Biology subjects

Becker, J. A.

Publications and source records attributed to Becker, J. A..

5 recordsLinked to original sources

bioRxiv2026

Tilted striatofugal balance and beneficial effects of facilitating mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome

Fragile X Syndrome (FXS) is the leading monogenic cause of autism spectrum disorder (ASD). To date, no approved pharmacological treatment alleviates social impairments in patients with FXS. Since D1 and D2 dopamine receptor-expressing striatal projection neurons (SPNs) were shown to regulate ASD-sensitive behaviors, we explored whether the balance of activity between D1- and D2-SPNs would be biased in the Fmr1-/- mouse model of FXS. We evaluated striatal function in Fmr1-/- and Fmr1+/+ mice under pharmacological challenge and performed RNAscope(R) in situ hybridization following social interaction to assess the activity of SPNs in the nucleus accumbens (NAc) and dorsal striatum (DS). We evidenced a decrease in D1-SPN activity, biasing the D1/D2-SPN balance towards an excessive weight of D2-SPN outputs. We then evaluated the effects of compounds that repress D2-SPN activity on behavioral impairments in Fmr1-/- mice. Systemically facilitating mGlu4 or blocking A2A receptor activity relieved behavioral deficits in this model. Finally, we tested the hypothesis that a tilt of the D1/D2-SPN balance in Fmr1-/- mice may contribute to their social deficit by facilitating mGlu4 activity directly in the projection site of NAc D2-SPNs. Social interaction in Fmr1-/- mice was fully rescued by photopharmacological activation of mGlu4 in the ventral pallidum (VP), where NAc D2-SPNs project. This result supports our hypothesis of excessive D2-SPN outputs and highlights the contribution of the VP in controlling social behavior. In conclusion, pharmacological compounds that repress D2-SPN activity demonstrate a promising therapeutic potential to relieve ASD-like deficits in FXS.

neuroscience↗

bioRxiv2025

Vibrio harveyi plasmids as drivers of virulence in barramundi (Lates calcarifer)?

Vibrio species are an emerging public and animal health risk in marine environments and the opportunistic bacterial pathogen Vibrio harveyi is a major disease risk for tropical aquaculture. Current understanding of virulence in V. harveyi is limited by strain-specific variability and complex host-pathogen dynamics. This study sought to integrate genomic investigation, phenotypic characterisation and in vivo challenge trials in barramundi (Lates calcarifer) to increase our understanding of V. harveyi virulence. We identified two hypervirulent isolates, Vh-14 and Vh-15 that caused 100% mortality in fish within 48 hours, and that were phenotypically and genotypically distinct from other V. harveyi isolates. Virulent isolates contained multiple plasmids, including a 105,412 bp conjugative plasmid with type III secretion system genes originally identified in Yersinia pestis. The emergence of this hypervirulent plasmid-mediated patho-variant poses a potential threat to the sustainable production of marine finfish in Southeast Asia, the Mediterranean and Australia. In addition, we observed an effect of temperature on phenotypic indicators of virulence with an increase in activity at 28{degrees}C and 34{degrees}C compared to 22{degrees}C. This suggests that temperature fluctuations associated with climate change may act as a stressor on bacteria, increasing virulence gene secretion and host adaptation. Our results utilising a myriad of technologies and tools, highlights the importance of a holistic view to virulence characterisation.

microbiology↗

bioRxiv2024

Hierarchical population genetic structure and signatures of adaptation in Lates calcarifer

ContextLates calcarifer is a widespread Indo-Pacific fish that is important in aquaculture, recreational and commercial fisheries. Genetic divergences from different data sources and sampling schemes have been reported. AimsTo conduct phylogenetic and population genetic analyses from a geographically and phylogenetically representative data set to identify hierarchical divisions within L. calcarifer. We further test the evolutionary significance of genetic units in terms of signatures of adaptation. MethodsUsing a whole-genome sequence data set of 61 fish including an outgroup, we conducted phylogenetic and population genetic analyes. We also generated measures of Fst, nucleotide diversity ({pi}) and Tajimas D (D). Key ResultsWe identify three main lineages of L. calcarifer corresponding to the Indian subcontinent, Southeast Asia and Australasia. Subdivision within each of the three main lineages is also identified and characterized. Adaptively significant differences are indicated within and between the three main lineages. ConclusionsL. calcarifer exhibits genetic divergences at different levels that originate before and during the Pleistocene. These divergences are associated with adaptive divergence but unclear phenotypic changes. ImplicationsThis study highlights the need for comprehensive sampling and integrative study of genotypes and phenotypes across the range of L. calcarifer.

genetics↗

bioRxiv2021

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1-/- , Fmr1-/- and Shank3{Delta}ex13-16-/- mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1-/- mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1-/- mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

neuroscience↗

bioRxiv2020

Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure

BackgroundUnderstanding the neurobiological underpinnings of abstinence from drugs of abuse is critical to allow better recovery and ensure relapse prevention in addicted subjects. MethodsBy comparing the long-term transcriptional consequences of morphine and cocaine exposure, we identified the metabotropic glutamate receptor subtype 4 (mGluR4) as a promising pharmacological target in morphine abstinence. We evaluated the behavioral and molecular effects of facilitating mGluR4 activity in abstinent mice. ResultsTranscriptional regulation of marker genes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) allowed best discriminating between 4-week morphine and cocaine abstinence. Among these markers, Grm4, encoding mGluR4, displayed down-regulated expression in the caudate putamen and NAc of morphine, but not cocaine, abstinent mice. Remarkably, chronic administration of the mGluR4 positive allosteric modulator (PAM) VU0155041 (2.5 and 5 mg/kg) rescued social abilities, normalized stereotypies and anxiety and blunted locomotor sensitization in morphine abstinent mice. This treatment improved social preference but increased stereotypies in cocaine abstinent mice. Finally, the beneficial behavioral effects of VU0155041 treatment in morphine abstinent animals were correlated with restored expression of key MSN and neural activity marker genes in the NAc. ConclusionsThis study is the first report of relieving effects of a pharmacological treatment, chronic administration of the mGluR4 PAM VU0155041, on long-term deleterious consequences of morphine exposure. It illustrates the neurobiological differences between opiate and psychostimulant abstinence and points to pharmacological repression of excessive activity of D2-MSNs in the NAc as a promising therapeutic lever in drug addiction.

neuroscience↗