1995 |
Thiele, Todd Eric |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Memory Mechanisms of Learned Alcohol Aversions in Rats @ Kansas State University |
0.942 |
1999 — 2002 |
Thiele, Todd Eric |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Neuronal Mediation of Ethanol Induced Taste Aversions @ University of Washington
The applicant of this award is an experience animal behavior research scientist who has studied the properties or alcohol using several behavioral paradigms. His immediate career goal is to go beyond the behavioral analysis of alcohol-related behaviors and begin a career investigating the biological mechanisms involved in determinants of risk for alcohol abuse. The training program outlined in this grant would be critically important for allowing the applicant to reach his goals by providing him with a unique set of skills for examining the anatomy and molecular physiology of neuronal pathways involved in alcohol's aversive effects and how these interact with earning to influence alcohol-seeking behavior. As a result, he will develop a scientific identity which will make him a truly competitive behavioral neuroscientist as he seeks his long-term career goal of obtaining an academic faculty position. The training environment at the University of Washington includes laboratories and faculty in the Departments of Psychology and Psychiatry. In addition to courses and technical training, a steering committee will provide the applicant with regular input and feedback throughout the project. The hypotheses outlined in the present proposal are designed to examine the neurochemical pathways that mediate the aversive properties to alcohol and alcohol-induced conditioned taste aversions (CTA). Previous research, using cFos-like immunoreactivity (cFLI) as an indication of cellular activation, has shown that the brainstem regions thought to be involved in taste aversion learning (particularly, the nucleus of the solitary tract (NTS)) are activated by alcohol and by tastes that have been paired with this drug. Proposed experiments are designed to assess the following questions about the cellular activity in the brainstem associated with alcohol administration and CTA expression: A) What are the sources of neuronal input to the brainstem which cause this cellular activation and which may mediate taste aversion learning? To examine this question, electrolytic lesions will be made in specific brain regions and subsequent effects on cFLI in the NTS and CTA acquisition/expression will be assessed. B) What is the neurochemical phenotype of cells in the brainstem that are activated by alcohol and by tastes paired with alcohol? Double-labeling-procedures with in situ hybridization histochemistry and immunohistochemistry will be used to examine this question. And C), What neurotransmitters and receptors are responsible for mediating this cellular activity in the NTS, and are these neurotransmitter systems involved with taste aversion learning? This question will be addressed by using specific receptor antagonists and receptor autoradiography. A better understanding of the neuronal mechanisms that underlie the aversive effects associated with ethanol may allow one to more accurately predict the predisposition towards alcoholism, and may be useful for the development of pharmacological treatments targeted at preventing alcohol abuse.
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1 |
2001 — 2021 |
Thiele, Todd E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Neuropeptide Y: Role in Ethanol Intake and Sensitivity @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood alcohol concentrations (BACs) greater than 0.08% (80 mg/dL) within a short period of time. Frequent binge drinking has been linked to numerous negative consequences, including an increased likelihood of developing mood disorders, high blood pressure and heart disease, and type-2 diabetes. Of greatest concern, regular binge drinking significantly increases ones risk of developing alcohol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. Neuropeptide Y (NPY) is expressed in brain regions implicated in neurobiological responses to alcohol and NPY protects against excessive alcohol intake associated with dependence. Thus, we recently studied the role of NPY receptor signaling in binge-like drinking. Central administration of NPY significantly blunted binge-like alcohol drinking (in mice that achieved BACs of >100 mg/dL in the absence of NPY) but did not decrease drinking in mice with moderate levels of consumption (associated with BACs of <25 mg/dL). The effects of NPY on binge-like drinking are modulated by the Y1R and Y2R (but not Y5R) receptors. Importantly, our preliminary observations also revealed that binge-like drinking is associated with a significant reduction of NPY immunoreactivity in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Thus, the guiding hypothesis for the present proposal is that NPY signaling modulates binge- like alcohol intake. The proposed Aims will use powerful and innovative electrophysiological, histological (immunoreactivity), genetic (real-time PCR), and anatomical (site-directed manipulation of NPY signaling) techniques to determine if: A) binge-like alcohol drinking will be associated with altered NPY expression and receptor signaling that become rigid with repeated binge-like episodes (Aims 1 & 3), B) NPY receptor signaling within the extended amygdala modulates binge-like alcohol drinking (Aim 2), and C) the mechanism that triggers blunted NPY signaling and motivates binge-like drinking involves epigenetic elements, specifically alterations of histone acetylation (Aim 2). Expected results from the current project would identify Y1R agonists, Y2R antagonists, and compounds that increase histone acetylation as attractive targets for treating binge drinking. Pharmaceutical interventions useful for curbing and/or preventing binge drinking will not only help individuals avoid many of the dangerous health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.
