Imaging mitral cells in the olfactory bulb revealed that increased neurogenesis in the olfactory epithelium enhanced odor sensitivity and discriminability. Our findings uncover activity-dependent cellular mechanisms linking peripheral nervous system regeneration to central olfactory processing, offering new avenues for treating olfactory dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/692562v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1a6a0b7org.highwire.dtl.DTLVardef@817a4forg.highwire.dtl.DTLVardef@84f063org.highwire.dtl.DTLVardef@1c20f8b_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTS- Olfactory training (OT) is a common clinical practice of unknown cellular mechanisms - OT in mice triggers stem cell activation and neurogenesis in the olfactory epithelium - Artificial stimulation of olfactory neurons is sufficient to trigger neural stem cell activity - Neurogenesis in the olfactory epithelium improves odor discrimination by mitral cells

cell biology↗

bioRxiv2025

The olfactory bulb reflects structural plasticity within a genetically stable olfactory network

The olfactory bulb (OB), the first central relay of the olfactory pathway, plays a critical role in odor perception and exhibits remarkable structural plasticity shaped by environmental influences. This raises a fundamental question about the extent to which the structure of the OB is genetically determined. While both OB volume and function have been implicated in a range of neurodegenerative and neuropsychiatric disorders, such as Parkinsons disease, schizophrenia, and depression, all of which involve known genetic risk factors, the heritability of the OB structure remains poorly understood. Here, we investigated the heritability of OB volume and the broader olfactory network architecture in a large sample of healthy young adults (n = 941; aged 22-35 years), including monozygotic and dizygotic twin pairs. Using a deep learning-based segmentation model, we first automatically segmented OB volumes and then employed a support vector machine framework to classify zygosity based on within-pair morphological similarity. The OB volume alone showed weak classification performance in distinguishing between monozygotic and dizygotic twins, suggesting limited heritability. However, integrating OB volume with morphometric features from olfactory-associated brain regions, including the hippocampus, parahippocampal gyrus, entorhinal cortex, and medial orbitofrontal cortices, substantially improved classification performance. This effect was specific to the olfactory network, underscoring the distributed nature of genetic influence in this system. These findings suggest that the OB, despite being a highly plastic and environmentally responsive structure, is embedded within a genetically coordinated neural network.

neuroscience↗

bioRxiv2025

Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity.

Structural and functional differences between brain hemispheres are a common feature of animal nervous systems with reduced bilateral asymmetry often linked to impaired cognitive performance. How neuronal left-right asymmetry is initiated and integrated into a bilaterally symmetrical ground pattern is poorly understood. Here we show that directional asymmetry of a Drosophila central brain circuit originates from axonal interactions of two classes of bilateral pioneer neurons. Subsequent recruitment of neighboring neuron classes into the asymmetric neuropil precursor results in hemisphere-specific microcircuits. Circuit lateralization requires dynamic expression of the cell adhesion molecule Fasciclin 2 to maintain structural plasticity in axonal remodeling. Reduced circuit asymmetry following cell type-specific Fasciclin 2 manipulation affect adult brain function. These results reveal an unexpected degree of developmental plasticity of late-born Drosophila neurons in the formation of a new circuit node via the lateralized recruitment of symmetric circuit components.

neuroscience↗

bioRxiv2025

Integrative Multi-Omics Analysis Identifies Nuclear Factor I as a Key Driver of Dysregulated Purine Metabolism in DIPG

Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to misregulated purine metabolism. The mutation amplifies purine biosynthesis and degradation via the enzymes ATIC and PNP, respectively. Unregulated purine degradation relieves the negative feedback of purines on their own synthesis allowing continuous synthesis, use and degradation making DIPGs reliant on purine biosynthesis. Targeting ATIC reduced tumor progression and improved survival in mice. We propose ATIC as a potential novel target in DIPG.

cancer biology↗

bioRxiv2022

Subjective assessment and taste strips testing of gustatory function, at home, and in the lab

Gustatory ability is an important marker of health status, including COVID-19 disease. We compare self-reporting with home and lab psychophysical "taste strips" tests in healthy subjects. The taste test consisted of paper strips impregnated with sweet, bitter, salty, or sour tastants, and with the trigeminal stimulus capsaicin, each in high and in low concentration. The test was carried out either in a controlled lab environment (74 participants, 47 women) with the strips being administered by the experimenter or self-administered by the participants at home (77 participants, 59 women). After self-reporting their subjective assessment of chemosensory ability, the participant identified the taste of each strip and rated intensity and pleasantness. Identification score, intensity, and pleasantness averaged over the 8 taste strips were similar between the lab and the home-administered tests. Self-rated taste ability did not correlate with any of these scores, but strongly correlated with self-rated smell ability in the lab group (r=0.73), and moderately correlated in the home group (r=0.51). Taste identification correlated with intensity ratings (r=0.63 lab, r=0.36 home) but not with the pleasantness ratings (r=-0.14 lab, r=0.1 home). The results of the taste strips test were similar in the lab and at home for healthy young participants and provide a baseline against which taste tests can be compared in future applications.

