34 results on '"Sarah A. Wolfe"'
Search Results
2. Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses
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Larry Rodriguez, Dean Kirson, Sarah A. Wolfe, Reesha R. Patel, Florence P. Varodayan, Angela E. Snyder, Pauravi J. Gandhi, Sophia Khom, Roman Vlkolinsky, Michal Bajo, and Marisa Roberto
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corticotropin releasing factor (CRF) ,patch-clamp electrophysiology ,sex difference ,alcohol use disorder (AUD) ,Gamma-Aminobutyric Acid (GABA) ,central amygdala (CeA) ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by the recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin-releasing factor (CRF)-CRF1 receptor and Gamma-Aminobutyric Acid (GABA)-ergic signaling dysregulation occurring in alcohol-dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch-clamp electrophysiology to examine the effects of alcohol dependence on the CRF modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared to males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had fewer CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike in males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.
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- 2022
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3. Skin Viral Infections: Host Antiviral Innate Immunity and Viral Immune Evasion
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Vivian Lei, Amy J. Petty, Amber R. Atwater, Sarah A. Wolfe, and Amanda S. MacLeod
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cutaneous innate immunity ,skin viruses ,antiviral proteins ,skin antiviral response ,cutaneous microbiome ,skin aging ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The skin is an active immune organ that functions as the first and largest site of defense to the outside environment. Serving as the primary interface between host and pathogen, the skin’s early immune responses to viral invaders often determine the course and severity of infection. We review the current literature pertaining to the mechanisms of cutaneous viral invasion for classical skin-tropic, oncogenic, and vector-borne skin viruses. We discuss the skin’s evolved mechanisms for innate immune viral defense against these invading pathogens, as well as unique strategies utilized by the viruses to escape immune detection. We additionally explore the roles that demographic and environmental factors, such as age, biological sex, and the cutaneous microbiome, play in altering the host immune response to viral threats.
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- 2020
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4. FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties
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Sarah A. Wolfe, Emily R. Workman, Chelcie F. Heaney, Farr Niere, Sanjeev Namjoshi, Luisa P. Cacheaux, Sean P. Farris, Michael R. Drew, Boris V. Zemelman, R. Adron Harris, and Kimberly F. Raab-Graham
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Science - Abstract
Alcohol is thought to lead to neuroadaptive changes, although the underlying molecular mechanisms are unclear. Here, the authors find ethanol treatment alters GABAB-receptor expression via fragile-X mental retardation protein in mice, leading to antidepressant-like behaviours.
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- 2016
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5. The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder
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Florence P. Varodayan, Reesha R. Patel, Alessandra Matzeu, Sarah A. Wolfe, Dallece E. Curley, Sophia Khom, Pauravi J. Gandhi, Larry Rodriguez, Michal Bajo, Shannon D’Ambrosio, Hui Sun, Tony M. Kerr, Rueben A. Gonzales, Lorenzo Leggio, Luis A. Natividad, Carolina L. Haass-Koffler, Rémi Martin-Fardon, and Marisa Roberto
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Male ,Alcoholism ,Norepinephrine ,Alcohol Drinking ,Ethanol ,Central Amygdaloid Nucleus ,Animals ,Humans ,RNA, Messenger ,Article ,Biological Psychiatry ,Rats ,Receptors, Adrenergic - Abstract
BACKGROUND: Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline (NA) stress system is implicated in AUD relapse. METHODS: Here we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure (CIE) to induce dependence, or withdrawn from CIE for two weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by HPLC), in situ hybridization and behavioral brain-site specific pharmacology studies were performed. We also used qRT-PCR to assess gene expression of the α1(B), β1, and β2 adrenergic receptor in human post-mortem brain tissue from men diagnosed with AUD and matched controls. RESULTS: We found that α1 receptors potentiate CeA GABAergic transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, though there are some long-lasting differences in the cellular patterns of adrenergic receptor mRNA expression. Additionally, post-mortem brain analyses reveal increased α1B receptor mRNA in the amygdala of humans with AUD. CONCLUSIONS: Thus, CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, support ongoing new medication development for AUD.
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- 2022
6. Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects
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Dean Kirson, Sarah A. Wolfe, Larry Rodriguez, Michael Q. Steinman, Sophia Khom, Christopher S. Oleata, and Marisa Roberto
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Behavioral Neuroscience ,Health (social science) ,Neurology ,General Medicine ,Toxicology ,Biochemistry - Published
- 2023
7. Sex and context differences in the effects of trauma on comorbid alcohol use and post‐traumatic stress phenotypes in actively drinking rats
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Samantha R. Spierling Bagsic, Michal Bajo, Michael Q. Steinman, Sarah A. Wolfe, Eric P. Zorrilla, Ilhem Messaoudi, Suhas Sureshchandra, Dean Kirson, Christopher S. Oleata, and Marisa Roberto
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Male ,Alcohol Drinking ,media_common.quotation_subject ,Physiology ,Context (language use) ,Comorbidity ,Alcohol use disorder ,Amygdala ,Article ,Stress Disorders, Post-Traumatic ,Cellular and Molecular Neuroscience ,mental disorders ,medicine ,Animals ,Post-traumatic stress disorder (PTSD) ,media_common ,business.industry ,Alcohol dependence ,Traumatic stress ,Abstinence ,medicine.disease ,Rats ,Alcoholism ,Phenotype ,medicine.anatomical_structure ,Female ,business - Abstract
Alcohol use disorder (AUD) and affective disorders are frequently comorbid and share underlying mechanisms that could be targets for comprehensive treatment. Post-traumatic stress disorder (PTSD) has high comorbidity with AUD, but comprehensive models of this overlap are nascent. We recently characterized a model of comorbid AUD and PTSD-like symptoms, wherein stressed rats receive an inhibitory avoidance (IA)-related footshock on two occasions followed by two-bottle choice (2BC) voluntary alcohol drinking. Stressed rats received the second footshock in a familiar (FAM, same IA box as the first footshock) or novel context (NOV, single-chambered apparatus); the FAM paradigm more effectively increased alcohol drinking in males and the NOV paradigm in females. During abstinence, stressed males displayed avoidance-like PTSD symptoms, and females showed hyperarousal-like PTSD symptoms. Rats in the model had altered spontaneous action potential-independent GABAergic transmission in the central amygdala (CeA), a brain region key in alcohol dependence and stress-related signaling. However, PTSD sufferers may have alcohol experience prior to their trauma. Here, we therefore modified our AUD/PTSD comorbidity model to provide 3 weeks of intermittent extended alcohol access before footshock and then studied the effects of NOV and FAM stress on drinking and PTSD phenotypes. NOV stress suppressed the escalation of alcohol intake and preference seen in male controls, but no stress effects were seen on drinking in females. Additionally, NOV males had decreased action potential-independent presynaptic GABA release and delayed postsynaptic GABAA receptor kinetics in the CeA compared to control and FAM males. Despite these changes to alcohol intake and CeA GABA signaling, stressed rats showed broadly similar anxiogenic-like behaviors to our previous comorbid model, suggesting decoupling of the PTSD symptoms from the AUD vulnerability for some of these animals. The collective results show the importance of alcohol history and trauma context in vulnerability to comorbid AUD/PTSD-like symptoms.
