Medical Sciences Commons^™

Mechanisms Of Brain Edema Formation In Mouse Models Of Intracerebral Hemorrhage, Qingyi Ma

Loma Linda University Electronic Theses, Dissertations & Projects

Perihematomal edema causes major neurologic deterioration following intracerebral hemorrhage (ICH), mainly resulting from the disruption of the blood-brain barrier (BBB) by multiple mediators, including inflammatory mediators and thrombin. The objective of our study was to investigate the mechanisms by which inflammation and thrombin respectively lead to the formation of brain edema following ICH. Our long-term goal is to develop new therapeutic strategies against ICH-induced brain edema by targeting: (1) VAP-1 mediated inflammatory response and (2) PDGFR-α orchestrated BBB impairment. Vascular adhesion protein-1 (VAP-1) was previously shown to promote leukocyte adhesion and transmigration. Additionally, PDGFR-α was also found to play a …

Role Of Vima In Cell Surface Biogenesis In Porphyromonas Gingivalis, Devon Osbourne Jr.

Loma Linda University Electronic Theses, Dissertations & Projects

Porphyromonas gingivalis is an important etiological agent of periodontal disease - a disease that affects an estimated 49,000,000 people in the United States of America. Periodontal disease includes gingivitis – inflammation of the gums, and periodontitis – destruction of the teeth and their supporting tissues. Porphyromonas gingivalis is associated with the chronic form of periodontal disease in addition to several systemic diseases.

The vimA gene of P. gingivalis has been previously shown to play a significant role in the biogenesis of gingipains (trypsin-like cysteine proteases). The vimA has also been demonstrated to play a role in hemolysis, hemagglutination, autoaggregation, posttranslational …

Chronic Hypoxia Induces Epigenetic Modifications In The Fetal Rat Heart, Andrew James Grant Patterson

Loma Linda University Electronic Theses, Dissertations & Projects

Heart disease remains the leading cause of death worldwide. As a result of studies done by Barker and associates, our awareness of the significance of stress during gestation as a risk factor for heart diseases has expanded. We now know that events in utero can significantly alter gene expression patterns in heart tissue leading to increase susceptibility to ischemia reperfusion injury in adulthood. The focus of this project was to elucidate the role of chronic hypoxia in the programming of the cardio-protective gene, Protein Kinase C epsilon (PKCε) in fetal rat heart. We used an animal, organ base, and cell …

Mechanisms Of Erythropoietin-Induced Neuroprotection In: In-Vivo And In-Vitro Models Of Hypoxia Ischema, Rhonda Andrea Souvenir

Loma Linda University Electronic Theses, Dissertations & Projects

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Approximately 60 % of preterm babies and 2% of full term infants suffer from asphyxia. Asphyxia related death accounts for approximately 23% of neonatal mortality annually. Many therapeutic interventions show promise in the laboratory but fail in clinics. A thorough understanding of mechanisms by which promising therapeutic intervention confers its neuroprotection is necessary to promote smoother transitions from bench to the bedside. Erythropoietin (EPO), a hematopoietic growth factor that increases oxygen availability during hypoxia/ischemia is associated with cell survival and neuroprotection in: in vivo and in …

Characterization Of Palmitic Acid Induced Lipotoxicity In Schwann Cells, Amelia Padilla

Loma Linda University Electronic Theses, Dissertations & Projects

Lipotoxicity is a response to lipid overload that has been associated with cellular dysfunction leading to cellular death. The mechanism of lipotoxicity and its impact on the nervous system is critical as it can lead to debilitating neurological conditions. This study examines key cellular events induced by palmitic acid lipotoxicity (PA-LTx) in Schwann cells cultured in euglycemic and hyperglycemic conditions. The data show that immortalized Schwann cell (iSC), as well as primary Schwann cell (pSC) cultures exposed to elevated levels of PA induced an apoptotic cell death that is dose and time-dependent. The earliest indication of cellular dysfunction was a …

The Role Of Receptor Tyrosine Kinase Axl In Pancreatic Ductal Adenocarcinoma And Its Regulation By Hematopoietic Progenitor Kinase 1, Xianzhou Song

