Biology subjects

Walsh, J. J.

Publications and source records attributed to Walsh, J. J..

8 recordsLinked to original sources

bioRxiv2026

No evidence for direct physical interaction of 5-HT2A-mGluR2 receptors in vitro or in vivo

Activation of mGluR2 (metabotropic glutamate receptor 2), the primary presynaptic autoreceptor for glutamate in the brain, is well established to attenuate the psychedelics-mediated behavioral and electrophysiological effects. However, the mechanisms responsible for these actions are controversial. The two competing mechanistic hypotheses have been proposed to explain this phenomenon are: (1) direct actions mediated by mGluR2/5-HT2A heterodimers, and (2) inhibition of 5-HT2A-mediated excitation of pyramidal neurons via presynaptic inhibition of glutamate release by mGluR2 receptors. Consistent with prior reports, we show that mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice engineered to express mGluR2-mCherry and 5-HT2A-eGFP-CT tagged receptors. We next employed multiple orthogonal in vivo and in vitro approaches to explore the potential for direct physical interactions between mGluR2 and 5-HT2A receptors. Across all approaches, we found no evidence for receptor colocalization or oligomerization under basal or 5-HT2A agonist-exposed conditions in vitro or in vivo. Radioligand binding and kinetic analyses revealed no evidence for mGluR2-mediated modulation of 5-HT2A ligand binding in vitro or in vivo. Collectively, our findings support models in which mGluR2 signaling modulates the activity of Gq-coupled 5-HT2A receptors in layer V pyramidal neurons, rather than models positing the requirement of mGluR2/5-HT2A multimers.

neuroscience↗

bioRxiv2026

Integrating longitudinal hyperspectral phenotyping with AI and GWAS to dissect barley waterlogging responses

Waterlogging is a major constraint on barley productivity, yet its dynamic, multi-phase nature makes it challenging to dissect using traditional phenotyping approaches. High-throughput phenotyping (HTP) platforms address this by enabling temporal, multi-sensor imaging of large populations, but generate complex datasets that demand new analytical frameworks. Here, we imaged 230 barley accessions over 14 days of waterlogging stress and seven days of recovery using visible, chlorophyll fluorescence, and hyperspectral sensors. Explainable AI was applied to classify stress responses into early stress, late stress, and recovery phases, achieving 86% classification accuracy, and to identify the hyperspectral indices most informative for each phase. Water index (WATER1) and structure insensitive pigment index (SIPI) emerged as primary predictors of stress response. Longitudinal genome-wide association studies (GWAS), using a treatment-by-marker interaction model, identified 236 significant loci across 12 linkage disequilibrium blocks, implicating candidate genes involved in oxidative stress regulation, transcriptional control, and auxin transport. MYB transcription factors were consistently identified across all stress phases, underscoring their central role in waterlogging adaptation. To support interpretation of longitudinal GWAS results, we developed 3D-QTLVis, an interactive visualisation tool that extends Manhattan plots across time, enabling clearer identification of dynamic genomic regions underlying stress tolerance.

plant biology↗

bioRxiv2025

Acute exogenous ketone monoester supplementation decreases cardiac vagal modulation in a dose-dependent manner

Exogenous ketone supplementation can elevate heart rate (HR) but the effects on cardiac autonomic modulation remain unclear. HR variability was analyzed from 18 healthy adults (23 {+/-} 3 yrs; n=10 females) ingesting 0.3 (low-dose) or 0.6 g/kg (high-dose) ketone monoester or placebo in a randomized crossover, double-blind design. Compared to placebo, both ketone doses increased capillary {beta}-hydroxybutyrate and reduced the percentage of successive R-R intervals that differ by [≥]50-ms (pRR50) and the root mean square of successive differences (RMSSD) at 45- and 120-min post-ingestion (all p<0.05). Acute ketone ingestion decreases HR variability measures associated with reduced cardiac vagal modulation.

