Biology subjects

Winchester, S.

Publications and source records attributed to Winchester, S..

6 recordsLinked to original sources

bioRxiv2026

Age- and sex- dependent effects of moderate gestational day 12 prenatal alcohol exposure on anxiety-like behaviors, ethanol intake, and mechanical sensitivity

RationalePrenatal alcohol exposure (PAE) can result in Fetal Alcohol Spectrum Disorder (FASD), which consists of a group of diagnosable medical conditions that can include an increased risk for anxiety disorders and/or alcohol misuse, and sensory issues, such as increased mechanical sensitivity. ObjectiveThis study investigated how a single moderate PAE on gestational day 12 (G12) alters anxiety-like behavior, ethanol (EtOH) intake, and mechanical sensitivity across the lifespan of Sprague Dawley rats. MethodsPregnant dams were exposed to vaporized EtOH or room air (control) for 6 hours (BECs [~]108 mg/dL). Testing in male and female offspring began at three different ages: juveniles ([~]postnatal day (P) 25), adolescents ([~]P45) and adults ([~]P80). ResultsThe greatest PAE effects were observed in adolescent animals, with alterations in anxiety-like behaviors demonstrated in the light-dark box and elevated plus maze. Additionally, adolescent female animals consumed more sweetened EtOH compared to males. However, PAE adolescent animals consuming less sweetened EtOH compared to their counterparts, which was also observed in adult PAE females. Interestingly, this effect is reversed in juvenile and adolescent males when tested with unsweetened EtOH, with juvenile females consuming more EtOH also. Finally, PAE and air animals exhibited increased mechanical sensitivity following post-natal EtOH consumption across all ages. ConclusionThese data demonstrate that there are age- and sex-specific effects of PAE on anxiety-like behaviors, EtOH intake, and mechanical sensitivity that are more distinct in adolescent animals.

neuroscience↗

bioRxiv2025

Moderate prenatal alcohol exposure differentially alters acute ethanol sensitivity of GABAergic transmission in CRFR1- and CRFR1+ CeM neurons

AbstractPrenatal exposure to alcohol (PAE) increases the risk for misusing alcohol and/or developing an alcohol use disorder (AUD) by adulthood. The corticotropin releasing factor (CRF) system is a major target of pre- and post-natal ethanol (EtOH) exposure. CRF and its receptor (CRFR1), in part, mediate EtOH potentiated GABA release in the medial nucleus of the central amygdala (CeM) of adult male rodents. Interestingly, our lab has shown a disruption in the function and expression of CeM CRFR1 and acute EtOHs effects on GABA transmission in PAE adolescent animals, but it is unknown whether these alterations to the CRF system persist into adulthood or alter the actions of acute EtOH on GABAergic transmission in the CeM. Using CRF1-Cre-tdTomato rats, this study examined how moderate PAE alters acute EtOH modulation of GABAergic neurotransmission onto CRFR1+ and CRFR1-CeM neurons in adult offspring (P80-105). Pregnant dams were exposed to vaporized ethanol or room air (control) on gestational day 12 (G12) for 6 hours and whole-cell electrophysiology was performed in the CeM to assess the actions of acute EtOH (44, 66, & 88 mM) on GABAergic transmission onto CRFR1+ and CRFR1-neurons. We found unique effects of PAE that were cell type- and concentration-dependent in males and females, suggesting PAE dysregulates acute EtOHs modulation of GABA transmission within the CeM in a sex-specific manner. This study contributes to the expanding body of research exploring the effects of PAE and how a single exposure can impact neurophysiological mechanisms in brain regions associated with AUD. HighlightsO_LIModerate PAE alters the actions of alcohol on synaptic transmission in adult rats C_LIO_LIPAE differentially impacts GABAergic transmission onto CeM CRFR1- and CRFR1+ C_LIO_LILong-term PAE effects in the CeM are sex-specific C_LI

neuroscience↗

bioRxiv2024

Moderate prenatal alcohol exposure alters GABAergic transmission and the action of acute alcohol in the CeM of adolescent rats

Individuals with prenatal alcohol exposure (PAE) are at a higher risk for developing alcohol use disorder (AUD). Using a rat model of PAE on gestational day 12 (G12; ~2nd trimesters in humans), a critical period for amygdala development, we have shown disruptions in medial central amygdala (CeM) function, an important brain region associated with the development of AUD. In addition to this, acute ethanol (EtOH) increases GABA transmission in the CeM of rodents in a sex-dependent manner, a mechanism that potentially contributes to alcohol misuse. How PAE alters acute alcohols effects within the CeM is unknown. Given these findings, we investigated how PAE may interact with acute alcohol to alter neuronal and synaptic mechanisms in the CeM of adolescent rats in order to understand PAE-induced alcohol-related behaviors. Under basal conditions, PAE males showed reduced rheobase, indicative of reduced excitability, and females showed a reduction in GABA transmission, indicated by lower spontaneous inhibitory postsynaptic currents (sIPSCs). We found that acute EtOH increased sIPSCs in control males at a moderate concentration (66 mM), while PAE males showed increased sIPSCs only at a high concentration (88 mM). Adolescent females, regardless of PAE status, were largely insensitive to EtOHs effects at all tested concentrations. However, PAE females showed a significant increase in sIPSCs at the highest concentration (88 mM). Overall, these findings support the hypothesis that PAE leads to sex-specific changes in synaptic activity and neuronal function. Future research is needed to better understand the specific mechanisms by which acute EtOHs affects neurotransmission in the adolescent brain of individuals with a history of PAE.

neuroscience↗

bioRxiv2024

A TBX5-dependent compartment boundary patterns the cardiac interventricular septum

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. Here, we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors cause IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.

developmental biology↗

bioRxiv2022

A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors

Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.

developmental biology↗

bioRxiv2020

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

Gene regulatory networks control tissue plasticity during basal homeostasis and disease in a cell-type specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue-specificity of their function is achieved are poorly understood. BRD4, a member of the BET (Bromo- and Extra-Terminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease, and has been implicated as a pharmacologic target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. Here, we show that cardiomyocyte-specific deletion of BRD4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature enriched for decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes and preferentially co-localizes with GATA4, a lineage determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. Co-immunoprecipitation assays demonstrate that BRD4 and GATA4 form a complex in a bromodomain-independent manner, revealing a new interaction partner for BRD4 that has functional consequences for target transactivation and may allow for locus and tissue specificity. These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte specific gene program governing bioenergetic homeostasis in the adult heart.

molecular biology↗