Biology subjects

Doyle, M. A.

Publications and source records attributed to Doyle, M. A..

9 recordsLinked to original sources

bioRxiv2026

Individual differences in ethanol drinking meal structure are shaped by social environments

Alcohol use disorder (AUD) is marked by substantial heterogeneity in drinking behaviors and health outcomes, underscoring the need for preclinical models that capture interindividual variability. We recently developed open-source capacitive lickometer systems for high-resolution monitoring of mouse fluid intake. Using LIQ PARTI and LIQ HD, we found substantial individual differences in alcohol intake that varied across sex and housing status in C57Bl6/J mice. Here, we conducted a secondary analysis of this continuous access ethanol drinking data to quantify behavioral variability in group and singly housed mice. We introduce a fluid "meal" pattern analysis that integrates drinking across ethanol and water sippers to define discrete drinking episodes. Using this approach, we observed sex- and housing-dependent reorganization of drinking structure across group and single-housed settings, with group-housed male mice exhibiting fewer but faster liquid meals. To further characterize multidimensional drinking patterns, we applied principal component analysis to meal variables and identified a "distributed meal" phenotype defined by increased meal number, reduced meal size, earlier onset of drinking, and higher ethanol preference. Considering factors that influence behaviors in a social environment, we next examined whether social hierarchy was associated with these patterns using a tube test dominance assay. Social rank was unrelated to ethanol and meal measures; however, offensive dominance behavior positively correlated with principal component scores in males. Together, these findings demonstrate that high-resolution, longitudinal analysis of ethanol drinking reveals distinct behavioral phenotypes that are associated with key components of social behaviors, providing a potential framework for understanding heterogeneity in AUD-related drinking. HighlightsO_LILIQ PARTI and HD enable high-resolution analysis of ethanol drinking patterns. C_LIO_LIFluid meal analysis captures sex- and housing-dependent drinking structures. C_LIO_LIBehavioral phenotyping reveals individual differences beyond total ethanol intake. C_LIO_LIPCA identifies a meal phenotype associated with male offensive dominance behavior. C_LI

neuroscience↗

bioRxiv2026

Sex-specific control of feeding and defensive behaviors by MC3R neurons in the bed nuclei of the stria terminalis

The bed nuclei of the stria terminalis (BST) is a nuclear complex that coordinates neuroendocrine, autonomic, and behavioral responses associated with maintaining homeostasis. Here, we demonstrate that melanocortin 3 receptor (MC3R) neurons in the BST (BSTMC3R) play a key role in modulating feeding behaviors and responses to stressful events. BSTMC3R neurons are primarily GABAergic and colocalize with neuropeptides known to regulate feeding and affective behaviors. Chemogenetic activation of BSTMC3R neurons causes reduced feeding, particularly in males. BSTMC3R neurons are also robustly activated by stress and can control responses to stress and defensive behaviors in both sexes. Whole-brain monosynaptic rabies tracing identified multiple sexually dimorphic inputs to BSTMC3R neurons that may contribute to observed functional sexual dimorphisms. Altogether, these data reveal that BSTMC3R neurons participate in sexually dimorphic circuits that influence feeding and defensive behaviors, responses to stress, and may represent a potential therapeutic target for stress- and eating-related disorders.

neuroscience↗

bioRxiv2024

Cocaine, via ΔFosB, remodels gene expression and excitability in ventral hippocampus

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor {Delta}FosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of {Delta}FosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by {Delta}FosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification (TRAP) to assess cocaine-induced, {Delta}FosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a {Delta}FosB-dependent increase in the expression of calreticulin, an ER-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a novel, non-canonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

neuroscience↗

bioRxiv2024

A novel mouse home cage lickometer system reveals sex- and housing-based influences on alcohol drinking

Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these efects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology. Significance StatementLoneliness has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. Here we developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source group-housed lickometer system to investigate how social housing, isolation, and sex influence alcohol consumption patterns in C57Bl/6J mice. LIQ PARTI accurately identifies mouse drinking events and uncovered significant housing- and fluid-dependent diferences in ethanol consumption and bout microstructure between male and female mice. Social isolation-induced changes to ethanol drinking behavior and microstructure were highly plastic, as resocialization generally reversed these changes. These findings expand on the complex interplay between sex, social isolation, and alcohol use.