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- 2021
8. Dose-dependent emergence of acute and recurrent corneal lesions in sulfur mustard-exposed rabbit eyes
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Amber C. Altvater, Patrick M. McNutt, Skylar M. L. Bodt, Celinia A. Ondeck, Megan E Lyman, Matthieu T. Conroy, Kyle E.M. Kelly, Sean O'Brien, Tracey A. Hamilton, Marian R. Nelson, Nicole B. Hall, Susan Schulz, Sarah E Wolfe, and Denise M. Kniffin
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Stromal cell ,Dose dependence ,Toxicology ,Drug Administration Schedule ,Cornea ,Neovascularization ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mustard Gas ,medicine ,Animals ,Chemical Warfare Agents ,Dose-Response Relationship, Drug ,business.industry ,Sulfur mustard ,General Medicine ,eye diseases ,Pathophysiology ,Acute toxicity ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Toxicity ,Female ,Rabbits ,sense organs ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Corneal Injuries - Abstract
Sulfur mustard (SM) is a lipid soluble alkylating agent that causes genotoxic injury. The eye is highly sensitive to SM toxicity and exposures exceeding 400 mg min/m3 can elicit irreversible corneal pathophysiologies. Development of medical countermeasures for ocular SM exposure has been hindered by a limited understanding of dose-dependent effects of SM on corneal injury. Here, clinical, histological and ultrastructural analyses were used to characterize the effects of SM dose on corneal injury progression. Corneas were evaluated for up to 20 wk following exposure to saturated SM vapor for 30−150 s, which corresponds to 300−1,500 mg min/m3. In acute studies, a ceiling effect on corneal edema developed at doses associated with full-thickness corneal lesions, implicating endothelial toxicity in corneal swelling. Recurrent edematous lesions (RELs) transiently emerged after 2 wk in a dose-dependent fashion, followed by the development of secondary corneal pathophysiologies such as neovascularization, stromal scarring and endothelial abnormalities. RELs appeared in 96 % of corneas exposed for ≥ 90 s, 52 % of corneas exposed for 60 s and 0 % of corneas exposed for 30 s. While REL latency was variable in corneas exposed for 60 s, REL emergence was synchronized at exposures ≥ 90 s. Corneas did not exhibit more than one REL, suggesting RELs are part of a programmed pathophysiological response to severe alkylating lesions. In post-mortem studies at 12 wk, corneal edema was positively correlated to severity of endothelial pathologies, consistent with previous findings that endothelial toxicity influences long-term outcomes. These results provide novel insight into long-term corneal pathophysiological responses to acute toxicity and identify exposure conditions suitable for therapeutic testing.
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- 2021
9. Sex Differences in Acute Alcohol Sensitivity of Naïve and Alcohol Dependent Central Amygdala GABA Synapses
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Roman Vlkolinsky, Reesha R. Patel, Sarah A. Wolfe, Michal Bajo, Larry Rodriguez, Pauravi J Gandhi, Marisa Roberto, Dean Kirson, Florence P. Varodayan, and Sophia Khom
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Male ,0301 basic medicine ,medicine.medical_specialty ,Alcohol use disorder ,Amygdala ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,gamma-Aminobutyric Acid ,Ethanol ,business.industry ,Central Amygdaloid Nucleus ,Alcohol dependence ,General Medicine ,medicine.disease ,Rats ,Alcoholism ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,GABAergic ,Anxiety ,Female ,Synaptic signaling ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Sex characteristics - Abstract
Aims Alcohol use disorder (AUD) is linked to hyperactivity of brain stress systems, leading to withdrawal states which drive relapse. AUD differs among the sexes, as men are more likely to have AUD than women, but women progress from casual use to binge and heavy alcohol use more quickly and are more likely to relapse into repetitive episodes of heavy drinking. In alcohol dependence animal models of AUD, the central amygdala (CeA) functions as a hub of stress and anxiety processing and gamma-Aminobutyric acid (GABA)ergic signaling within the CeA is involved in dependence-induced increases in alcohol consumption. We have shown dysregulation of CeA GABAergic synaptic signaling in alcohol dependence animal models, but previous studies have exclusively used males. Methods Here, we used whole-cell patch clamp electrophysiology to examine basal CeA GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) and the effects of acute alcohol in both naïve and alcohol dependent rats of both sexes. Results We found that sIPSC kinetics differ between females and males, as well as between naïve and alcohol-dependent animals, with naïve females having the fastest current kinetics. Additionally, we find differences in baseline current kinetics across estrous cycle stages. In contrast to the increase in sIPSC frequency routinely found in males, acute alcohol (11–88 mM) had no effect on sIPSCs in naïve females, however the highest concentration of alcohol increased sIPSC frequency in dependent females. Conclusion These results provide important insight into sex differences in CeA neuronal function and dysregulation with alcohol dependence and highlight the need for sex-specific considerations in the development of effective AUD treatment.
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- 2021
10. The meaning of autonomy when living with dementia: A Q-method investigation
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Beth Greenhill, Jennie Day, Sarah E Wolfe, and Sarah Butchard
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Subjectivity ,Sociology and Political Science ,media_common.quotation_subject ,Decision Making ,Q-method ,rights-based approaches ,World health ,03 medical and health sciences ,0302 clinical medicine ,subjectivity ,medicine ,Humans ,Dementia ,030212 general & internal medicine ,Meaning (existential) ,autonomy ,media_common ,030214 geriatrics ,General Social Sciences ,Articles ,General Medicine ,medicine.disease ,Epistemology ,Caregivers ,Action plan ,Key (cryptography) ,Psychology ,Autonomy - Abstract
Background and Aims Sensitivity to the rights of people with dementia is a key principle cited in the World Health Organisation’s global action plan on dementia. Some critics question whether rights-based approaches embody loose and ill-defined ideas incapable of bringing about meaningful change. Exercising the right to autonomy is considered a core problem for people living with dementia. The tradition of individual sovereignty dominates ideas about autonomy, although the person as an individual is not a cross-culturally universal concept. This study explored the viewpoints of people with dementia and family carers regarding the meaning of autonomy with a view to informing rights-based practice. Methods Twenty participants, people living with dementia and family carers, each conducted a Q-sort of statements regarding the meaning of autonomy. A by-person factor analysis was used to identify patterns in how the range of statements about autonomy were ranked. Results Three factors emerged: retaining independence and self-expression, accepting dependence but being included and opportunity for connection. There was some agreement across these different views regarding the importance of being given time to think before making decisions and being kept active. Conclusions This study highlights the need for a person-centred approach to supporting people with dementia to claim their rights and the importance of adopting a stance of curiosity and critical thinking in rights-based training and professional practice. The findings suggest a variety of meaningful stories of autonomy and the possibility of further developing existing rights-based frameworks for dementia care.
