Biology subjects

Tobet, S. A.

Publications and source records attributed to Tobet, S. A..

3 recordsLinked to original sources

bioRxiv2024

Sex specific effects of environmental toxin-derived alpha synuclein on enteric neuronal-epithelial interactions

BackgroundParkinsons Disease (PD) is a neurodegenerative disorder with prodromal gastrointestinal (GI) issues often emerging decades before motor symptoms. Pathologically, PD can be driven by accumulation of misfolded alpha synuclein (aSyn) protein in the brain and periphery, including the GI tract. Disease epidemiology differs by sex, with men twice as likely to develop PD. Women, however, experience faster disease progression, higher mortality, and more severe GI symptoms. Gut calcitonin gene related peptide (CGRP) is a key regulator of intestinal contractions and visceral pain. The current study tests the hypothesis that sex differences in GI symptomology in PD are the result of aSyn aggregation altering enteric CGRP signaling pathways. MethodsTo facilitate peripheral aSyn aggregation, the pesticide rotenone was administered intraperitoneally once daily for two weeks to male and female mice. Mice were sacrificed two weeks after the last rotenone injection and immunohistochemistry was performed on sections of proximal colon. Key ResultsLevels of aSyn were heightened in myenteric plexus neurons and a subset of neurons immunoreactive to CGRP in rotenone treated mice. Female mice exhibited 153% more myenteric aSyn, 26% more apical CGRP immunoreactivity, and 66.7% more aSyn in apical CGRP+ fibers after rotenone when compared to males. Goblet cell numbers were diminished but the individual cells were larger in the apical regions of crypts in the colons of rotenone treated mice. ConclusionsThis study used a mouse model of PD to uncover sex specific alterations in enteric neuronal and epithelial populations, underscoring the importance of considering sex as a biological variable while investigating prodromal GI symptoms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=143 HEIGHT=200 SRC="FIGDIR/small/625701v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@19a6dforg.highwire.dtl.DTLVardef@1a9324org.highwire.dtl.DTLVardef@b253d4org.highwire.dtl.DTLVardef@19d89cf_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIMouse model of Parkinsons Disease (PD) was used to investigate sex specific impact of enteric alpha synuclein (aSyn) on colonic goblet cells and CGRP+ neurons and fibers. C_LIO_LISex specific alterations in intestinal neuronal and epithelial signaling pathways in response to aSyn provides insight into sex differences in PD etiology and prodromal gastrointestinal symptoms. C_LI

physiology↗

bioRxiv2024

Prenatal Dexamethasone Programs Autonomic Dysregulation in Female Rats

Autonomic dysfunction is associated with cardiovascular and neurological disease, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero (gestation days [GD]18-21). At 11-12-weeks of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (1-adrenoceptor + {beta}1-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in adrenals and left ventricle, and gene expression for the {beta}1 adrenergic receptor was measured in left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in Vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry. New and NoteworthyThese studies use pharmacological antagonists to characterize the nature of the autonomic dysregulation induced in female offspring exposed to the synthetic glucocorticoid, dexamethasone, in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females leading to a shift in the sympathovagal balance.

physiology↗

bioRxiv2023

Microfluidic organotypic device to test intestinal mucosal barrier permeability ex vivo

To protect the body from external pathogens, the intestines have sophisticated epithelial and mucosal barriers. Disruptions to barrier integrity are associated with a variety of disorders such as irritable bowel disease, Crohns Disease, and celiac disease. One critical component of all barriers are collagens in the extracellular matrix. While the importance of the intestinal barrier is established, current models lack the ability to represent the complex biology that occurs at these barriers. For the current study a microfluidic device model was modified to determine the effectiveness of collagen breakdown to cause barrier disruption. Bacterial collagenase was added for 48 h to the luminal channel of a dual flow microfluidic device to examine changes in intestinal barrier integrity. Tissues exhibited dose-dependent alterations in immunoreactive collagen-1 and claudin-1, and coincident disruption of the epithelial monolayer barrier as indicated by goblet cell morphologies. This ex vivo model system offers promise for further studies exploring factors that affect gut barrier integrity and potential downstream consequences that cannot be studied in current models.

bioengineering↗