Biology subjects

Edwards, C. M.

Publications and source records attributed to Edwards, C. M..

9 recordsLinked to original sources

bioRxiv2026

SNRNP70 interacts with TDP-43 to promote RNP granule localisation and regulate motor neuron development

SNRNP70 is a core spliceosomal protein that localises to both the nucleus and cytoplasm. Previous studies have implicated SNRNP70 in regulating axonal stability and the transport of specific mRNAs during motor neuron development in zebrafish. Although the molecular functions and protein interactions of SNRNP70 in pre-mRNA splicing are well established, the mechanisms underlying its cytoplasmic functions remain poorly understood. Here, we show that SNRNP70 and TDP-43 exhibit similar localisation patterns in developing and mature neurons and co-associate in both nuclear and non-nuclear compartments, including axonal projections. We identify a functional interaction between SNRNP70 and TDP-43 that is essential for motor neuron development and demonstrate that the recruitment of SNRNP70 to cytoplasmic ribonucleoprotein (RNP) granules depends on TDP-43. These findings identify a previously unrecognised cytoplasmic function of TDP-43 in directing SNRNP70-containing RNP granule assembly, thereby linking TDP-43 to the splicing-independent functions of SNRNP70 during motor neuron development.

neuroscience↗

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↗

bioRxiv2025

Adolescent onset of volitional ethanol intake normalizes sex differences observed with adult-onset ethanol intake and negative affective behaviors during protracted forced abstinence

RationaleNegative affect during ethanol abstinence can lead to relapse and dependence. Voluntary ethanol drinking models are crucial for examining negative affect following chronic ethanol access, but female rodents often drink more ethanol than males, complicating comparisons between sexes. Since chronic adolescent ethanol use poses a substantial risk for later alcohol use disorder, we hypothesize that adolescence is a critical window for consolidating drinking behavior before major hormonal changes affect ethanol consumption. ObjectivesThis study compared sex differences in voluntary ethanol consumption and negative affective behavior in mice that initiated ethanol consumption during early adolescence ([~]PND30) or early adulthood (>PND49). MethodsMale and female C57BL/6J mice underwent the Chronic Drinking Forced Abstinence (CDFA) paradigm, with the "Ethanol" group given two-bottle choice access to ethanol and water, and the "Water" group given two water bottles. Ethanol intake and preference were measured over six weeks. Two weeks following ethanol removal, mice underwent behavioral testing for negative affective-like behavior. ResultsAdult-onset female mice consumed significantly more ethanol and displayed higher ethanol preference compared to adult-onset male mice. In contrast, adolescent-onset male and female mice consumed similar ethanol levels and displayed similar preference. We observed increased immobility during the forced swim test in adult-onset ethanol females, but not males, during protracted abstinence. However, both sexes of adolescent-onset ethanol mice displayed increased immobility during forced abstinence. ConclusionsThese findings highlight adolescence as a critical period during which both sexes voluntarily consume ethanol and are equally vulnerable to the behavioral disturbances associated with ethanol abstinence.

neuroscience↗

bioRxiv2025

High cholesterol increases myeloma tumour burden and promotes resistance to bortezomib

Multiple myeloma (MM) is an incurable hematologic cancer where malignant plasma cells accumulate in the bone marrow (BM), with disease progression highly dependent on cellular interactions. Obesity is a major risk factor for myeloma, however the underlying mechanisms are unclear. Here we used a murine myeloma model to show that a high cholesterol diet increases local and circulating levels of low density lipoprotein cholesterol (LDL), increasing bone marrow tumour burden in vivo. Exogenous LDL induced bortezomib-specific drug resistance in metabolically stressed myeloma cells in vitro and ex vivo. RNA-seq analysis revealed bortezomib-induced changes in the cholesterol biosynthesis/homeostasis pathway that were completely reverted with LDL pretreatment. In silico analysis of patient data supported a role for cholesterol in response to bortezomib-based therapies. Targeted proteome profiling revealed changes in expression of the adipokine resistin in the bone marrow of cholesterol-treated or myeloma-bearing mice, with elevated resistin expression observed in MGUS patients. Bone marrow adipocytes were found to be a major source of resistin, which was further increased in response to LDL. In summary, we demonstrate that high cholesterol promotes both myeloma development and bortezomib resistance, identifying resistin as a potential mediator so revealing new mechanisms underlying myeloma pathogenesis.

cancer biology↗

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

An ascending vagal sensory-central noradrenergic pathway modulates retrieval of passive avoidance memory

BackgroundVisceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay "gut feelings" to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. ResultsTo examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. ConclusionsThese new findings support the view that a gut vagal afferent-to-cNTSNA-to-vlBNST circuit plays a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

neuroscience↗

bioRxiv2022

Ghrelin receptor signaling contributes to fasting-induced suppression of conditioned avoidance behavior and neural circuit activation in male rats

Interoceptive feedback to the brain regarding the bodys physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. To test this, ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. GRA restored passive avoidance in fasted rats as measured both by latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before re-exposure to the shock-paired context displayed more activation of prolactin-releasing peptide (PrRP)-positive noradrenergic neurons in the caudal nucleus of the solitary tract, accompanied by more activation of downstream neurons in the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus. These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive noradrenergic neurons and their downstream hypothalamic and limbic forebrain targets.

neuroscience↗

bioRxiv2021

Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons

Competing motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fed ad libitum prior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. Overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.

neuroscience↗