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples …

Novel Amino Acid Transporter-Targeted Radiotracers For Breast Cancer Imaging, Fanlin Kong

Dissertations and Theses (Open Access)

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. ¹⁸F-2-Fluoro-2-deoxy-glucose (¹⁸F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, ¹⁸F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, ¹⁸F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake …

Evaluation Of Deformable Image Registration For Improved 4d Ct-Derived Ventilation For Image Guided Radiotherapy, Richard Castillo

Dissertations and Theses (Open Access)

Recent treatment planning studies have demonstrated the use of physiologic images in radiation therapy treatment planning to identify regions for functional avoidance. This image-guided radiotherapy (IGRT) strategy may reduce the injury and/or functional loss following thoracic radiotherapy. 4D computed tomography (CT), developed for radiotherapy treatment planning, is a relatively new imaging technique that allows the acquisition of a time-varying sequence of 3D CT images of the patient's lungs through the respiratory cycle. Guerrero et al. developed a method to calculate ventilation imaging from 4D CT, which is potentially better suited and more broadly available for IGRT than the current standard …

We Can Do It Together: Par1/Par2 Heterodimer Signaling In Vsmcs., Rafal Pawlinski, Michael Holinstat

Department of Medicine Faculty Papers

In this issue, Sevigny and colleagues demonstrate that a protease-activated receptor 1 (PAR1)-PAR2 heterodimer regulates vascular smooth muscle cell (VSMC) hyperplasia following vascular injury ¹. PARs belong to a family of G-protein coupled receptors that are proteolytically activated by a variety of proteases ^{2, 3}. Cleavage of PARs results in intracellular signaling mediated by activation of various G proteins including G_12/13, G_q, and G_i ^{2, 4-6}. The PAR family consists of 4 members, PAR1-PAR4, with PARs 1, 3, and 4 being primarily activated by thrombin, while PAR2 is activated by trypsin and …

Epitope Characterization Of Sero-Specific Monoclonal Antibody To Clostridium Botulinum Neurotoxin Type A., Cindi R Corbett, Erin Ballegeer, Kelly A Weedmark, M D Elias, Fetweh H Al-Saleem, Denise M Ancharski, Lance L Simpson, Jody D Berry

Department of Medicine Faculty Papers

Botulinum neurotoxins (BoNTs) are extremely potent toxins that can contaminate foods and are a public health concern. Anti-BoNT antibodies have been described that are capable of detecting BoNTs; however there still exists a need for accurate and sensitive detection capabilities for BoNTs. Herein, we describe the characterization of a panel of eight monoclonal antibodies (MAbs) generated to the non-toxic receptor-binding domain of BoNT/A (H(C)50/A) developed using a high-throughput screening approach. In two independent hybridoma fusions, two groups of four IgG MAbs were developed against recombinant H(C)50/A. Of these eight, only a single MAb, F90G5-3, bound to the whole BoNT/A protein …

B1b Lymphocyte-Derived Antibodies Control Borrelia Hermsii Independent Of Fcα/Μ Receptor And In The Absence Of Host Cell Contact., Matthew J. Colombo, David Abraham, Akira Shibuya, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

The critical role of IgM in controlling pathogen burden has been demonstrated in a variety of infection models. In the murine model of Borrelia hermsii infection, IgM is necessary and sufficient for the rapid clearance of bacteremia. Convalescent, but not naïve, B1b cells generate a specific IgM response against B. hermsii, but the mechanism of IgM-mediated protection is unknown. Here, we show that neither Fcα/μR, a high-affinity receptor for IgM, nor IgM-dependent complement activation is required for controlling B. hermsii. Bacteria in diffusion chambers with a pore size impermeable to cells were killed when diffusion chambers were implanted into either …

Autoimmune Consequences Of Histone Deimination During Neutrophil Activation, Nishant Dwivedi

Theses and Dissertations (ETD)

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or "trap" bacterial pathogens. Neutrophil …

Testing Whether Mrp4 (A Camp Efflux Pump) And The Beta 2 Andrenergic Receptor (An Upstream Regulator Of Camp Signaling Pathways, Praveen Kumar Potukuchi

Theses and Dissertations (ETD)