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1 |
2003 — 2004 |
Thiele, Todd Eric |
P60Activity Code Description: To support a multipurpose unit designed to bring together into a common focus divergent but related facilities within a given community. It may be based in a university or may involve other locally available resources, such as hospitals, computer facilities, regional centers, and primate colonies. It may include specialized centers, program projects and projects as integral components. Regardless of the facilities available to a program, it usually includes the following objectives: to foster biomedical research and development at both the fundamental and clinical levels; to initiate and expand community education, screening, and counseling programs; and to educate medical and allied health professionals concerning the problems of diagnosis and treatment of a specific disease. |
Pilot--the Role of Protein Kinase a in Neurological Resp @ University of North Carolina Chapel Hill
Many neurotransmitters and hormones transduce their signal into a cell by activating G-protein-coupled receptors that modulate adenylyl cyclase; this changes intracellular cAMP levels which subsequently alters cAMP-dependent protein kinase (PKA) activity. A growing body of evidence from both the human and animal literature suggests that genetic variation of the cAMP/PKA system alters ethanol-seeking behavior and acute physiological responses to this drug. We have recently found that genetically altered mice completely lacking production of the RIIbeta subunit of PKA (RIIbeta -/-) showed increased consumption of 6%, 10%, and 20% (v/v) ethanol when compared to wild-type mice (RIIbeta +/+). Furthermore, the RIIbeta -/- mice are less sensitive to the sedative effects of ethanol as measured by duration of the loss of righting reflex. The main hypothesis to be tested is that PKA activity in specific brain regions modulates ethanol sensitivity and intake. As a strategy for delineating brain regions where RIIbeta subunit of PKA modulates ethanol sensitivity, Aim 1 will measure ethanol-induced c-Fos expression in RIIbeta -/- and RIIbeta +/+ mice. Aim 2 will determine if PKA signaling modulates voluntary ethanol consumption in brain regions where PKA signaling modulates sensitivity to the acute effects of ethanol. Parameters of ethanol ingestion and sensitivity will be determined in RIIbeta -/- and RIIbeta +/+ mice following infusion of cAMP/PKA stimulator (Sp-cAMPs) or inhibitor (Rp-cAMPs) into specific brain regions. Data collected during this project would provide a foundation for the future development of an R01 grant.
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1 |
2005 — 2011 |
Thiele, Todd E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Melanocortin Neuropeptides &Ethanol Intake @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): There is a growing body of evidence that endogenous opioid peptides, including proopiomelanocortin (POMC)- derived b-endorphin, can modulate the neurobiological responses to ethanol and that administration of ethanol alters the expression of POMC and b-endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include a-melanocyte stimulating hormone (a-MSH), which is synthesized in the arcuate nucleus of the hypothalamus and projects to many brain regions of known relevance to alcoholism. Agouti-related protein, synthesized in the arcuate nucleus and secreted in the same terminals as a-MSH, is a natural MC receptor (MCR) antagonist. Consistent with a role in modulating neurobiological responses to ethanol, recent work has shown that MCR agonists reduce, and MCR antagonists increase, ethanol consumption in rodents, and that the MC-4 receptor (MC4R) modulates the effects of MCR compounds on ethanol drinking. Additionally, exposure to ethanol significantly reduces central a-MSH immunoreactivity (IR), and increases central AgRP IR, indicating that these endogenous MCR ligands modulate neurobiological responses to ethanol. The specific aims proposed below will extend our recent findings by testing the guiding hypothesis that MC4R signaling modulates the reinforcing properties of ethanol and ethanol relapse-like behaviors, in a brain-region-specific and protein kinase A (PKA)- dependent fashion. Specifically, we will determine if operant self-administration of ethanol alters a-MSH, AgRP, MC3R and/or MC4R IR in specific brain regions (Specific Aim 1), if a MC4R agonist modulates ethanol self-administration in brain regions implicated in ethanol reinforcement (Specific Aim 2), if MC4R signaling requires normal PKA activity to modulate operant self-administration of ethanol (Specific Aim 3), and if MC4R signaling modulates relapse-like behaviors (Specific Aim 4). These studies will provide important insight into the mechanisms by which MC4R signaling modulates the reinforcing properties of ethanol and relapse of ethanol-seeking behaviors. PUBLIC HEALTH RELEVANCE: Despite years of research and a wealth of important information, the neurobiological factors that leave some individuals vulnerable to alcohol abuse and alcoholism remain unclear. One hypothesis is that some individuals show increased sensitivity to the reinforcing properties of alcohol, leading to increased early use and a subsequent increased risk of dependence. The work that is outlined in the current proposal will show that melanocortin neuropeptides modulate the reinforcing properties of alcohol and relapse of alcohol-seeking behavior following abstinence.