physiology↗

bioRxiv2021

Acquired olfactory loss alters functional connectivity and morphology

Removing function from a developed and functional sensory system is known to alter both cerebral morphology and functional connections. To date, a majority of studies assessing sensory-dependent plasticity have focused on effects from either early onset or long-term sensory loss and little is known how the recent sensory loss affects the human brain. With the aim of determining how recent sensory loss affects cerebral morphology and functional connectivity, we assessed differences between individuals with acquired olfactory loss (duration 7-36 months, n=20) and matched healthy controls (n=23) in their grey matter volume, using multivariate pattern analyses, and functional connectivity, using dynamic connectivity analyses, within and from the olfactory cortex. Our results demonstrate that acquired olfactory loss alters grey matter volume in, among others, posterior piriform cortex, a core olfactory processing area, as well as the inferior frontal gyrus and angular gyrus. In addition, compared to controls, individuals with acquired anosmia displayed significantly stronger dynamic functional connectivity from the posterior piriform cortex to, among others, the angular gyrus, a known multisensory integration area. No significantly stronger connectivity in healthy control participants were demonstrated. When assessing differences in dynamic functional connectivity from the angular gyrus, individuals with acquired anosmia had stronger connectivity from the angular gyrus to areas primary responsible for basic visual and taste processing. These results demonstrate that recently acquired sensory loss alters both cerebral morphology within core olfactory areas and increase dynamic functional connectivity from olfactory cortex to cerebral areas processing multisensory integration.

neuroscience↗

bioRxiv2020

A tropane-based ibogaine analog rescues folding-deficient SERT and DAT

Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutants, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild type transporters, and for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG601,602AA and DAT-PG584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperone in vivo, in Drosophila harboring DAT-PG584,585AA and rescued six out of 13 disease-associated human DAT mutants in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutants.

pharmacology and toxicology↗

bioRxiv2020

Parallel visual pathways with topographic versus non-topographic organization connect the Drosophila eyes to the central brain

One hallmark of the visual system is the strict retinotopic organization from the periphery towards the central brain, spanning multiple layers of synaptic integration. Recent Drosophila studies on the computation of distinct visual features have shown that retinotopic representation is often lost beyond the optic lobes, due to convergence of columnar neuron types onto optic glomeruli. Nevertheless, functional imaging revealed a spatially accurate representation of visual cues in the central complex (CX), raising the question how this is implemented on a circuit level. By characterizing the afferents to a specific visual glomerulus, the anterior optic tubercle (AOTU), we discovered a spatial segregation of topographic versus non-topographic projections from molecularly distinct classes of medulla projection neurons (medullo-tubercular, or MeTu neurons). Distinct classes of topographic versus non-topographic MeTus form parallel channels, terminating in separate AOTU domains. Both types then synapse onto separate matching topographic fields of tubercular-bulbar (TuBu) neurons which relay visual information towards the dendritic fields of central complex ring neurons in the bulb neuropil, where distinct bulb sectors correspond to a distinct ring domain in the ellipsoid body. Hence, peripheral topography is maintained due to stereotypic circuitry within each TuBu class, providing the structural basis for spatial representation of visual information in the central complex. Together with previous data showing rough topography of lobula projections to a different AOTU subunit, our results further highlight the AOTUs role as a prominent relay station for spatial information from the retina to the central brain.

neuroscience↗

bioRxiv2017

A topographic visual pathway into the central brain of Drosophila

The visual system is characterized by a strict topographic organization from the retina towards multiple layers of synaptic integration. Recent studies in Drosophila have shown that in the transition from the optic lobes to the central brain, due to convergence of columnar neurons onto optic glomeruli, distinct synaptic units employed in the computation of different visual features, the retinotopic representation is lost in these circuits. However, functional imaging revealed a spatial representation of visual cues in the Drosophila central complex, raising the question about the underlying circuitry, which bypasses optic glomerulus convergence.\n\nWhile characterizing afferent arborizations within Drosophila visual glomeruli, we discovered a spatial segregation of topographic and non-topographic projections from distinct molecular classes of medulla projection neurons, medullo-tubercular (MeTu) neurons, into a specific central brain glomerulus, the anterior optic tubercle (AOTu). Single cell analysis revealed that topographic information is organized by ensembles of MeTu neurons (type 1), forming parallel channels within the AOTu, while a separate class of MeTu neurons (type 2) displays convergent projection, associated with a loss of spatial resolution. MeTu afferents in the AOTu synapse onto a matching topographic field of output projection neurons, these tubercular-bulbar (TuBu) neurons relay visual information towards dendritic fields of central complex ring neurons in the bulb neuropil. Within the bulb, neuronal proximity of the topographic AOTu map as well as channel identity is maintained despite the absence of a stereotyped map organization, providing the structural basis for spatial representation of visual information in the central complex (CX). TuBu neurons project onto dendritic fields of efferent ring neurons, where distinct sectors of the bulb correspond to a distinct ring domain in the ellipsoid body. We found a stereotypic circuitry for each analyzed TuBu class, thus the individual channels of peripheral topography are maintained in the central complex structure. Together with previous data showing rough topography within the lobula AOTu domain, our results on the organization of medulla projection neurons define the AOTu neuropil as the main relay station for spatial information from the optic lobes into the central brain.

neuroscience↗