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- 2020
11. Mortality management and climate action: A review and reference for using Terror Management Theory methods in interdisciplinary environmental research
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Lauren K. M. Smith, Hanna C. Ross, Stephanie A. Shouldice, and Sarah Elizabeth Wolfe
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Atmospheric Science ,Global and Planetary Change ,Geography, Planning and Development - Published
- 2022
12. The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System
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Sarah A, Wolfe, Valentina, Vozella, and Marisa, Roberto
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Psychiatry and Mental health ,Clinical Psychology ,Alcoholism ,Ethanol ,Cannabinoids ,Medicine (miscellaneous) ,Humans ,Receptors, Cannabinoid ,Synaptic Transmission ,Endocannabinoids - Abstract
A growing body of evidence has implicated the endocannabinoid (eCB) system in the acute, chronic, and withdrawal effects of alcohol/ethanol on synaptic function. These eCB-mediated synaptic effects may contribute to the development of alcohol use disorder (AUD). Alcohol exposure causes neurobiological alterations similar to those elicited by chronic cannabinoid (CB) exposure. Like alcohol, cannabinoids alter many central processes, such as cognition, locomotion, synaptic transmission, and neurotransmitter release. There is a strong need to elucidate the effects of ethanol on the eCB system in different brain regions to understand the role of eCB signaling in AUD.For the scope of this review, preclinical studies were identified through queries of the PubMed database.This search yielded 459 articles. Clinical studies and papers irrelevant to the topic of this review were excluded.The endocannabinoid system includes, but is not limited to, cannabinoid receptors 1 (CB
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- 2022
13. Functional basis for dose-dependent antagonism of rat and rabbit neuromuscular transmission by the bis-pyridinium oxime MMB4
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Sarah E Wolfe, Kevin M. Bounader, Kathleen T Pagarigan, Patrick M. McNutt, Michael Adler, Shane A. Kasten, James P. Apland, James B. Machamer, and Brittany M. Winner
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0301 basic medicine ,Health, Toxicology and Mutagenesis ,Neuromuscular transmission ,General Medicine ,010501 environmental sciences ,Pharmacology ,Toxicology ,01 natural sciences ,Acetylcholinesterase ,Neuromuscular junction ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,Nicotinic agonist ,chemistry ,Muscle tension ,medicine ,Cholinergic ,Respiratory function ,medicine.symptom ,0105 earth and related environmental sciences ,Muscle contraction - Abstract
Organophosphorus (OP) compounds inhibit central and peripheral acetylcholinesterase (AChE) activity, overstimulating cholinergic receptors and causing autonomic dysfunction (e.g., bronchoconstriction, excess secretions), respiratory impairment, seizure and death at high doses. Current treatment for OP poisoning in the United States includes reactivation of OP-inhibited AChE by the pyridinium oxime 2-pyridine aldoxime (2-PAM). However, 2-PAM has a narrow therapeutic index and its efficacy is confined to a limited number of OP agents. The bis-pyridinium oxime MMB4, which is a more potent reactivator than 2-PAM with improved pharmaceutical properties and therapeutic range, is under consideration as a potential replacement for 2-PAM. Similar to other pyridinium oximes, high doses of MMB4 lead to off-target effects culminating in respiratory depression and death. To understand the toxic mechanisms contributing to respiratory depression, we evaluated the effects of MMB4 (0.25–16 mM) on functional and neurophysiological parameters of diaphragm and limb muscle function in rabbits and rats. In both species, MMB4 depressed nerve-elicited muscle contraction by blocking muscle endplate nicotinic receptor currents while simultaneously prolonging endplate potentials by inhibiting AChE. MMB4 increased quantal content, endplate potential rundown and tetanic fade during high frequency stimulation in rat but not rabbit muscles, suggesting species-specific effects on feedback mechanisms involved in sustaining neurotransmission. These data reveal multifactorial effects of MMB4 on cholinergic neurotransmission, with the primary toxic modality being reduced muscle nicotinic endplate currents. Evidence of species-specific effects on neuromuscular function illustrates the importance of comparative toxicology when studying pyridinium oximes and, by inference, other quaternary ammonium compounds.
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- 2020
14. Corneal Endothelial Cell Toxicity Determines Long-Term Outcome After Ocular Exposure to Sulfur Mustard Vapor
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Dominique L. Nguyen, Megan E Lyman, Marian R. Nelson, Tracey A. Hamilton, Sarah E Wolfe, Margaret M Eisen, Mark Mangkhalakhili, Kathleen T Pagarigan, Celinia A. Ondeck, Denise M. Kniffin, and Patrick M. McNutt
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Pathology ,medicine.medical_specialty ,Time Factors ,genetic structures ,Endothelium ,Basement Membrane ,Lesion ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Mustard Gas ,medicine ,Animals ,Basement membrane ,Chemistry ,Endothelium, Corneal ,Sulfur mustard ,eye diseases ,Disease Models, Animal ,Ophthalmology ,medicine.anatomical_structure ,Toxicity ,Disease Progression ,030221 ophthalmology & optometry ,Ultrastructure ,Female ,Rabbits ,sense organs ,medicine.symptom ,030217 neurology & neurosurgery ,Corneal Injuries ,Follow-Up Studies - Abstract
Purpose Ocular exposure to sulfur mustard (SM) vapor causes acute loss of corneal endothelial cells (CECs). Persistent corneal endothelial pathologies are observed in eyes that do not recover from SM exposure, suggesting that endothelial toxicity contributes to mustard gas keratopathy (MGK). Here, we evaluated the contributions of endothelial loss to acute and chronic corneal injuries in SM-exposed eyes. Methods Rabbit eyes were exposed in vivo to equivalent doses of SM using 9-, 11-, or 14-mm vapor caps. The effects of exposure area on corneal injury progression were longitudinally evaluated over 12 weeks using clinical evaluations. The effects of exposure area on CEC morphology, endothelial and epithelial ultrastructure, and endothelial barrier function were determined from 1 day to 12 weeks. Results SM exposure caused loss of CECs and failure of endothelial barrier integrity at 1 day, independent of exposure cap size. By 3 weeks, eyes exposed with the 14-mm vapor cap exhibited increased corneal permeability, repopulation of the endothelium by cells with fibroblastic morphology, and abnormal deposition of extracellular matrix. Eyes exposed with 9- or 11-mm vapor caps exhibited transient symptoms of injury that fully resolved, with the rate of recovery correlated with cap size. Conclusions The nonlinear correlation between endothelial lesion size and probability of developing MGK suggests that the CEC loss is a determinative factor for emergence of MGK. These studies illustrate the importance of endothelial repair in preventing MGK. Furthermore, they exclude chemical modification of basement membrane as a mechanistic cause of recurrent epithelial erosions in MGK eyes.