neuroscience↗

bioRxiv2024

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh+ neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh+ neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naive female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

neuroscience↗

bioRxiv2023

Optimizing Short-format Training: an International Consensus on Effective, Inclusive, and Career-spanning Professional Development in the Life Sciences and Beyond

Science, technology, engineering, mathematics, and medicine (STEMM) fields change rapidly and are increasingly interdisciplinary. Commonly, STEMM practitioners use short-format training (SFT) such as workshops and short courses for upskilling and reskilling, but unaddressed challenges limit SFTs effectiveness and inclusiveness. Prior work, including the NSF 2026 Reinventing Scientific Talent proposal, called for addressing SFT challenges, and a diverse international group of experts in education, accessibility, and life sciences came together to do so. This paper describes the phenomenography and content analyses that produced a set of 14 actionable recommendations to systematically strengthen SFT. Recommendations were derived from findings in the educational sciences and the experiences of several of the largest life science SFT programs. Recommendations cover the breadth of SFT contexts and stakeholder groups and include actions for instructors (e.g., make equity and inclusion an ethical obligation), programs (e.g., centralize infrastructure for assessment and evaluation), as well as organizations and funders (e.g., professionalize training SFT instructors; deploy SFT to counter inequity). Recommendations are aligned into a purpose-built framework-- "The Bicycle Principles"--that prioritizes evidenced-based teaching, inclusiveness, and equity, as well as the ability to scale, share, and sustain SFT. We also describe how the Bicycle Principles and recommendations are consistent with educational change theories and can overcome systemic barriers to delivering consistently effective, inclusive, and career-spanning SFT. SIGNIFICANCE STATEMENTSTEMM practitioners need sustained and customized professional development to keep up with innovations. Short-format training (SFT) such as workshops and short-courses are relied upon widely but have unaddressed limitations. This project generated principles and recommendations to make SFT consistently effective, inclusive, and career-spanning. Optimizing SFT could broaden participation in STEMM by preparing practitioners more equitably with transformative skills. Better SFT would also serve members of the STEMM workforce who have several decades of productivity ahead, but who may not benefit from education reforms that predominantly focus on undergraduate STEMM. The Bicycle Principles and accompanying recommendations apply to any SFT instruction and may be especially useful in rapidly evolving and multidisciplinary fields such as artificial intelligence, genomics, and precision medicine.

scientific communication and education↗

bioRxiv2022

LIQ HD (Lick Instance Quantifier Home cage Device): An open-source tool for recording undisturbed two-bottle drinking behavior in a home cage environment

Investigation of rodent drinking behavior has provided insight into drivers of thirst, circadian rhythms, anhedonia, and drug and ethanol consumption. Traditional methods of recording fluid intake involve weighing bottles, which is cumbersome and lacks temporal resolution. Several open-source devices have been designed to improve drink monitoring, particularly for two-bottle choice tasks. However, recent designs are limited by the use of infrared photobeam sensors and incompatibility with prolonged undisturbed use in ventilated home cages. Beam-break sensors lack accuracy for bout microstructure analysis and are prone to damage from rodents. Thus, we designed LIQ HD (Lick Instance Quantifier Home cage Device) with the goal of utilizing capacitive sensors to increase accuracy and analyze lick microstructure, building a device compatible with ventilated home cages, increasing scale with prolonged undisturbed recordings, and creating a design that is easy to build and use with an intuitive touchscreen graphical user interface. The system tracks two-bottle choice licking behavior in up to 18 rodent cages, or 36 single bottles, on a minute-to-minute timescale controlled by a single Arduino microcontroller. The data are logged to a single SD card, allowing for efficient downstream analysis. With sucrose, quinine, and ethanol two-bottle choice tasks, we validated that LIQ HD has superior accuracy compared to photobeam sensors. The system measures preference over time and changes in bout microstructure, with undisturbed recordings lasting up to 7 days. All designs and software are open-source to allow other researchers to build upon the system and adapt LIQ HD to their animal home cages. Significance StatementTwo-bottle choice drinking tasks are traditionally performed by periodically weighing bottles, which is cumbersome and lacks temporal resolution. Several open-source tools have been developed to improve drink monitoring in various settings. However, no open-source devices have been designed specifically to investigate temporally precise two-bottle choice drinking behavior and bout microstructure during prolonged undisturbed tasks in mouse ventilated home cages at a large scale. Our design, LIQ HD (Lick Instance Quantifier Home cage Device), is a home cage compatible system that utilizes capacitive sensors for highly accurate lick detection during two-bottle choice tasks in up to 18 cages driven by a single Arduino microcontroller. The system is low-cost, easy to build, and controlled via touchscreen with an intuitive graphical user interface.

