Browsing by Author "Jarvis, Erin E."

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    Chronic Ethanol Consumption Alters Glucocorticoid Receptor Isoform Expression in Stress Neurocircuits and Mesocorticolimbic Brain Regions of Alcohol-Preferring Rats
    (Elsevier, 2020-06-15) Alhaddad, Hasan; Gordon, Darren M.; Bell, Richard L.; Jarvis, Erin E.; Kipp, Zachary A.; Hinds, Terry D., Jr.; Sari, Youssef; Psychiatry, School of Medicine
    Evidence suggests the hypothalamic-pituitary-adrenal (HPA) axis is involved in Alcohol Use Disorders (AUDs), which might be mediated by an imbalance of glucocorticoid receptor (GR), GRα and GRβ, activity. GRβ antagonizes the GRα isoform to cause glucocorticoid (GC) resistance. In the present study, we aimed to investigate the effects of chronic continuous free-choice access to ethanol on GR isoform expression in subregions of the mesocorticolimbic reward circuit. Adult male alcohol-preferring (P) rats had concurrent access to 15% and 30% ethanol solutions, with ad lib access to lab chow and water, for six weeks. Quantitative Real-time PCR (RT-PCR) analysis showed that chronic ethanol consumption reduced GRα expression in the nucleus accumbens shell (NAcsh) and hippocampus, whereas ethanol drinking reduced GRβ in the nucleus accumbens core (NAcc), prefrontal cortex (PFC), and hippocampus. An inhibitor of GRα, microRNA-124-3p (miR124-3p) was significantly higher in the NAcsh, and GC-induced gene, GILZ, as a measure of GC-responsiveness, was significantly lower. These were not changed in the NAcc. Likewise, genes associated with HPA axis activity were not significantly changed by ethanol drinking [i.e., corticotrophin-releasing hormone (Crh), adrenocorticotrophic hormone (Acth), and proopiomelanocortin (Pomc)] in these brain regions. Serum corticosterone levels were not changed by ethanol drinking. These data indicate that the expression of GRα and GRβ isoforms are differentially affected by ethanol drinking despite HPA-associated peptides remaining unchanged, at least at the time of tissue harvesting. Moreover, the results suggest that GR changes may stem from ethanol-induced GC-resistance in the NAcsh. These findings confirm a role for stress in high ethanol drinking, with GRα and GRβ implicated as targets for the treatment of AUDs.
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    Estimating the synaptic density deficit in Alzheimer’s disease using multi-contrast CEST imaging
    (Public Library of Science, 2024-03-14) Shahid, Syed Salman; Dzemidzic, Mario; Butch, Elizabeth R.; Jarvis, Erin E.; Snyder, Scott E.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of Medicine
    In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aβ) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 μT and 5.9 μT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aβ-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.
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    Mapping alterations in the hippocampal subfields in the ARTE10 mouse model of Alzheimer's disease using dMRI derived soma and neurite density maps
    (Wiley, 2025-01-09) Shahid, Syed Salman; Jarvis, Erin E.; Butch, Elizabeth R.; Snyder, Scott E.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of Medicine
    Background: The hippocampus, a region vital for memory and cognition, is prone to abnormal deposition of beta‐amyloid (Aß) during the early stages of the Alzheimer’s disease. Aß‐associated pathophysiological mechanisms instigate dendritic deficit, neuronal loss, and neuroinflammation, leading to abnormal functional and behavioral changes. These factors directly impact tissue microstructures. Histological studies suggest subfield specific Aß accumulation. The aim of the current study is to map the changes in soma‐ and neurite‐density in the hippocampal‐subfields due to Aß load in the ARTE10 mouse‐model of AD using a compartment‐specific diffusion model. Method: Ten‐month‐old male ARTE10 (N=8) and age‐matched littermate controls underwent MRI on a 9.4T scanner (Bruker BioSpin, GmbH, Germany) equipped with an 1H cryogenic surface coil. DWIs were acquired using a 2D multi‐shot spin‐echo echo planar imaging sequence using the following parameters: TE/TR=26/4000 ms; voxel size=125x125x400 µm3, 20 slices, 4 segments, b values= (500, 1000, 2500, 4000, 5500, 7000) s/mm2 and 5 b0 per b‐shell. The averaged b0 image was non‐linearly registered to Badhwar hippocampus atlas. The hippocampal‐subfields (CA1, CA2, CA3, CA4‐DG, subiculum, and stratum‐granulosum of hippocampus (SGH)) in atlas space were inverse transformed to diffusion space. Multi‐compartment microstructural estimation was performed using soma and neurite density imaging (SANDI) model. This model provided volume fractions for extra‐cellular (fec), intra‐neurite (fin), and intra‐soma (fsoma) compartments (Figure 1). The regional mean values of microstructural parameters of individual subfields were extracted and used in a general linear model for group comparisons. Result: The group‐level differences (WT vs. ARTE10) in fin were observed in CA1 (p=0.02; d=‐1.25), CA2 (p=0.03; d=‐1.20), CA4‐DG (0.01; d=‐1.34), and SGH (p=0.03; d=‐1.22) Figure 2. Group differences in fsoma were significant in CA1 (p=0.04; d=1.08), CA2 (p=0.02; d=1.22), CA4DG (p=0.04; d=1.10), and SGH (p=0.03; d=0.99). In general, the ARTE10 AD mice had reduced neurite density and elevated soma density in the hippocampal subfields. Conclusion: The results demonstrated that the SANDI model is sensitive to the microstructural alterations in the hippocampal subfields of the animal model with profound AD pathologies.