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- 2020
15. Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol
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Reesha R. Patel, Sarah A. Wolfe, Vittoria Borgonetti, Pauravi J. Gandhi, Larry Rodriguez, Angela E. Snyder, Shannon D’Ambrosio, Michal Bajo, Alain Domissy, Steven Head, Candice Contet, R. Dayne Mayfield, Amanda J. Roberts, and Marisa Roberto
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Neurons ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Alcoholism ,Ethanol ,Corticotropin-Releasing Hormone ,Humans ,Anxiety ,Molecular Biology ,Receptors, Corticotropin-Releasing Hormone ,Substance Withdrawal Syndrome - Abstract
Prefrontal circuits are thought to underlie aberrant emotion contributing to relapse in abstinence; however, the discrete cell-types and mechanisms remain largely unknown. Corticotropin-releasing factor and its cognate type-1 receptor, a prominent brain stress system, is implicated in anxiety and alcohol use disorder (AUD). Here, we tested the hypothesis that medial prefrontal cortex CRF1-expressing (mPFCCRF1+) neurons comprise a distinct population that exhibits neuroadaptations following withdrawal from chronic ethanol underlying AUD-related behavior. We found that mPFCCRF1+ neurons comprise a glutamatergic population with distinct electrophysiological properties and regulate anxiety and conditioned rewarding effects of ethanol. Notably, mPFCCRF1+ neurons undergo unique neuroadaptations compared to neighboring neurons including a remarkable decrease in excitability and glutamatergic signaling selectively in withdrawal, which is driven in part by the basolateral amygdala. To gain mechanistic insight into these electrophysiological adaptations, we sequenced the transcriptome of mPFCCRF1+ neurons and found that withdrawal leads to an increase in colony-stimulating factor 1 (CSF1) in this population. We found that selective overexpression of CSF1 in mPFCCRF1+ neurons is sufficient to decrease glutamate transmission, heighten anxiety, and abolish ethanol reinforcement, providing mechanistic insight into the observed mPFCCRF1+ synaptic adaptations in withdrawal that drive these behavioral phenotypes. Together, these findings highlight mPFCCRF1+ neurons as a critical site of enduring adaptations that may contribute to the persistent vulnerability to ethanol misuse in abstinence, and CSF1 as a novel target for therapeutic intervention for withdrawal-related negative affect.
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- 2021
16. Echoes of a Timeless Lament: Euripides' Trojan Women as a War Play
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Sarah Douglas Wolfe
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- 2020
17. Microglia control escalation of drinking in alcohol dependent mice: Genomic and synaptic drivers
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Sarah A. Wolfe, Florence P. Varodayan, Roman Vlkolinsky, Marisa Roberto, Reesha R. Patel, Amanda J. Roberts, Ilham Polis, R. Adron Harris, Sarah E. Montgomery, R. Dayne Mayfield, Sophia Khom, Anna S. Warden, Tali Nadav, Michal Bajo, and Michael Q. Steinman
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0301 basic medicine ,Alcohol use disorder ,Article ,Colony stimulating factor 1 receptor ,03 medical and health sciences ,Glutamatergic ,Mice ,0302 clinical medicine ,medicine ,Animals ,Prefrontal cortex ,Biological Psychiatry ,Neurons ,Microglia ,Ethanol ,business.industry ,Central nucleus of the amygdala ,Alcohol dependence ,Glutamate receptor ,Genomics ,medicine.disease ,Alcoholism ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake. Methods We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies. Results PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABAA and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. Conclusions Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.
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- 2020
18. IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake
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Shannon R. D'Ambrosio, Rana Nikzad, Reesha R. Patel, Marisa Roberto, Silke Paust, Amanda J. Roberts, Michal Bajo, Shawn Abeynaike, Scott Edwards, Sarah A. Wolfe, Vittoria Borgonetti, and Amanda R. Pahng
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0301 basic medicine ,Alcohol Drinking ,Inflammation ,Alcohol use disorder ,Anxiety ,Amygdala ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Medicine ,Premovement neuronal activity ,Animals ,PI3K/AKT/mTOR pathway ,gamma-Aminobutyric Acid ,Microglia ,Ethanol ,business.industry ,General Neuroscience ,Alcohol dependence ,Central Amygdaloid Nucleus ,medicine.disease ,Interleukin-10 ,Alcoholism ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Alcohol elicits a neuroimmune response in the brain contributing to the development and maintenance of alcohol use disorder (AUD). While pro-inflammatory mediators initiate and drive the neuroimmune response, anti-inflammatory mediators provide an important homeostatic mechanism to limit inflammation and prevent pathological damage. However, our understanding of the role of anti-inflammatory signaling on neuronal physiology in critical addiction-related brain regions and pathological alcohol-dependence induced behaviors is limited, precluding our ability to identify promising therapeutic targets. Here, we hypothesized that chronic alcohol exposure compromises anti-inflammatory signaling in the central amygdala, a brain region implicated in anxiety and addiction, consequently perpetuating a pro-inflammatory state driving aberrant neuronal activity underlying pathological behaviors. We found that alcohol dependence alters the global brain immune landscape increasing IL-10 producing microglia and T-regulatory cells but decreasing local amygdala IL-10 levels. Amygdala IL-10 overexpression decreases anxiety-like behaviors, suggesting its local role in regulating amygdala-mediated behaviors. Mechanistically, amygdala IL-10 signaling through PI3K and p38 MAPK modulates GABA transmission directly at presynaptic terminals and indirectly through alterations in spontaneous firing. Alcohol dependence-induces neuroadaptations in IL-10 signaling leading to an overall IL-10-induced decrease in GABA transmission, which normalizes dependence-induced elevated amygdala GABA transmission. Notably, amygdala IL-10 overexpression abolishes escalation of alcohol intake, a diagnostic criterion of AUD, in dependent mice. This highlights the importance of amygdala IL-10 signaling in modulating neuronal activity and underlying anxiety-like behavior and aberrant alcohol intake, providing a new framework for therapeutic intervention.
