Biology subjects

Homman-Ludiye, J.

Publications and source records attributed to Homman-Ludiye, J..

8 recordsLinked to original sources

bioRxiv2026

Early-life medial pulvinar disruption drives schizophrenia-relevant prefrontal inhibitory and cognitive deficits in primates

Schizophrenia is thought to arise from disrupted postnatal maturation of prefrontal circuits, but the developmental events linking early vulnerability to adult cortical dysfunction remain unclear. Here, we tested whether the primate medial pulvinar, a higher-order thalamic nucleus interconnected with prefrontal cortex, contributes to prefrontal maturation. Bilateral medial pulvinar lesions in neonatal marmosets altered adolescent prefrontal diffusion trajectories and produced adult working memory deficits, the latter of which did not follow comparable lesions in adulthood. Early-life lesioned animals showed reduced thalamocortical input to layer 3 parvalbumin interneurons, diminished prefrontal gamma power, reduced parvalbumin expression, and immature-like physiology in fast-spiking interneurons. These findings reveal a developmental window in which thalamic input shapes prefrontal inhibitory maturation, suggesting that some forms of cortical dysfunction in psychiatric disease originate not in the cortex itself, but in its thalamic inputs.

neuroscience↗

bioRxiv2025

Bacterial species and surface structures shape gene transfer and the transcriptional landscape during early conjugation

Conjugative plasmids drive bacterial evolution and niche adaptation, yet how their active acquisition reshapes host transcription remains poorly understood. Most studies focus on stable plasmid carriage, overlooking the dynamic transcriptional changes during conjugation itself. Here, we show that active RP4 conjugation triggers an immediate, host- and surface factor-dependent transcriptional response. This includes activation of non-SOS stress pathways, motility, exopolysaccharide production, anaerobic respiration, and metabolic adaptation. These responses do not inhibit conjugation, suggesting they serve to maintain host homeostasis. Capsule expression blocks these responses by preventing conjugation, and also inhibits RP4 activation by physically blocking donor-recipient contact. Unexpectedly, RP4 overcomes this barrier by exploiting single-cell variation in recipient capsule thickness, successfully conjugating with thin-capsulated recipients. These findings reveal a striking interplay between plasmid, host, and surface architecture in shaping the conjugation transcriptional landscape, with broad implications for plasmid dissemination and bacterial evolution.

microbiology↗

bioRxiv2024

Developmental dynamics of the prefrontal cortical SST and PV interneuron networks: Insights from the monkey highlight human-specific features

The primate prefrontal cortex (PFC) is a quintessential hub of cognitive functions. Amidst its intricate neural architecture, the interplay of distinct neuronal subtypes, notably parvalbumin (PV) and somatostatin (SST) interneurons (INs), emerge as a cornerstone in sculpting cortical circuitry and governing cognitive processes. While considerable strides have been made in elucidating the developmental trajectory of these neurons in rodent models, our understanding of their postmigration developmental dynamics in primates still needs to be studied. Disruptions to this developmental trajectory can compromise IN function, impairing signal gating and circuit modulation within cortical networks. This study examined the expression patterns of PV and SST, ion transporter KCC2, and ion channel subtypes Kv3.1b, and Nav1.1 -associated with morphophysiological stages of development in the postnatal marmoset monkey in different frontal cortical regions (granular areas 8aD, 8aV, 9, 46; agranular areas 11, 47L). Our results demonstrate that the maturation of PV+ INs extends into adolescence, characterized by discrete epochs associated with specific expression dynamics of ion channel subtypes. Interestingly, we observed a postnatal decrease in SST interneurons, contrasting with studies in rodents. This endeavor broadens our comprehension of primate cortical development and furnishes invaluable insights into the etiology and pathophysiology of neurodevelopmental disorders characterized by perturbations in PV and SST IN function. Summary StatementThe prefrontal cortex (PFC) in primates is crucial for cognitive functions, with parvalbumin (PV) and somatostatin (SST) interneurons playing key roles. This study in marmoset monkeys explores their developmental dynamics, revealing prolonged maturation of PV interneurons and contrasting SST patterns from rodents, enhancing understanding of primate cortical development.

neuroscience↗

bioRxiv2023

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms.