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1 |
2012 — 2014 |
Thiele, Todd E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Melanocortin Neuropeptides & Ethanol Intake @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): There is a growing body of evidence that endogenous opioid peptides, including proopiomelanocortin (POMC)- derived b-endorphin, can modulate the neurobiological responses to ethanol and that administration of ethanol alters the expression of POMC and b-endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include a-melanocyte stimulating hormone (a-MSH), which is synthesized in the arcuate nucleus of the hypothalamus and projects to many brain regions of known relevance to alcoholism. Agouti-related protein, synthesized in the arcuate nucleus and secreted in the same terminals as a-MSH, is a natural MC receptor (MCR) antagonist. Consistent with a role in modulating neurobiological responses to ethanol, recent work has shown that MCR agonists reduce, and MCR antagonists increase, ethanol consumption in rodents, and that the MC-4 receptor (MC4R) modulates the effects of MCR compounds on ethanol drinking. Additionally, exposure to ethanol significantly reduces central a-MSH immunoreactivity (IR), and increases central AgRP IR, indicating that these endogenous MCR ligands modulate neurobiological responses to ethanol. The specific aims proposed below will extend our recent findings by testing the guiding hypothesis that MC4R signaling modulates the reinforcing properties of ethanol and ethanol relapse-like behaviors, in a brain-region-specific and protein kinase A (PKA)- dependent fashion. Specifically, we will determine if operant self-administration of ethanol alters a-MSH, AgRP, MC3R and/or MC4R IR in specific brain regions (Specific Aim 1), if a MC4R agonist modulates ethanol self-administration in brain regions implicated in ethanol reinforcement (Specific Aim 2), if MC4R signaling requires normal PKA activity to modulate operant self-administration of ethanol (Specific Aim 3), and if MC4R signaling modulates relapse-like behaviors (Specific Aim 4). These studies will provide important insight into the mechanisms by which MC4R signaling modulates the reinforcing properties of ethanol and relapse of ethanol-seeking behaviors.
|
0.988 |
2013 — 2017 |
Thiele, Todd E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Corticotropin Releasing Factor in Binge-Like Ethanol Drinking @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood ethanol concentrations (BECs) greater than 0.08% (80 mg/dL) within a short period of time. Of great concern, regular binge drinking significantly increases ones risk of developing ethanol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. We have found that binge-like ethanol drinking increases corticotropin releasing factor (CRF) immunoreactivity (IR) in the central amygdala (CeA) and that a type-1 receptor (CRF1R) antagonist, when injected into the CeA, protects against excessive binge-like drinking in C57BL/6J mice. On the other hand, CRF1R antagonists fail to alter moderate non-binge-like ethanol intake. These observations parallel evidence that CRF1R antagonists blunt dependence-like drinking without altering ethanol intake in non-dependent animals. The guiding hypothesis for this grant is that acute binge-like ethanol drinking transiently engages CRF signaling in the CeA, and at sites that are innervated by CRF pathways arising from the CeA, and drives continued excessive ethanol intake. We further hypothesize that increased CRF signaling fails to normalize with repeated binge-like drinking episodes, ultimately contributing to persistent increases in alcohol drinking. The proposed Aims will use powerful and innovative electrophysiological, histological, genetic, and behavioral techniques to determine if: A) A history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and function (Aim 1), B) CRF1R antagonist and a CRF2R agonist will protect against binge-like ethanol drinking when injected into the CeA and regions that receive CRF innervation from the CeA (Aim 2), and C) inhibition of CRF-producing neurons in the CeA and/or bed nucleus of the stria terminalis (BNST) with designer receptors that are exclusively activated by designer drugs (DREADDs) will protect against binge-like ethanol drinking, and DREADD-induced activation of CRF-producing neurons in these regions will increase binge-like drinking (Aim 3). These highly innovative projects will provide a shift in pre-clinical alcoholism research by providing insight into the role for CRF1R and CRF2R signaling in excessive binge-like ethanol drinking and the transition to a dependence-like state, and establish new technologies for studying the neurocircuitry that modulates excessive ethanol intake.