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- 2020
19. Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala
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Dean Kirson, David M. Hedges, Florence P. Varodayan, Sarah A. Wolfe, Sophia Khom, Marisa Roberto, Reesha R. Patel, and Michal Bajo
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0301 basic medicine ,Male ,medicine.medical_specialty ,Serotonin ,Action Potentials ,Alcohol use disorder ,Serotonergic ,Synaptic Transmission ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Dorsal raphe nucleus ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,Receptor ,gamma-Aminobutyric Acid ,Research Articles ,business.industry ,General Neuroscience ,Central nucleus of the amygdala ,Alcohol dependence ,Central Amygdaloid Nucleus ,medicine.disease ,Rats ,Substance Withdrawal Syndrome ,Alcoholism ,030104 developmental biology ,Endocrinology ,Inhibitory Postsynaptic Potentials ,business ,030217 neurology & neurosurgery - Abstract
Excessive serotonin (5-HT) signaling plays a critical role in the etiology of alcohol use disorder. The central nucleus of the amygdala (CeA) is a key player in alcohol-dependence associated behaviors. The CeA receives dense innervation from the dorsal raphe nucleus, the major source of 5-HT, and expresses 5-HT receptor subtypes (e.g., 5-HT2C and 5-HT1A) critically linked to alcohol use disorder. Notably, the role of 5-HT regulating rat CeA activity in alcohol dependence is poorly investigated. Here, we examined neuroadaptations of CeA 5-HT signaling in adult, male Sprague Dawley rats using an established model of alcohol dependence (chronic intermittent alcohol vapor exposure), ex vivo slice electrophysiology and ISH. 5-HT increased frequency of sIPSCs without affecting postsynaptic measures, suggesting increased CeA GABA release in naive rats. In dependent rats, this 5-HT-induced increase of GABA release was attenuated, suggesting blunted CeA 5-HT sensitivity, which partially recovered in protracted withdrawal (2 weeks). 5-HT increased vesicular GABA release in naive and dependent rats but had split effects (increase and decrease) after protracted withdrawal indicative of neuroadaptations of presynaptic 5-HT receptors. Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn. Alcohol dependence and protracted withdrawal did not alter either 5-HT1A-mediated decrease of CeA GABA release or Htr1a expression but disrupted 5-HT2C-signaling without affecting Htr2c expression. Collectively, our study provides detailed insights into modulation of CeA activity by the 5-HT system and unravels the vulnerability of the CeA 5-HT system to chronic alcohol and protracted withdrawal. SIGNIFICANCE STATEMENT Elevated GABA signaling in the central nucleus of the amygdala (CeA) underlies key behaviors associated with alcohol dependence. The CeA is reciprocally connected with the dorsal raphe nucleus, the main source of serotonin (5-HT) in the mammalian brain, and excessive 5-HT signaling is critically implicated in the etiology of alcohol use disorder. Our study, using a well-established rat model of alcohol dependence, ex vivo electrophysiology and ISH, provides mechanistic insights into how both chronic alcohol exposure and protracted withdrawal dysregulate 5-HT signaling in the CeA. Thus, our study further expands our understanding of CeA cellular mechanisms involved in the pathophysiology of alcohol dependence and withdrawal.
- Published
- 2020
20. Functional basis for dose-dependent antagonism of rat and rabbit neuromuscular transmission by the bis-pyridinium oxime MMB4
- Author
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James B, Machamer, James P, Apland, Brittany M, Winner, Sarah E, Wolfe, Kathleen T, Pagarigan, Kevin M, Bounader, Shane A, Kasten, Michael, Adler, and Patrick M, McNutt
- Subjects
Male ,Cholinesterase Reactivators ,Pralidoxime Compounds ,Dose-Response Relationship, Drug ,Muscles ,Synaptic Transmission ,Rats ,Rats, Sprague-Dawley ,Organophosphate Poisoning ,Species Specificity ,Oximes ,Acetylcholinesterase ,Animals ,Female ,Rabbits ,Respiratory Insufficiency - Abstract
Organophosphorus (OP) compounds inhibit central and peripheral acetylcholinesterase (AChE) activity, overstimulating cholinergic receptors and causing autonomic dysfunction (e.g., bronchoconstriction, excess secretions), respiratory impairment, seizure and death at high doses. Current treatment for OP poisoning in the United States includes reactivation of OP-inhibited AChE by the pyridinium oxime 2-pyridine aldoxime (2-PAM). However, 2-PAM has a narrow therapeutic index and its efficacy is confined to a limited number of OP agents. The bis-pyridinium oxime MMB4, which is a more potent reactivator than 2-PAM with improved pharmaceutical properties and therapeutic range, is under consideration as a potential replacement for 2-PAM. Similar to other pyridinium oximes, high doses of MMB4 lead to off-target effects culminating in respiratory depression and death. To understand the toxic mechanisms contributing to respiratory depression, we evaluated the effects of MMB4 (0.25-16 mM) on functional and neurophysiological parameters of diaphragm and limb muscle function in rabbits and rats. In both species, MMB4 depressed nerve-elicited muscle contraction by blocking muscle endplate nicotinic receptor currents while simultaneously prolonging endplate potentials by inhibiting AChE. MMB4 increased quantal content, endplate potential rundown and tetanic fade during high frequency stimulation in rat but not rabbit muscles, suggesting species-specific effects on feedback mechanisms involved in sustaining neurotransmission. These data reveal multifactorial effects of MMB4 on cholinergic neurotransmission, with the primary toxic modality being reduced muscle nicotinic endplate currents. Evidence of species-specific effects on neuromuscular function illustrates the importance of comparative toxicology when studying pyridinium oximes and, by inference, other quaternary ammonium compounds.
- Published
- 2020
21. Corticotropin-Releasing Factor Receptor-1 Neurons in the Lateral Amygdala Display Selective Sensitivity to Acute and Chronic Ethanol Exposure
- Author
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Matthew W. Buczynski, Harpreet Sidhu, Abigail E. Agoglia, Marisa Roberto, Rose Ying, Sarah A. Wolfe, Melissa A. Herman, Luis A. Natividad, Candice Contet, Loren H. Parsons, Manhua Zhu, and School of Neuroscience
- Subjects
Male ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Population ,Neuronal Excitability ,Receptors, Corticotropin-Releasing Hormone ,Amygdala ,lateral amygdala ,Mice ,03 medical and health sciences ,Glutamatergic ,GABA ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Tonic (music) ,education ,gamma-Aminobutyric Acid ,030304 developmental biology ,Neurons ,0303 health sciences ,education.field_of_study ,Ethanol ,GABAA receptor ,Chemistry ,alcohol ,General Neuroscience ,Glutamate receptor ,Corticotropin-Releasing Factor Receptor 1 ,General Medicine ,CRF ,Alcoholism ,Endocrinology ,medicine.anatomical_structure ,nervous system ,CRF1 receptor ,Research Article: New Research ,030217 neurology & neurosurgery ,basolateral amygdala ,Basolateral amygdala - Abstract
The lateral amygdala (LA) serves as the point of entry for sensory information within the amygdala complex, a structure that plays a critical role in emotional processes and has been implicated in alcohol use disorders. Within the amygdala, the corticotropin-releasing factor (CRF) system has been shown to mediate some of the effects of both stress and ethanol, but the effects of ethanol on specific CRF1 receptor circuits in the amygdala have not been fully established. We used male CRF1:GFP reporter mice to characterize CRF1-expressing (CRF1(+)) and nonexpressing (CRF1(-)) LA neurons and investigate the effects of acute and chronic ethanol exposure on these populations. The CRF1(+) population was found to be composed predominantly of glutamatergic projection neurons with a minority subpopulation of interneurons. CRF1(+) neurons exhibited a tonic conductance that was insensitive to acute ethanol. CRF1(-) neurons did not display a basal tonic conductance, but the application of acute ethanol induced a delta GABA(A) receptor subunit-dependent tonic conductance and enhanced phasic GABA release onto these cells. Chronic ethanol increased CRF1(+) neuronal excitability but did not significantly alter phasic or tonic GABA signaling in either CRF1(+) or CRF1(-) cells. Chronic ethanol and withdrawal also did not alter basal extracellular GABA or glutamate transmitter levels in the LA/BLA and did not alter the sensitivity of GABA or glutamate to acute ethanol-induced increases in transmitter release. Together, these results provide the first characterization of the CRF1(+) population of LA neurons and suggest mechanisms for differential acute ethanol sensitivity within this region. Bowles Center for Alcohol Studies; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32-AA-007573, T32-NS-007431, AA-023002, AA-011605, AA-015566, AA-021491, AA-006420, T32-AA-007456, AA-026685, AA-024952] This work was supported by the Bowles Center for Alcohol Studies; and National Institutes of Health Grants T32-AA-007573 (A.E.A.), T32-NS-007431 (M.Z.), AA-023002 (M.A.H.), AA-011605 (M.A.H.), AA-015566 (M.R.), AA-021491 (M.R.), AA-006420 (C.C., M.R.), T32-AA-007456 (S.A.W.), AA-026685 (C.C.), and AA-024952 (H.S.).
