Biology subjects

Svedberg, D.

Publications and source records attributed to Svedberg, D..

5 recordsLinked to original sources

bioRxiv2025

Congruent neuronal modulation across competing actions challenges the role of the substantia nigra in action selection

The basal ganglia are involved in the control of movement, but their exact role is unclear. Paradoxically, most of the inhibitory projection neurons in the main output nuclei increase firing around the time of movement; only a small fraction decrease firing. This antagonistic activity pattern could subserve action selection, with the small "decrease" population selectively disinhibiting the desired movement, and the larger "increase" population inhibiting competing movements. The action-selection hypothesis makes an implicit assumption: neurons that decrease firing to disinhibit a specific action should increase firing to inhibit that action when a different action is desired. To test this hypothesis, we recorded projection neurons in the substantia nigra pars reticulata (SNr) of mice trained to alternate between two different types of movements. Many SNr neurons showed a "ramping" pattern of pre-movement firing-rate modulation, with most neurons increasing firing, consistent with previous findings. However, contrary to the action-selection model, the overwhelming majority of SNr neurons exhibited congruent modulation between the competing actions, either increasing or decreasing their firing rates for both actions; only a small fraction of neurons exhibited opposite signs of modulation. Similar results were observed among SNr neurons identified as projecting to the arm or orofacial zones of motor superior colliculus. In addition, brief pauses in SNr firing outside explicit operant tasks were not accompanied by stereotyped movements. Our results are not easily reconciled with simple antagonistic mechanisms for action selection in the basal ganglia output nuclei. We also found that ramping activity in SNr neurons typically began hundreds of ms before self-timed and spontaneous movements, in contrast to previous findings suggesting that basal ganglia output is modulated too late to be involved in movement initiation. Our findings suggest constraints - and raise new questions - about the role of the basal ganglia in movement initiation and action selection.

neuroscience↗

bioRxiv2024

Experience-induced drift in the neural coding of individual differences in perception

As is true in humans, no two rodents prefer precisely the same tastes. Furthermore, no one rodent keeps precisely the same taste preferences forever. Here, we have made use of this between- and within-animal variability to generate and test novel hypotheses about the stability and malleability of neural perceptual coding. We used a brief-access task (BAT) to reveal both individual differences in taste preferences and shifting preferences within individual rats (quantified in terms of lick bout lengths). We moved on to show that these phenomena are not simply random variation: first, by demonstrating that gustatory cortical (GC) taste response dynamics, the late part of which reflect palatability, match that individual rat's BAT preferences (evaluated almost 2 weeks prior) better than canonical preference patterns; that is, individual differences in preferences reflect differences in neural taste processing. This match, however, links neural taste processing only to the most recent BAT session--GC palatability processing does not reflect performance in earlier BAT sessions. We hypothesized that any tasting experience might impact taste processing (i.e., not just BAT licking), and tested this hypothesis by adding a second session of GC taste-response recordings; palatability-epoch taste responses in this later session no longer matched the most recent pre-recording BAT session, demonstrating that responses following the first electrophysiology session had changed. Together, these data demonstrate that every tasting experience (regardless of the method of taste delivery) changes the rat's processing of those tastes.

neuroscience↗

bioRxiv2023

Systematic screens for fertility genes essential for malaria parasite transmission reveal conserved aspects of sex in a divergent eukaryote

Sexual reproduction in malaria parasites is essential for their transmission to mosquitoes. It also offers a divergent eukaryote model to understand the evolution of sex. Through a panel of genetic screens, where each sex of Plasmodium berghei was mutagenised separately with barcoded vectors, we identify 401 sex and transmission-related gene functions and define roles for hundreds of unstudied fertility genes as putative targets for transmission blocking interventions. The functional data provide a deeper understanding of female metabolic reprogramming, meiosis and the axoneme. We identify a protein complex of a SUN domain protein, SUN1, and a moonlighting putative allantoicase, ALLC1, that is essential for male fertility by linking the microtubule organising centre to the nuclear envelope and enabling mitotic spindle formation during male gametogenesis. Both proteins have orthologs in mouse testis, and the data point to an ancient role for atypical SUN domain proteins in fertility. Altogether, our data provide an unbiased picture of the molecular processes that underpin malaria parasite transmission but also highlight ancestral aspects of sex that have evolved close to the last eukaryotic common ancestor.

developmental biology↗

bioRxiv2023

Functional annotation of a divergent genome using sequence and structure-based homology.

BackgroundMicrosporidia are a large taxon of intracellular pathogens characterized by extraordinarily streamlined genomes with unusually high sequence divergence and many species-specific adaptations. These unique factors pose challenges for traditional genome annotation methods based on sequence homology. As a result, many of the microsporidian genomes sequenced to date contain numerous genes of unknown function. Recent innovations in rapid and accurate structure prediction and comparison, together with the growing amount of data in structural databases, provide new opportunities to assist in the functional annotation of newly sequenced genomes. ResultsIn this study, we established a workflow that combines sequence and structure-based functional gene annotation approaches employing a ChimeraX plugin, allowing for visual inspection and manual curation. We employed this workflow on a high-quality telomere-to-telomere sequenced tetraploid genome of Vairimorpha necatrix. First, the 3080 predicted open reading frames, of which 89 % were confirmed with RNA sequencing data, were used as input. Next, ColabFold was used to create protein structure predictions, followed by a Foldseek search for structural matching to the PDB and AlphaFold databases. The subsequent manual curation, using sequence and structure-based hits, increased the accuracy and quality of the functional genome annotation compared to results using only traditional annotation tools. Our workflow resulted in a comprehensive description of the V. necatrix genome, along with a structural summary of the most prevalent protein groups, such as the ricin B lectin family. In addition, and to test our tool, we identified the functions of several previously uncharacterized Encephalitozoon cuniculi genes. ConclusionWe provide a new functional annotation tool for divergent organisms and employ it on a newly sequenced, high-quality microsporidian genome to shed light on this uncharacterized intracellular pathogen of Lepidoptera. The addition of a structure-based annotation approach can serve as a valuable template for studying other microsporidian or similarly divergent species.

genomics↗

bioRxiv2022

Reductive evolution in the structure of the microsporidian proteasome.

Proteasomes play an essential role in the life cycle of intracellular pathogens with extracellular stages by ensuring proteostasis in environments with limited resources. In microsporidia, divergent parasites with extraordinarily streamlined genomes, the proteasome complexity and structure are unknown, which limits our understanding of how these unique pathogens adapt and compact essential eukaryotic complexes. We present cryo-electron microscopy structures of the microsporidian 20S and 26S proteasome isolated from dormant or germinated Vairimorpha necatrix spores. The presence of distinct densities within the central cavity of the dormant spore proteasome suggests reduced activity in the environmental stage. In contrast, the absence of these densities and the existence of 26S particles post-germination indicates rapid reactivation of proteasomes after host infection. Structual and phylogenetic analyses reveal that microsporidian proteasomes have undergone extreme reductive evolution, lost three regulatory proteins, and compacted nearly every subunit. The highly derived microsporidian proteasome structure presented here reinforces the feasibility of the development of specific inhibitors and provides insight into the unique evolution and biology of these medically and economically important pathogens.

evolutionary biology↗