Background and Aim: MRP4/ABCC4 is an ABC transporter that can efflux the second-messenger, cAMP, from cells. MRP4 has a PDZ interacting motif at its carboxy terminal end through which it binds to scaffolding proteins NHERF1 and PDZK1. Previous studies have shown that PDZK1 serves as a scaffold physically coupling MRP4 with the cystic fibrosis transmembrane conductance regulator (CFTR). This protein complex functionally couples cAMP regulation of CFTR function with MRP4 cAMP transporter activity [Li, C., et al., Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia. Cell, 2007. 131(5): p. 940-51]. We hypothesized that the …

The Effects Of Pten Deletion On Cell Size And Plasticity In The Hippocampus, Margaret Sperow

Theses and Dissertations (ETD)

The tumor suppressor phosphatase and tensin homolog (PTEN) is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) -signaling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size and synaptic transmission and plasticity. Neurologic abnormalities such as autism, seizures, and ataxia are associated with inherited PTEN mutations. Yet, how PTEN loss contributes to neurologic dysfunction remains unknown. PTEN loss during early development is associated with extensive deficits in neuronal migration and substantial hypotrophy of neurons and synaptic densities. However, whether its effect on synaptic transmission and plasticity is direct …

Characterization Of The Mechanism Of Pparγ-Mediated Neointima Formation In Rodents, Ryoko Tsukahara

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) and its ether analog alkyl glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for …

Characterization Of The Key Mouse Cochlear Developmental Genes For Auditory Hair Cell Regeneration, Zhiyong Liu

Theses and Dissertations (ETD)

Mammalian inner ear cochlear auditory hair cells (HCs) and adjacent supporting cells (SCs) are believed to derive from the same progenitors during development. However, unlike SCs of nonmammalian vertebrates, mammalian cochlear SCs cannot be converted into functional hair cells (HCs) after damage, thus leading to permanent deafness. To entitle mammals with the ability to restore hearing capacity after HC damage, we first achieved proliferation of SCs by acute ablation of p27 or Sox2. Secondly, we overactivated Notch1 signaling in the mouse inner ear at different developmental stages, and found that the ability of Notch signaling in generating new HCs declines …

Improving The Accuracy Of Radiation Pneumonitis Dose Response Models, Yevgeniy Vinogradskiy

Dissertations and Theses (Open Access)

The prognosis for lung cancer patients remains poor. Five year survival rates have been reported to be 15%. Studies have shown that dose escalation to the tumor can lead to better local control and subsequently better overall survival. However, dose to lung tumor is limited by normal tissue toxicity. The most prevalent thoracic toxicity is radiation pneumonitis. In order to determine a safe dose that can be delivered to the healthy lung, researchers have turned to mathematical models predicting the rate of radiation pneumonitis. However, these models rely on simple metrics based on the dose-volume histogram and are not yet …

Contribution Of Ectodomain Mutations In Epidermal Growth Factor Receptor To Signaling In Glioblastoma Multiforme, Marta L. Rojas

Dissertations and Theses (Open Access)

CONTRIBUTION OF ECTODOMAIN MUTATIONS IN EPIDERMAL GROWTH FACTOR RECEPTOR TO SIGNALING IN GLIOBLASTOMA MULTIFORME

Publication No._________

Marta Rojas, M.S.

Supervisory Professor: Oliver Bögler, Ph.D.

The Cancer Genome Atlas (TCGA) has conducted a comprehensive analysis of a large tumor cohort and has cataloged genetic alterations involving primary sequence variations and copy number aberrations of genes involved in key signaling pathways in glioblastoma (GBM). This dataset revealed missense ectodomain point mutations in epidermal growth factor receptor (EGFR), but the biological and clinical significance of these mutations is not well defined in the context of gliomas.

In our study, we focused on understanding …

Modelling Β2ar Regulation, Sharat J. Vayttaden

Dissertations and Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical models …

An Evaluation Of Neuroplasticity And Behavior After Deep Brain Stimulation Of The Nucleus Accumbens In An Animal Model Of Depression., Steven M Falowski, Ashwini Sharan, Beverly A S Reyes, Carl Sikkema, Patricia Szot, Elisabeth J Van Bockstaele

Department of Neurosurgery Faculty Papers

BACKGROUND: Recent interest has demonstrated the nucleus accumbens (NAcc) as a potential target for the treatment of depression with deep brain stimulation (DBS).