- Published
- 2020
22. Skin Injury Activates TRPV1+ Nociceptive Fibers to Stimulate a Rapid Innate Antiviral Protein Response
- Author
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Vivian Lei, Brian Fanelli, Chelsea Handfield, Qingjian Han, Kaiyuan Wang, J. Kwock, Ru-Rong Ji, Sarah A Wolfe, Amanda S. MacLeod, Margaret Coates, Jennifer G. Powers, Manoj Dadlani, Min Jin Lee, and David L. Corcoran
- Subjects
Immune system ,Innate immune system ,integumentary system ,Antiviral protein ,TRPV1 ,Skin immunity ,Interleukin ,Biology ,Signal transduction ,ISG15 ,Cell biology - Abstract
The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate antiviral protein production remains largely unknown. Here, we identify and characterize the induction and regulation of antiviral proteins following skin injury. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of antiviral proteins in both mice and humans, and interleukin (IL)-27 was found to be necessary and sufficient to induce this pattern of expression. Notably, we here link the IL-27-mediated antiviral protein response to a neuro-immune axis. We herein identify how damage to the skin barrier elicits cutaneous nociceptive signaling to activate innate antiviral immune responses. Remarkably, pharmacology or genetic ablation of TRPV1-mediated nociception unveiled that TRPV1 signaling contributes significantly to the induction of antiviral proteins Oas2, Oasl2, and Isg15 via IL-27 in vivo, suggesting that nociception promotes skin antiviral competence through activation of antiviral signaling pathways upon wounding.
- Published
- 2020
23. The Number of Meiotic Double-Strand Breaks Influences Crossover Distribution in Arabidopsis
- Author
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Ming Xue, Jun Wang, Sarah A. Wolfe, Yingxiang Wang, Yan He, Luguang Jiang, Wojciech P. Pawlowski, and Minghui Wang
- Subjects
0301 basic medicine ,Spo11 ,DNA Repair ,Centromere ,Arabidopsis ,Plant Science ,Chromosomes, Plant ,Chromosome segregation ,03 medical and health sciences ,Meiosis ,Chromosome Segregation ,Arabidopsis thaliana ,DNA Breaks, Double-Stranded ,Crossing Over, Genetic ,Research Articles ,biology ,urogenital system ,Arabidopsis Proteins ,Topoisomerase ,fungi ,Cell Biology ,Plants, Genetically Modified ,biology.organism_classification ,Cell biology ,Chromosome Pairing ,030104 developmental biology ,Mutation ,biology.protein ,Homologous recombination ,Recombination - Abstract
Meiotic recombination generates genetic diversity and ensures proper chromosome segregation. Recombination is initiated by the programmed formation of double-strand breaks (DSBs) in chromosomal DNA by DNA Topoisomerase VI-A Subunit (SPO11), a topoisomerase-like enzyme. Repair of some DSBs leads to the formation of crossovers (COs). In most organisms, including plants, the number of DSBs greatly exceeds the number of COs and which DSBs become CO sites is tightly controlled. The CO landscape is affected by DNA sequence and epigenome features of chromosomes as well as by global mechanisms controlling recombination dynamics. The latter are poorly understood and their effects on CO distribution are not well elucidated. To study how recombination dynamics affects CO distribution, we engineered Arabidopsis thaliana plants to carry hypomorphic alleles of SPO11-1. Two independent transgenic lines showed ∼30% and 40% reductions in DSB numbers, which were commensurate with the dosage of the SPO11-1 transcript. The reduction in DSB number resulted in proportional, although smaller, reductions of the number of COs. Most interestingly, CO distribution along the chromosomes was dramatically altered, with substantially fewer COs forming in pericentromeric chromosome regions. These results indicate that SPO11 activity, and the resulting DSB numbers are major factors shaping the CO landscape.