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0.988 |
2016 |
Thiele, Todd E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Corticotropin Releasing Factor in Binge-Like Ethanol Drinking - Diversity Supplement @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood ethanol concentrations (BECs) greater than 0.08% (80 mg/dL) within a short period of time. Of great concern, regular binge drinking significantly increases ones risk of developing ethanol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. We have found that binge-like ethanol drinking increases corticotropin releasing factor (CRF) immunoreactivity (IR) in the central amygdala (CeA) and that a type-1 receptor (CRF1R) antagonist, when injected into the CeA, protects against excessive binge-like drinking in C57BL/6J mice. On the other hand, CRF1R antagonists fail to alter moderate non-binge-like ethanol intake. These observations parallel evidence that CRF1R antagonists blunt dependence-like drinking without altering ethanol intake in non-dependent animals. The guiding hypothesis for this grant is that acute binge-like ethanol drinking transiently engages CRF signaling in the CeA, and at sites that are innervated by CRF pathways arising from the CeA, and drives continued excessive ethanol intake. We further hypothesize that increased CRF signaling fails to normalize with repeated binge-like drinking episodes, ultimately contributing to persistent increases in alcohol drinking. The proposed Aims will use powerful and innovative electrophysiological, histological, genetic, and behavioral techniques to determine if: A) A history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and function (Aim 1), B) CRF1R antagonist and a CRF2R agonist will protect against binge-like ethanol drinking when injected into the CeA and regions that receive CRF innervation from the CeA (Aim 2), and C) inhibition of CRF-producing neurons in the CeA and/or bed nucleus of the stria terminalis (BNST) with designer receptors that are exclusively activated by designer drugs (DREADDs) will protect against binge-like ethanol drinking, and DREADD-induced activation of CRF-producing neurons in these regions will increase binge-like drinking (Aim 3). These highly innovative projects will provide a shift in pre-clinical alcoholism research by providing insight into the role for CRF1R and CRF2R signaling in excessive binge-like ethanol drinking and the transition to a dependence-like state, and establish new technologies for studying the neurocircuitry that modulates excessive ethanol intake.
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0.988 |
2018 — 2021 |
Thiele, Montserrat Navarro Thiele, Todd E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Brainstem Norepinephrine in Binge Alcohol Drinking and Taste Aversion @ Univ of North Carolina Chapel Hill
Project Summary/Abstract Frequent binge drinking has been linked to numerous negative consequences, include and increased risk of developing ethanol dependence. Thus, it is of paramount importance to identify neuronal mechanisms that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior and the transition to ethanol dependence. Considerable attention has been paid to the reinforcing effects of ethanol and how these effects motivate ethanol intake. There is strong evidence that ethanol also entails aversive effects and that these effects, because they are clearly dose related, can act as a deterrent to overconsumption. One pre-clinical behavioral assay for the aversive effects of ethanol is the development of a conditioned taste aversion (CTA). When a taste is paired with a treatment which produces aversive internal symptoms, a strong aversion to the taste develops. Studies comparing different rodent strains suggest a link between sensitivity to the aversive effects of ethanol and the propensity to voluntarily ingest ethanol. Importantly, recent data show that mice selectively bred to achieve high blood ethanol concentrations (BECs) while binge drinking exhibit reduced sensitivity to the aversive properties of ethanol without alterations in sensitivity to ethanol?s reinforcing properties. Thus, binge-like ethanol drinking in these mice may be driven by reduced sensitivity to ethanol?s aversive effects. Because the neurocircuitry underlying the aversive effects of ethanol is still poorly understood, we propose to combine cutting-edged chemogenetic, molecular, and behavioral tools to characterize the neurocircuitry modulating aversive reactions to ethanol and binge-like ethanol consumption. Based on previous studies and compelling pilot data, we will test the novel hypothesis that brainstem norepinephrine (NE) nuclei, specifically the locus coeruleus (LC) and A2 region (caudal nucleus of the solitary tract; NTS), are activated during binge-like ethanol drinking and serve as protective mechanisms to ?break? ethanol drinking by promoting aversive responses. Specific Aim 1 will use Designer Receptors Exclusively Activated by Designer Drugs (DREADD) viral vectors to study the role of a NE circuit from the LC to the rostromedial tegmental nucleus (RMTg) in the modulation of ethanol-induced CTA and binge-like ethanol consumption, and Aim 2 will use DREADD viral vectors to study the role of a NE circuit from the A2 region to the lateral parabrachial nucleus (PBN) in the modulation of ethanol-induced CTA and binge-like ethanol consumption. Aim 3 will use immunohistochemistry and real-time PCR approaches to test the hypothesis that binge-like ethanol drinking increases NE signaling in the LC and A2, and that this signaling will become blunted after repeated binge-like drinking episodes, a mechanism that may contribute to the transition to dependence. As the mechanisms underlying the aversive effects of ethanol are not well understood, and the roles of the NE circuits under investigation have never been studies with respect to neurobiological response to ethanol, the proposed studies are highly novel and innovative.