OBJECTIVE: To demonstrate that DBS of the NAcc is an effective treatment modality for depression and that chemical and structural changes associated with these behavioral changes are markers of neuroplasticity.

METHODS: A deep brain stimulator was placed in the NAcc of male Wistar-Kyoto rats. Groups were divided into sham (no stimulation), intermittent (3 h/d for 2 weeks), or continuous (constant stimulation for 2 weeks). Exploratory and anxietylike behaviors were evaluated with the open-field test before and after …

Stimulation Of The Hypothalamic Ventromedial Nuclei By Pituitary Adenylate Cyclase-Activating Polypeptide Induces Hypophagia And Thermogenesis, Jon M. Resch, Joanne P. Boisvert, Allison E. Hourigan, Christopher R. Mueller, Sun Shin Yi, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Numerous studies have demonstrated that the hypothalamic ventromedial nuclei (VMN) regulate energy homeostasis by integrating and utilizing behavioral and metabolic mechanisms. The VMN heavily express pituitary adenylate cyclase-activating polypeptide(PACAP) type I receptors (PAC1R). Despite the receptor distribution, most PACAP experiments investigating affects on feeding have focused on intracerebroventricular (icv) administration or global knockout mice. To identify the specific contribution of PACAP signaling in the VMN, we injected PACAP directly into the VMN and measured feeding behavior and indices of energy expenditure. Following an acute injection of PACAP, nocturnal food intake was significantly reduced for six hours after injections without evidence …

Arsenic Represses Myogenesis And Neurogenesis Through Epigenetic Mechanisms, Repressed Transcription Factors, And Altered Wnt Signaling Pathway, Gia-Ming Hong

All Dissertations

Arsenic is a toxicant commonly found in water systems around the world. Evidence from epidemiological studies indicates that chronic arsenic exposure can result in cancer, central nervous system and sensory deficits, effects on development, and neuromuscular deficits. However, the molecular mechanism of arsenic's toxicity remains largely unclear. In this study, both C2C12 mouse myoblast cells and mouse embryonic stem cells (mESCs) were used as models of arsenic mediated developmental toxicity in humans to investigate the effects of sodium arsenite on cellular differentiation.
Results from our first and second studies indicate that exposure of 20nM sodium arsenite to C2C12 mouse myocyte …

Impacts Of Psychotropic Pharmaceuticals On Hybrid Striped Bass: Altered Predation Behavior As A Function Of Changes In Brain Chemistry, Joseph Bisesi

All Dissertations

Advances in Analytical Chemistry have led to the detection of low concentrations of pharmaceuticals and personal care products (PPCPs) in wastewater treatment plant effluents as well as their receiving waters. Antidepressants are routinely found among these contaminants, but have been shown to be relatively non-toxic at environmentally measured concentrations using traditional toxicity testing techniques. The neurochemical mode of action of antidepressants warrants investigation of the effects these chemicals may have on fish behavior due to the highly conserved nature of neurotransmitter transporter targets. Using a predator prey bioassay designed in our laboratory, previous studies has shown that the antidepressant fluoxetine …

Using Lectinmicroarrays To Identify Regulatory Mechanisms For Mammalian Glycosylation, John F. Rakus

Chemistry Faculty Research

Glycosylation involves the post-translational addition of carbohydrates to protein molecules and is an intricate and indispensable biochemical process. Study of this complicated network of interactions is hindered by the lack of a coding template analogous to the genetic code, and by the vast structural complexity inherent to carbohydrate polymers. We use lectins (non-enzymatic carbohydrate-binding proteins of non-immunological origin) as microarray probes to identify carbohydrate features expressed on cellular surfaces. Specifically, we utilized lectin microarray technology to investigate the differences in carbohydrates expressed by the cell lines of the Nation Cancer Institute’s NCI-60 panel. Our investigation identified tissue-specific expression differences in …