- Published
- 2018
24. Importance of sex and trauma context on circulating cytokines and amygdalar GABAergic signaling in a comorbid model of posttraumatic stress and alcohol use disorders
- Author
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Samantha R. Spierling Bagsic, Christopher S. Oleata, Suhas Sureshchandra, Noah K Hoang, Roman Vlkolinský, Sophia Khom, Dean Kirson, Anshita Singhal, Marisa Roberto, Michael Q. Steinman, Ilhem Messaoudi, Eric P. Zorrilla, Sarah A. Wolfe, Michal Bajo, and Shannon R. D'Ambrosio
- Subjects
0301 basic medicine ,Male ,sex differences ,medicine.medical_specialty ,Alcohol Drinking ,AUD ,media_common.quotation_subject ,Context (language use) ,Alcohol use disorder ,Amygdala ,Synaptic Transmission ,Article ,Stress Disorders, Post-Traumatic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,stress ,GABA ,0302 clinical medicine ,Sex Factors ,Internal medicine ,medicine ,cytokine ,Animals ,GABAergic Neurons ,Rats, Wistar ,Molecular Biology ,media_common ,Sleep disorder ,business.industry ,Leptin ,PTSD ,Abstinence ,medicine.disease ,Rats ,Psychiatry and Mental health ,Alcoholism ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,central amygdala ,GABAergic ,Anxiety ,Cytokines ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid and share mechanisms that could be therapeutic targets. To facilitate mechanistic studies, we adapted an inhibitory avoidance-based "2-hit" rat model of posttraumatic stress disorder (PTSD) and identified predictors and biomarkers of comorbid alcohol (ethanol)/PTSD-like symptoms in these animals. Stressed Wistar rats received a single footshock on two occasions. The first footshock occurred when rats crossed into the dark chamber of a shuttle box. Forty-eight hours later, rats received the second footshock in a familiar (FAM) or novel (NOV) context. Rats then received 4 weeks of two-bottle choice (2BC) ethanol access. During subsequent abstinence, PTSD-like behavior responses, GABAergic synaptic transmission in the central amygdala (CeA), and circulating cytokine levels were measured. FAM and NOV stress more effectively increased 2BC drinking in males and females, respectively. Stressed male rats, especially drinking-vulnerable individuals (≥0.8 g/kg average 2-h ethanol intake with >50% ethanol preference), showed higher fear overgeneralization in novel contexts, increased GABAergic transmission in the CeA, and a profile of increased G-CSF, GM-CSF, IL-13, IL-6, IL-17a, leptin, and IL-4 that discriminated between stress context (NOV > FAM > Control). However, drinking-resilient males showed the highest G-CSF, IL-13, and leptin levels. Stressed females showed increased acoustic startle and decreased sleep maintenance, indicative of hyperarousal, with increased CeA GABAergic transmission in NOV females. This paradigm promotes key features of PTSD, including hyperarousal, fear generalization, avoidance, and sleep disturbance, with comorbid ethanol intake, in a sex-specific fashion that approximates clinical comorbidities better than existing models, and identifies increased CeA GABAergic signaling and a distinct pro-hematopoietic, proinflammatory, and pro-atopic cytokine profile that may aid in treatment.
- Published
- 2019
25. Molecular, Morphological, and Functional Characterization of Corticotropin-Releasing Factor Receptor 1-Expressing Neurons in the Central Nucleus of the Amygdala
- Author
-
Shannon R. D'Ambrosio, Reesha R. Patel, Marisa Roberto, Candice Contet, Sarah A. Wolfe, Harpreet Sidhu, and Max Kreifeldt
- Subjects
Male ,Dendritic spine ,glutamatergic signaling ,Dendritic Spines ,Neuropeptide ,Glutamic Acid ,Neuronal Excitability ,Mice, Transgenic ,Calbindin ,Receptors, Corticotropin-Releasing Hormone ,Synaptic Transmission ,calcium binding proteins ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Animals ,030304 developmental biology ,Neurons ,0303 health sciences ,biology ,General Neuroscience ,Central nucleus of the amygdala ,Central Amygdaloid Nucleus ,Glutamate receptor ,neuropeptides ,corticotropin-releasing factor ,stress and anxiety ,General Medicine ,New Research ,Cell biology ,Mice, Inbred C57BL ,nervous system ,6.1 ,biology.protein ,Calretinin ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
The central nucleus of the amygdala (CeA) is a brain region implicated in anxiety, stress-related disorders and the reinforcing effects of drugs of abuse. Corticotropin-releasing factor (CRF,Crh)acting at cognate type 1 receptors (CRF1,Crhr1) modulates inhibitory and excitatory synaptic transmission in the CeA. Here, we used CRF1:GFP reporter mice to characterize the morphological, neurochemical and electrophysiological properties of CRF1-expressing (CRF1+) and CRF1-non-expressing (CRF1–) neurons in the CeA. We assessed these two neuronal populations for distinctions in the expression of GABAergic subpopulation markers and neuropeptides, dendritic spine density and morphology, and excitatory transmission. We observed that CeA CRF1+ neurons are GABAergic but do not segregate with calbindin (CB), calretinin (CR), parvalbumin (PV), or protein kinase C-δ (PKCδ). Among the neuropeptides analyzed,PenkandSsthad the highest percentage of co-expression withCrhr1in both the medial and lateral CeA subdivisions. Additionally, CeA CRF1+ neurons had a lower density of dendritic spines, which was offset by a higher proportion of mature spines compared to neighboring CRF1– neurons. Accordingly, there was no difference in basal spontaneous glutamatergic transmission between the two populations. Application of CRF increased overall vesicular glutamate release onto both CRF1+ and CRF1– neurons and does not affect amplitude or kinetics of EPSCs in either population. These novel data highlight important differences in the neurochemical make-up and morphology of CRF1+ compared to CRF1– neurons, which may have important implications for the transduction of CRF signaling in the CeA.
- Published
- 2019
26. Pain Management in Patients With Hidradenitis Suppurativa Requiring Surgery
- Author
-
Tarannum Jaleel, Sarah A Wolfe, and Charles J. Puza
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,MEDLINE ,Pain ,Dermatology ,Administration, Cutaneous ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacotherapy ,Internal medicine ,Medicine ,Humans ,Pain Management ,Hidradenitis suppurativa ,In patient ,Young adult ,Aged ,Pain Measurement ,Retrospective Studies ,business.industry ,030208 emergency & critical care medicine ,Retrospective cohort study ,General Medicine ,Pain management ,Analgesics, Non-Narcotic ,Middle Aged ,medicine.disease ,Hidradenitis Suppurativa ,Treatment Outcome ,Surgery ,Drug Therapy, Combination ,Female ,business ,Combination method - Published
- 2018
27. FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties
- Author
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Farr Niere, Luisa P. Cacheaux, Chelcie F. Heaney, Michael R. Drew, Sarah A. Wolfe, Sean P. Farris, Kimberly F. Raab-Graham, Emily R. Workman, R. Adron Harris, Sanjeev Namjoshi, and Boris V. Zemelman
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.drug_class ,Science ,Regulator ,General Physics and Astronomy ,chemistry.chemical_element ,Alcohol ,Pharmacology ,GABAB receptor ,Calcium ,Anxiolytic ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Receptor ,Multidisciplinary ,Ethanol ,General Chemistry ,030104 developmental biology ,Endocrinology ,chemistry ,Antidepressant ,030217 neurology & neurosurgery - Abstract
Alcohol promotes lasting neuroadaptive changes that may provide relief from depressive symptoms, often referred to as the self-medication hypothesis. However, the molecular/synaptic pathways that are shared by alcohol and antidepressants are unknown. In the current study, acute exposure to ethanol produced lasting antidepressant and anxiolytic behaviours. To understand the functional basis of these behaviours, we examined a molecular pathway that is activated by rapid antidepressants. Ethanol, like rapid antidepressants, alters γ-aminobutyric acid type B receptor (GABABR) expression and signalling, to increase dendritic calcium. Furthermore, new GABABRs are synthesized in response to ethanol treatment, requiring fragile-X mental retardation protein (FMRP). Ethanol-dependent changes in GABABR expression, dendritic signalling, and antidepressant efficacy are absent in Fmr1-knockout (KO) mice. These findings indicate that FMRP is an important regulator of protein synthesis following alcohol exposure, providing a molecular basis for the antidepressant efficacy of acute ethanol exposure.