neuroscience↗

bioRxiv2022

Galaxy Training: A Powerful Framework for Teaching!

There is an ongoing explosion of scientific datasets being generated, brought on by recent technological advances in many areas of the natural sciences. As a result, the life sciences have become increasingly computational in nature, and bioinformatics has taken on a central role in research studies. However, basic computational skills, data analysis and stewardship are still rarely taught in life science educational programs [1], resulting in a skills gap in many of the researchers tasked with analysing these big datasets. In order to address this skills gap and empower researchers to perform their own data analyses, the Galaxy Training Network (GTN) has previously developed the Galaxy Training Platform (https://training.galaxyproject.org); an open access, community-driven framework for the collection of FAIR training materials for data analysis utilizing the user-friendly Galaxy framework as its primary data analysis platform [2]. Since its inception, this training platform has thrived, with the number of tutorials and contributors growing rapidly, and the range of topics extending beyond life sciences to include topics such as climatology, cheminformatics and machine learning. While initially aimed at supporting researchers directly, the GTN framework has proven to be an invaluable resource for educators as well. We have focused our efforts in recent years on adding increased support for this growing community of instructors. New features have been added to facilitate the use of the materials in a classroom setting, simplifying the contribution flow for new materials, and have added a set of train-the-trainer lessons. Here, we present the latest developments in the GTN project, aimed at facilitating the use of the Galaxy Training materials by educators, and its usage in different learning environments.

bioinformatics↗

bioRxiv2020

A single-cell RNA-seq Training and Analysis Suite using the Galaxy Framework

BackgroundThe vast ecosystem of single-cell RNA-seq tools has until recently been plagued by an excess of diverging analysis strategies, inconsistent file formats, and compatibility issues between different software suites. The uptake of 10x Genomics datasets has begun to calm this diversity, and the bioinformatics community leans once more towards the large computing requirements and the statistically-driven methods needed to process and understand these ever-growing datasets. ResultsHere we outline several Galaxy workflows and learning resources for scRNA-seq, with the aim of providing a comprehensive analysis environment paired with a thorough user learning experience that bridges the knowledge gap between the computational methods and the underlying cell biology. The Galaxy reproducible bioinformatics framework provides tools, workflows and trainings that not only enable users to perform one-click 10x preprocessing, but also empowers them to demultiplex raw sequencing from custom tagged and full-length sequencing protocols. The downstream analysis supports a wide range of high-quality interoperable suites separated into common stages of analysis: inspection, filtering, normalization, confounder removal and clustering. The teaching resources cover an assortment of different concepts from computer science to cell biology. Access to all resources is provided at the singlecell.usegalaxy.eu portal. ConclusionsThe reproducible and training-oriented Galaxy framework provides a sustainable HPC environment for users to run flexible analyses on both 10x and alternative platforms. The tutorials from the Galaxy Training Network along with the frequent training workshops hosted by the Galaxy Community provide a means for users to learn, publish and teach scRNA-seq analysis. Key PointsO_LISingle-cell RNA-seq has stabilised towards 10x Genomics datasets. C_LIO_LIGalaxy provides rich and reproducible scRNA-seq workflows with a wide range of robust tools. C_LIO_LIThe Galaxy Training Network provides tutorials for the processing of both 10x and non-10x datasets. C_LI

bioinformatics↗