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

neuroscience↗

bioRxiv2023

Forming nephrons promote nephron progenitor maintenance and branching morphogenesis via paracrine BMP4 signalling under the control of Wnt4

Kidney development is known to be driven by interactions between stromal, nephron and ureteric epithelium progenitors in the nephrogenic niche. In contrast, the epithelial nephrons generated in this environment have largely been considered a product of niche rather than an active participant in the signalling interactions that maintain it. However, knockout of Wnt4, a gene required for nephron formation and stromal development, results in hypoplastic kidneys. We hypothesised that the forming nephron may play a role in maintaining the nephrogenic niche. In support of this hypothesis, conditional deletion of Wnt4 from the nephron lineage resulted in nephron progenitor dispersal and death, reduced branching morphogenesis and nephron progenitor cell number. Bulk and single cell transcriptional profiling of Wnt4 mutant kidneys revealed a downregulation of BMP signalling effectors Id1, and Id3 in nephron progenitor cells, implicating Wnt4 target BMP4 as a paracrine signal mediating feedback from the committing nephron. Recombinant BMP4 restored nephron progenitor compaction in cultured Wnt4 mutant kidneys and blocked differentiation in wildtype controls mirroring the role of BMP7-MAPK signalling in progenitor self-renewal. Our data supports a revised model of the nephrogenic niche in which forming nephrons promote progenitor maintenance and branching morphogenesis, in part via paracrine BMP4 signalling under the control of Wnt4. This requirement for nephron-derived signals for maintenance of the nephrogenic niche provides new mechanistic insight into kidney morphogenesis and human renal hypodysplasia phenotypes associated with deleterious WNT4 mutations.

developmental biology↗

bioRxiv2022

5' transgenes drive leaky expression of 3' transgenes in inducible bicistronic vectors

Molecular cloning techniques enabling contemporaneous expression of two or more protein-coding sequences in a cell type of interest provide an invaluable tool for understanding the molecular regulation of cellular functions. DNA recombination employing the Cre-lox system is commonly used as a molecular switch for inducing the expression of recombinant proteins encoded within a bicistronic cassette. In such an approach, the two protein-coding sequences are separated by a 2A peptide or internal ribosome entry site (IRES), and expression is designed to be strictly Cre-dependent by using a lox-STOP-lox cassette or flip-excision (FLEX) switch. However, low-level or leaky expression of recombinant proteins is often observed in the absence of Cre activity, potentially compromising the utility of this approach. To investigate the mechanism of leaky gene expression, we generated pCAG-lox-GFP-STOP-lox-Transgene A-2A-Transgene B vectors, which are designed to express nuclear-targeted GFP in the absence of Cre, and express both transgenes A and B after Cre-mediated recombination. We found that cells transfected with these bicistronic vectors exhibited low-level Cre-independent expression specifically of the transgene positioned 3' of the 2A peptide. We observed similar results in vivo by viral transduction of the adult mouse cerebral cortex with AAV-mutagenesis of putative transcription factor binding sites that the 5' transgene confers promoter-like activity that drives expression of the 3' transgene. Finally, we demonstrate that inclusion of an additional lox-STOP-lox cassette between the 2A sequence and 3' transgene dramatically reduces the extent of Cre-independent leaky gene expression. Our findings highlight that caution should be applied to the use of Cre-dependent bicistronic constructs when tight regulation of transgene expression is desired and provide a guide to preventing leaky gene expression when the expression of more than one protein is required.

molecular biology↗

bioRxiv2021

VISUAL CORTICAL AREA MT IS REQUIRED FOR DEVELOPMENT OF THE DORSAL STREAM AND ASSOCIATED VISUOMOTOR BEHAVIOURS

The middle temporal (MT) area of the extrastriate visual cortex has long been studied in adulthood for its distinctive physiological properties and function as a part of the dorsal stream, yet interestingly possesses a similar maturation profile as the primary visual cortex (V1). Here we examined whether an early-life lesion of MT altered the dorsal stream development and the behavioural precision of reaching to grasp sequences. We observed permanent changes in the anatomy of cortices associated with both reaching (PE and MIP) and grasping (AIP), as well as in reaching and grasping behaviours. In addition, we observed a significant impact on the anatomy of V1 and the direction sensitivity of V1 neurons in the lesion projection zone. These findings indicate that area MT is a crucial node for the development of the primate vision, impacting both V1 and areas in the dorsal visual pathway known to mediate visually guided manual behaviours. TeaserThe early life loss of visual area MT leads to significant anatomical, physiological and behavioural changes.

neuroscience↗

bioRxiv2020

Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

neuroscience↗