- Published
- 2016
28. Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic transcriptome
- Author
-
Joshua E. Mayfield, Sarah A. Wolfe, R. Adron Harris, R. Dayne Mayfield, Sean P. Farris, Kimberly F. Raab-Graham, Emma K. Erickson, and Chelcie F. Heaney
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Gene Expression ,Comorbidity ,Biology ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Article ,Transcriptome ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Exon ,0302 clinical medicine ,Phenols ,Piperidines ,Internal medicine ,Gene expression ,medicine ,Animals ,Receptor ,Gene ,Pharmacology ,Depressive Disorder, Major ,Ethanol ,Alternative splicing ,Exons ,Antidepressive Agents ,Receptors, Neurotransmitter ,Mice, Inbred C57BL ,Alcoholism ,Alternative Splicing ,030104 developmental biology ,Endocrinology ,Models, Animal ,NMDA receptor ,Antidepressant ,sense organs ,030217 neurology & neurosurgery - Abstract
Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl-D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long-lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression.
- Published
- 2018
29. Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis
- Author
-
Kimberly F. Raab-Graham, Farr Niere, Darrin H. Brager, Sarah A. Wolfe, and Natasha M. Sosanya
- Subjects
Male ,Patch-Clamp Techniques ,Time Factors ,Action Potentials ,Status epilepticus ,In Vitro Techniques ,Biology ,Pharmacology ,Hippocampus ,Synaptic Transmission ,Epileptogenesis ,complex mixtures ,Potassium channels ,lcsh:RC321-571 ,Rats, Sprague-Dawley ,Epilepsy ,Status Epilepticus ,microRNA ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Rapamycin ,Protein kinase A ,Temporal lobe epilepsy ,Psychological repression ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,PI3K/AKT/mTOR pathway ,miRNA ,Sirolimus ,Kainic Acid ,TOR Serine-Threonine Kinases ,medicine.disease ,Potassium channel ,Rats ,Cell biology ,Disease Models, Animal ,MicroRNAs ,ELAV Proteins ,Gene Expression Regulation ,Neurology ,nervous system ,mTOR ,medicine.symptom ,Kv1.1 Potassium Channel - Abstract
Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21 days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1.
- Published
- 2015
30. Equilibrium distribution of petroleum hydrocarbons in freezing ground
- Author
-
David L. Barnes, Sarah M. Wolfe, and Dennis M. Filler
- Subjects
chemistry.chemical_compound ,Ecology ,Distribution (number theory) ,chemistry ,Geography, Planning and Development ,General Earth and Planetary Sciences ,Petroleum ,Environmental science ,Soil science ,complex mixtures - Abstract
Past documented laboratory measurements have shown movement of petroleum hydrocarbons to the freezing front in contaminated freezing soils. The mechanisms that are, in part, responsible for the increased contaminant concentration at the freezing front are illustrated in this study with a mass-balance model. Results from this quantitative analysis show that this concentration increase is due to exclusion of petroleum hydrocarbon from the crystalline ice structure and from physical displacement of liquid petroleum hydrocarbon from the pore space as water freezes and expands into ice. Consequences of this process in relation to contaminant migration in freezing soils through time are discussed.
- Published
- 2004
31. 699 Evaluation of colorimetry and biomechanical properties in wounds of dermatologic patients with postoperative infection
- Author
-
Sarah A Wolfe, Amanda S. MacLeod, Jennifer G. Powers, and J. Liu
- Subjects
medicine.medical_specialty ,business.industry ,medicine ,Postoperative infection ,Cell Biology ,Dermatology ,business ,Molecular Biology ,Biochemistry ,Colorimetry (chemical method) ,Surgery - Published
- 2017
32. The acute alcohol transcriptome parallels that of rapid antidepressants
- Author
-
Farr Niere, Chelcie F. Heaney, Kimberly F. Raab-Graham, R. A. Harris, Sarah A. Wolfe, Sean P. Farris, and R. D. Mayfield
- Subjects
Transcriptome ,Behavioral Neuroscience ,Health (social science) ,Neurology ,business.industry ,Medicine ,General Medicine ,Toxicology ,business ,Bioinformatics ,Biochemistry ,Acute alcohol - Published
- 2017
33. Global Precedence in Visual Search? Not So Fast: Evidence Instead for an Oblique Effect
- Author
-
Frank H. Durgin and Sarah E Wolfe
- Subjects
Visual search ,Psychological Tests ,Communication ,Computer science ,business.industry ,05 social sciences ,Oblique case ,Experimental and Cognitive Psychology ,050105 experimental psychology ,Sensory Systems ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,Pattern Recognition, Visual ,Artificial Intelligence ,Humans ,0501 psychology and cognitive sciences ,Oblique effect ,Symmetry (geometry) ,Global precedence ,business ,Algorithm ,030217 neurology & neurosurgery - Abstract
The evidence from an earlier report of global precedence in visual search is reexamined. Two new experiments are reported. The results of the first experiment indicate that the confusability of oblique orientations (a class-2 oblique effect) rather than global precedence was responsible for the earlier results. The results of the second experiment show that the effect critically depends on the presence of heterogeneous distractors rather than on differences in raw processing speed for different spatial scales. The possible role of symmetry is discussed.
- Published
- 1997
34. Distinct mechanisms drive sequential internalization and degradation of GABAARs during global ischemia and reperfusion injury
- Author
-
Joshua D. Garcia, Sarah E. Wolfe, Amber R. Stewart, Erika Tiemeier, Sara E. Gookin, Mayra Bueno Guerrero, Nidia Quillinan, and Katharine R. Smith
- Subjects
Cellular neuroscience ,Molecular physiology ,Science - Abstract
Summary: Synaptic inhibition is critical for controlling neuronal excitability and function. During global cerebral ischemia (GCI), inhibitory synapses are rapidly eliminated, causing hyper-excitability which contributes to cell-death and the pathophysiology of disease. Sequential disassembly of inhibitory synapses begins within minutes of ischemia onset: GABAARs are rapidly trafficked away from the synapse, the gephyrin scaffold is removed, followed by loss of the presynaptic terminal. GABAARs are endocytosed during GCI, but how this process accompanies synapse disassembly remains unclear. Here, we define the precise trafficking itinerary of GABAARs during the initial stages of GCI, placing them in the context of rapid synapse elimination. Ischemia-induced GABAAR internalization quickly follows their initial dispersal from the synapse, and is controlled by PP1α signaling. During reperfusion injury, GABAARs are then trafficked to lysosomes for degradation, leading to permanent removal of synaptic GABAARs and contributing to the profound reduction in synaptic inhibition observed hours following ischemia onset.
- Published
- 2023
- Full Text
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