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0.988 |
2020 — 2021 |
Lysle, Donald T (co-PI) [⬀] Thiele, Todd E. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A Role For Il-1beta in Ethanol Withdrawal-Induced Increase of Ptsd-Like Phenotype @ Univ of North Carolina Chapel Hill
Project Summary/Abstract Individuals that have been exposed to a traumatic event are at risk for developing a set of symptoms known as post-traumatic stress disorder (PTSD). Evidence suggests that there is a high comorbidity between PTSD and alcohol use disorders (AUDs), with a three-fold increased risk for experiencing an AUD in sufferers of PTSD. While it is generally thought PTSD proceeds, and is a risk factor for, AUDs, there is also evidence that a prior history of AUDs may leave individuals biologically more vulnerable to the impact of severe stress and thus more likely to develop PTSD. Despite converging evidence of co-morbidity between PTSD and AUDs, our understanding of the underlying neuronal substrates mediating these comorbid disorders, as well as available pharmaceutical treatments, are limited. This application brings together a team of investigators to address this scientific question in a convergent manner with the expertise of the neural immune mechanisms that underlie PTSD-like behavior (Lysle), the neurobiology of excessive alcohol (ethanol) intake (Thiele), and the understanding of astrocyte physiology (Reissner). Interestingly, a comparison of the present team?s research suggests that common overlapping neuroimmune mechanisms may underlie the development of each pathology. Dr. Lysle has discovered that severe stress induces a time-dependent increase in dorsal hippocampal (DH) interleukin-1? (IL-1?), and that directly blocking IL-1 signaling in the DH after severe stress (repeated unpredictable foot shock) prevents stress-enhanced fear learning (SEFL), an animal model of PTSD. Consistently, the present research team has found that withdrawal following chronic ethanol exposure increases hippocampal IL-1? mRNA, and a recent collaborative pilot project between the research team revealed that ethanol withdrawal potentiates the magnitude of SEFL. These observations support our overarching hypothesis, that hippocampal IL-1? represents a cellular mechanism for exacerbated stress response in alcohol- withdrawn/dependent individuals. Specific Aim 1 will test the hypothesis that withdrawal-induced potentiation of SEFL is associated with (A) a potentiation of IL-1? signaling specifically in astrocytes that correlates with the magnitude of SEFL, (B) pharmacological blockade of DH IL-1R during withdrawal will protect against withdrawal- induced potentiation of PTSD-like phenotypes, and (C) that DH-infusion of exogenous IL-1? will substitute for the effects of ethanol withdrawal. Specific Aim 2 will test the hypothesis that changes in the morphometric properties of astrocytes, and/or alterations of astrocyte/neuron interactions, correlate with increased astrocyte IL-1? levels stemming from ethanol withdrawal and the severe stress used in SEFL. The studies proposed here are appropriate for the R21 grant mechanism because they are high-reward, potentially filling a gap in our understanding of the role that astrocyte-derived cytokines play in co-morbid PTSD and AUD disorders. They are also high-risk because we currently do not have direct evidence that IL-1? signaling in the DH is a mechanism for withdrawal-induced potentiation of PTSD-like phenotypes.
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0.988 |