Hiv-1 Tat Protein Promotes Neuronal Dysfunction Through Disruption Of Micrornas, J Robert Chang, Ruma Mukerjee, Asen Bagashev, Luis Del Valle, Tinatin Chabrashvili, Brian J. Hawkins, Johnny J. He, Bassel E. Sawaya

School of Medicine Faculty Publications

Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release …

Oxidative Stress And Heme Oxygenase-1 Regulated Human Mesenchymal Stem Cells Differentiation, Luca Vanella, Christopher Sanford Jr., Dong Hyun Kim, Nader G. Abraham, Nabil Ebraheim

Biochemistry and Microbiology

This paper describes the effect of increased expression of HO-1 protein and increased levels of HO activity on differentiation of bone-marrow-derived human MSCs. MSCs are multipotent cells that proliferate and differentiate into many different cell types including adipocytes and osteoblasts. HO, the rate-limiting enzyme in heme catabolism, plays an important role during MSCs differentiation. HO catalyzes the stereospecific degradation of heme to biliverdin, with the concurrent release of iron and carbon monoxide. Upregulation of HO-1 expression and increased HO activity are essential for MSC growth and differentiation to the osteoblast lineage consistent with the role of HO-1 in hematopoietic stem …

Nuclease Modulates Biofilm Formation In Community-Associated Methicillin-Resistant Staphylococcus Aureus., Megan R. Kiedrowski, Jeffrey S. Kavanaugh, Cheryl L. Malone, Joe M. Mootz, Jovanka M. Voyich, Mark S. Smeltzer, Kenneth W. Bayles, Alexander R. Horswill

Journal Articles: Pathology and Microbiology

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging contributor to biofilm-related infections. We recently reported that strains lacking sigma factor B (sigB) in the USA300 lineage of CA-MRSA are unable to develop a biofilm. Interestingly, when spent media from a USA300 sigB mutant was incubated with other S. aureus strains, biofilm formation was inhibited. Following fractionation and mass spectrometry analysis, the major anti-biofilm factor identified in the spent media was secreted thermonuclease (Nuc). Considering reports that extracellular DNA (eDNA) is an important component of the biofilm matrix, we investigated the regulation and role of Nuc in USA300. The expression of …

Effect Of Protein Kinase C Delta (Pkc-Δ) Inhibition On The Transcriptome Of Normal And Systemic Sclerosis Human Dermal Fibroblasts In Vitro., Peter J Wermuth, Sankar Addya, Sergio A Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

Previous studies demonstrated that protein kinase C- δ (PKC-δ) inhibition with the selective inhibitor, rottlerin, resulted in potent downregulation of type I collagen expression and production in normal human dermal fibroblasts and abrogated the exaggerated type I collagen production and expression in fibroblasts cultured from affected skin from patients with the fibrosing disorder systemic sclerosis (SSc). To elucidate the mechanisms involved in the ability of PKC-δ to regulate collagen production in fibroblasts, we examined the effects of PKC-δ inhibition on the transcriptome of normal and SSc human dermal fibroblasts. Normal and SSc human dermal fibroblasts were incubated with rottlerin (5 …

Death Receptor 5 Signaling Promotes Hepatocyte Lipoapoptosis., Sophie C. Cazanave, Justin L. Mott, Steven F. Bronk, Nathan W. Werneburg, Christian D. Fingas, X Wei Meng, Niklas Finnberg, Wafik S. El-Deiry, Scott H. Kaufmann, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading …

Paradoxical Reversal Learning Enhancement By Stress Or Prefrontal Cortical Damage: Rescue With Bdnf., Carolyn Graybeal, Michael Feyder, Emily Schulman, Lisa M Saksida, Timothy J Bussey, Jonathan L Brigman, Andrew Holmes

Brain and Mind Institute Researchers' Publications

Stress affects various forms of cognition. We found that moderate stress enhanced late reversal learning in a mouse touchscreen-based choice task. Ventromedial prefrontal cortex (vmPFC) lesions mimicked the effect of stress, whereas orbitofrontal and dorsolateral striatal lesions impaired reversal. Stress facilitation of reversal was prevented by BDNF infusion into the vmPFC. These findings suggest a mechanism by which stress-induced vmPFC dysfunction disinhibits learning by alternate (for example, striatal) systems.