Biology subjects

Pearl, A.

Publications and source records attributed to Pearl, A..

4 recordsLinked to original sources

bioRxiv2026

Sex differences in neural circuits driving binge drinking: A female-specific role for an amygdalo-striatal pathway

BackgroundRates of binge drinking have converged significantly between the sexes over recent decades, driven by increased rates of alcohol misuse in women. However, understanding of fundamental circuitry and neurobiology driving alcohol use in females, or how this may differ from male subjects remains underexplored. MethodsWe quantified c-Fos expression across 40 brain regions in alcohol naive, alcohol anticipating and binge drinking male and female mice. In vivo fiber photometry examined sex differences in basolateral amygdala (BLA) activity changes to alcohol intake. Chemogenetic BLA inhibition investigated a functional role in binge drinking. We then assessed sex differences in BLA efferent projection activation following binge drinking. Finally, we functionally interrogated the BLA to nucleus accumbens core (AcbC) projection in binge drinking. ResultsBinge drinking reduced network modularity (number of communities with similar activation patterns) in both sexes relative to alcohol naive and anticipating same-sex counterparts. Female binge drinking mice had increased BLA c-Fos expression compared to female naive and male binge drinking counterparts. In vivo fiber photometry revealed greater and more prolonged BLA responsivity at the onset of alcohol intake in females. Global BLA inhibition reduced reward intake in both sexes. However, the BLA to AcbC projection was preferentially activated in female binge drinking mice, and inhibition of this pathway reduced binge alcohol intake exclusively in females. ConclusionsWe identified sex differences in the neural circuits engaged in binge drinking, highlighting the BLA to AcbC projection may in part underpin sex differences in alcohol misuse. This provides further evidence of distinct neurobiological drivers of alcohol-related behaviors between the sexes.

neuroscience↗

bioRxiv2024

Hunger alters approach-avoidance behaviours differently in male and female mice

BackgroundThe decision about whether to approach or avoid a reward while under threat requires balancing competing demands. Sex-specific prioritisations (e.g. mating, maternal care), or generalised prioritisations (e.g. feeding, drinking, sleeping) may differently influence approach-avoidance behaviours based on the level of "risk" and homeostatic need state of the organism. However, given known sex differences in key aspects that may influence this behaviour, direct comparison of how male and female mice make decisions to approach or avoid a dangerous area while in a fasted state have yet to be conducted. MethodsWe conducted several approach-avoidance tasks with varied levels of risk and reward in male and female mice that were either fasted or sated (fed). Mice underwent a light-dark box, elevated plus maze, baited large open field and runway task to assess their approach and avoidance behaviour. ResultIn the light-dark box and elevated plus maze, when no reward was available, fasted female mice showed greater approach behaviours than male counterparts. In the baited large open field, when reward was available, both sexes showed increased approach behaviours when fasted. However, when sated, male mice conversely showed greater approach behaviours compared to sated female mice. In the runway task, while sated mice failed to learn, fasted male mice inhibited their reward consumption in response to increased shock intensity; however, fasted female mice were resistant to increased shock intensity. ConclusionsOur study identifies sex differences in decision making behaviour in mice based on satiety state across a number of approach-avoidance tasks. We highlight several nuances of these differences based on reward availability and punishment intensity. These results shine a lens on fundamental differences between the sexes in innate, survival driven behaviours that should be taken into account for future studies. Plain English summaryEveryday decision making is often accompanied by conflict - whether we make the most appropriate decision or not can be influenced by both internal and external factors. Environmental threats and physiological pressures, such as hunger, can influence decision-making processes skewing the risk/reward ratio, yet how this may differ between the sexes has not been explored in detail. Here we used several tasks that assess decision-making in mice while manipulating the levels of risk or reward. Our findings show fasted female mice are more willing to engage in "risky" behaviour compared to fed female mice when risk levels were low, and no food reward was available. However, when a food reward was available, but risk levels were low, both male and female fasted mice were more likely to engage in risky behaviour compared to fed mice. Finally, when risk levels were high and food reward was available, fasted female mice continued to engage in risky behaviour, while male fasted mice were not. Together our study identifies nuanced sex differences in how male and female mice make decisions influenced by both physiological (hunger) and environmental threats and highlight the importance of understanding fundamental differences between the sexes in behaviour. Highlights- Fasted female mice showed greater approach behaviours compared to fasted male counterparts in tasks without reward availability. - Fasted mice of both sexes displayed greater approach behaviours when a reward was available, compared to sated controls. - Fasted male mice inhibited reward consumption under increased shock intensity, whereas fasted female mice were resistant to mild foot shock.

neuroscience↗

bioRxiv2024

Edinger-Westphal ghrelin receptor signalling regulates binge alcohol consumption in a sex specific manner

BackgroundRates of risky drinking are continuing to rise, particularly in women, yet sex as a biological variable has been largely ignored. An emerging yet understudied potential component of this circuitry is the central projecting Edinger-Westphal (EWcp), which is made up of two prominent, but distinct cell populations expressing either an array of neuropeptides (including cocaine and amphetamine regulated transcript; CART) or vGlut2 (glutamatergic). MethodsHere, we use a combination of approaches including genetic, molecular biology, behavioural testing, and electrophysiology to understand how the EWcp contributes to alcohol consumption in female versus male mice. ResultsChemogenetic inhibition of EWcpCART cells reduced binge drinking specifically in female, but not male mice. Further, inhibition of EWcpCART cells prevented ghrelin induced drinking, and viral-mediated ghrelin receptor (Ghsr) knockdown in the EWcp reduced binge drinking in female, but not male mice. RNAscope revealed Ghsr expression across peptidergic (marked by CART) and glutamatergic populations in the EWcp, with neurons from female mice more sensitive to bath application of ghrelin than male mice. Targeted knockdown of Ghsr from distinct EWcp populations revealed GHSR signalling on peptidergic, but not glutamatergic cells mediate binge drinking in female mice. Finally, both a GHSR inverse agonist and antagonist delivered directly within the EWcp reduced binge drinking in female mice. ConclusionsThese findings suggest the EWcp is a region mediating excessive alcohol bingeing through GHSR actions on peptidergic cells (CART-expressing) in female mice and expand our understanding of the neural mechanism(s) underpinning how the ghrelin system mediates alcohol consumption.

neuroscience↗

bioRxiv2021

Diet-induced modifications to human microbiome reshape colonic homeostasis in irritable bowel syndrome

Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we colonized gut organ cultures with longitudinal microbiota samples collected from newly-diagnosed and therapy-naive irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono- saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet, and reinforce the potential feasibility of microbiome based-therapies in IBS.

microbiology↗