physiology↗

bioRxiv2025

Cerebrovascular Responses to Static and Rhythmic Handgrip Exercises

Handgrip exercise (HGE) is a safe, accessible exercise modality shown to improve cardiovascular health and is particularly promising for individuals with limited mobility who cannot engage in traditional exercise. Given that contraction type and intensity influence systemic cardiorespiratory variables that affect cerebral blood flow regulation, this study examined the acute systemic hemodynamic and cerebrovascular responses to static and rhythmic HGE protocols at varying intensities. Thirty-three healthy young adults (17 males; 16 females age 22(1) years) performed four separate 5-minute HGE protocols in a randomized order: static HGE at 15% (S15) of maximal voluntary contraction (MVC), static HGE at 30% MVC, rhythmic HGE at 30% MVC, rhythmic HGE at 60% (R60) MVC. We hypothesized that rhythmic HGE at higher intensities would produce the greatest cerebrovascular responses due to enhanced venous return and cardiac output, while static HGE at higher intensities would elicit the greatest systemic (i.e., blood pressure, HR, ventilation) responses. Cerebral (middle cerebral artery blood velocity [MCAv] and cerebrovascular conductance index [MCACVCi], internal carotid artery [ICA] diameter, velocity, blood flow, and shear rate) and systemic hemodynamics (systolic [SBP], diastolic [DBP], mean arterial pressure [MAP], heart rate [HR], cardiac output [CO]), and end-tidal carbon dioxide (PETCO2) levels were averaged over the final 30s of each minute of exercise. There was a significant time and protocol interaction effect on HR (p<0.001). We found significant main effects of exercise protocol for MCAv (p<0.001), MCACVCi (p<0.001), ICA diameter (p=0.01) and blood flow (p=0.001), and PETCO2 (p=0.002). Greatest increases in MCAv alongside the largest reduction in ICA blood flow occurred in R60. The greatest increase in MCACVCi and ICA blood flow (from baseline) occurred in R30 compared to other protocols. In addition to the greater cerebrovascular responses, we also observed more modest systemic responses (lower HR, MAP, CO) and lower self-reported ratings of perceived exertion (p<0.001) in R30 compared to other protocols. Acute increases in MCACVCi and ICA blood flow observed in R30 (despite the lower perceived effort) may suggest that rhythmic HGE at low-moderate intensities can be a tolerable prescription for inducing exercise-related cerebrovascular adaptations (i.e., improved cerebral perfusion) in populations that may require adapted physical activity.

physiology↗

bioRxiv2025

Botanic Spectrum Analyser: A Deep Learning GUI for Plant Image Segmentation in Hyperspectral and RGB Phenotyping

Plant phenotyping systematically quantifies plant traits such as growth, morphology, physiology, or yield, assessing genetic and environmental influences on plant performance. The integration of advanced phenotyping technologies, including imaging sensors and data analytics, facilitates the non-destructive and longitudinal acquisition of high-throughput data. Nevertheless, the sheer volume of such phenotyping data introduces significant challenges for researchers, particularly related to data processing. To overcome these challenges, researchers are turning to artificial intelligence (AI), a tool that can autonomously process and learn from large amounts of data. Despite this advantage, accurate image segmentation remains a key hurdle due to the complexity of plant morphology and environmental noise. In this study, we present the Botanical Spectrum Analyser (BSA), a user-friendly graphical user interface (GUI) that integrates a modified U-Net deep neural network for plant image segmentation. Designed for accessibility, BSA enables non-technical users to apply advanced AI segmentation to RGB and hyperspectral (VNIR and SWIR) imagery. We evaluated BSAs performance across three case studies involving wheat, barley, and Arabidopsis, demonstrating its robustness across species and imaging modalities. Our results show that BSA achieves an average accuracy of 99.7%, with F1-scores consistently exceeding 98% and strong Jaccard and recall performance across datasets. For challenging root segmentation tasks, BSA outperformed commercial algorithms, achieving a 76% F1-score compared to 24%, representing a 50% improvement. These results highlight the adaptability of the BSA framework for diverse phenotyping scenarios, bridging the gap between advanced deep learning methods and accessible plant science applications.

plant biology↗

bioRxiv2025

Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of high-fat diet only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption. Significance StatementObesity and metabolic disorders are partly driven by dysregulated motivation for palatable foods, yet the neural circuits underlying hedonic feeding are not fully understood. This study shows that nucleus accumbens medium spiny neurons have differential, sex-specific roles in high-fat intake: D1-MSN activity suppresses intake in male mice, while D2-MSNs promote consumption in female mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings expand previous models of reward processing and highlight the experience and sex-dependent roles of MSN subtypes. By defining cell-type-specific contributions to non-homeostatic eating, this work offers key insight into the neural basis of hedonic intake and informs strategies for targeted intervention in obesity and related conditions.

neuroscience↗

bioRxiv2020

Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas

High sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane ({Delta}Na+mem) and weak transendothelial ({Delta}Na+end) gradients respectively, which reflect cell membrane potential (Vm) and blood-brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic contrast agent to measure {Delta}Na+mem and {Delta}Na+end. In vitro 23Na-MRSI established that the 23Na signal is strongly shifted by the agent compared to biological factors. In vivo 23Na-MRSI showed Na+i remained unshifted and Na+b was more shifted than Na+e, and these together created weakened {Delta}Na+mem and enhanced {Delta}Na+end in rat gliomas. Specifically, RG2 and U87 tumors maintained weakened {Delta}Na+mem (i.e., depolarized Vm) implying an aggressive state for proliferation, and RG2 tumors displayed elevated {Delta}Na+end suggesting altered BBB integrity. 23Na-MRSI will allow explorations of perturbed Na+ homeostasis in vivo for the tumor neurovascular unit.

cancer biology↗

bioRxiv2019

Distinct neural mechanisms for the prosocial and rewarding properties of MDMA

The extensively abused recreational drug MDMA has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMAs prosocial effect. MDMAs acute rewarding properties, in contrast, require dopaminergic signaling. MDMAs prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMAs prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.\n\nOne Sentence SummaryMDMA, which has both therapeutic and abuse potential, engages a brain region-specific serotonergic pathway to produce its prosocial effect.

neuroscience↗