Biology subjects

Shah, R. S.

Publications and source records attributed to Shah, R. S..

4 recordsLinked to original sources

bioRxiv2024

Brain-wide population activity during reaching integrates action-mediated goal expectation

Anticipating the outcomes of actions is central to goal-directed behaviour, but how such expectations are encoded across the brain during ongoing movement remains unclear. To address this, we recorded spiking activity from cortical and subcortical regions using multiple Neuropixels probes simultaneously in head-fixed mice performing a water-reaching task. We found that distributed neural population dynamics were strongly modulated by the availability of reward beyond their encoding of forelimb kinematics. Principal component analysis revealed conserved population dynamics across brain regions and sessions that depended on reach amplitude and reward availability. Generalized linear models revealed outcome-related encoding within region-specific population dynamics, in addition to kinematic encoding, with the strongest outcome signals expressed in frontal cortico-thalamic regions. Unsupervised cluster analysis further identified outcome-encoding subpopulations that were enriched in frontal cortices and disproportionally contributed to the shared global latent dynamics. Together, these findings demonstrate that action-mediated outcome expectations are encoded in movement-related population dynamics that are shaped by functional clusters of neurons across the brain.

neuroscience↗

bioRxiv2023

Pseudomonas aeruginosa kills Staphylococcus aureus in a polyphosphate-dependent manner

Due to their frequent coexistence in many polymicrobial infections, including in patients with burn or chronic wounds or cystic fibrosis, recent studies have started to investigate the mechanistic details of the interaction between the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus. P. aeruginosa rapidly outcompetes S. aureus under in vitro co-cultivation conditions, which is mediated by several of P. aeruginosas virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor in P. aeruginosa, plays a role for the pathogens ability to inhibit and kill S. aureus in a contact-independent manner. We show that P. aeruginosa cells characterized by low polyP level are less detrimental to S. aureus growth and survival while the gram-positive pathogen is significantly more compromised by the presence of P. aeruginosa cells that produce high level of polyP. We show that the polyP-dependent phenotype could be a direct effect by the biopolymer, as polyP is present in the spent media and causes significant damage to the S. aureus cell envelope. However, more likely is that polyPs effects are indirect through the regulation of one of P. aeruginosas virulence factors, pyocyanin. We show that pyocyanin production in P. aeruginosa occurs polyP-dependent and harms S. aureus through membrane damage and the generation of reactive oxygen species, resulting in increased expression of antioxidant enzymes. In summary, our study adds a new component to the list of biomolecules that the gram-negative pathogen P. aeruginosa generates to compete with S. aureus for resources. IMPORTANCEHow do interactions between microorganisms shape the course of polymicrobial infections? Previous studies have provided evidence that the two opportunistic pathogens P. aeruginosa and S. aureus generate molecules that modulate their interaction with potentially significant impact on disease outcomes. Our study identified the biopolymer polyP as a new effector molecule that impacts P. aeruginosas interaction with S. aureus. We show that P. aeruginosa kills S. aureus in a polyP-dependent manner, which occurs primarily through the polyP-dependent production of the P. aeruginosa virulence factor pyocyanin. Our findings add a new role for polyP to an already extensive list of functions. A more in-depth understanding of how polyP influences interspecies interactions is critical, as targeting polyP synthesis in bacteria such as P. aeruginosa may have a significant impact on other microorganisms and potentially result in dynamic changes in the microbial composition.

microbiology↗

bioRxiv2023

Hypogonadal (Gnrh1hpg) mice reveal niche-specific influence of reproductive axis and sex on intestinal microbial communities

The gut microbiome has been linked to many diseases with sex bias including autoimmune, metabolic, neurological, and reproductive disorders. Numerous studies report sex differences in fecal microbial communities, but how this differentiation occurs remains unclear. Using a genetic hypogonadal mouse model that does not produce sex steroids or go through puberty, we investigated how sex and the reproductive axis impact bacterial diversity within the small and large intestine. Both sex and reproductive axis inactivation altered bacterial composition in an intestinal section and niche-specific manner. Our results also implicated factors independent of the reproductive axis (i.e., sex chromosomes) in shaping intestinal communities. Additionally, our detailed profile of intestinal communities showed that fecal samples do not reflect bacterial diversity in the small intestine. Our results have ramifications for studying the impact of sex differences on the gut microbiome, particularly in sex-biased diseases and factoring in sex and steroid levels in microbial-based therapies.

microbiology↗

bioRxiv2021

Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKC{delta}-positive (PKC{delta}+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKC{delta}+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

neuroscience↗