1995 — 1998 |
Weiner, Jeffrey L. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Ethanol Modulation of Gabaa Receptor Function @ University of Colorado Denver |
0.943 |
1998 — 2002 |
Weiner, Jeffrey L. |
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. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Ethanol and Synaptic Gabaa Receptors
Over 100 million Americans consider themselves to be regular drinkers, and approximately 20 percent of these individuals will eventually develop alcohol-related problems. Despite the staggering socio-economic cost of alcoholism, little is known about either the physiological factors the predispose an individual to this disease or about the molecular mechanisms that mediate the intoxicating actions of alcohol. We hypothesize that a better understanding of the molecular targets of alcohol and the physiological mechanisms that regulate ethanol sensitivity at these sites will facilitate the development of more effective treatment strategies. The overall aim of this research project is to characterize the synaptic mechanisms underlying ethanol potentiation of GABAA receptor-gated inhibitory synaptic transmission. The GABAA receptor mediates the majority of fast inhibitory synaptic transmission in the mammalian CNS, and a considerable volume of evidence suggests that these receptors may be one of the major CNS mediators of ethanol intoxication. However this interaction has not been studied, in detail, at the level of the synapse. Preliminary evidence from our laboratory indicates that ethanol may enhance GABAA receptor-mediated synaptic transmission via both a postsynaptic effect (possibly reflecting a direct interaction with GABAA receptors) and a previously uncharacterized presynaptic facilitation of GABAA receptor-mediated synaptic transmission. The first set of experiments will use the whole cell patch clamp technique to record from hippocampal CA1 pyramidal neurons in brain slices from mature rats. By characterizing the effects of ethanol (1-100 mM) on spontaneous and miniature GABAA receptor- mediated synaptic currents and currents evoked by somatic application of low concentrations of GABA, the specific mechanisms through which ethanol enhances presynaptic and postsynaptic components of GABAA receptor-gated synaptic transmission at a central mammalian synapse will be elucidated. The second series of experiments will use similar electrophysiological methods to characterize the mechanisms through which antagonism of GABAB receptors and elevation of basal PKC activity facilitate ethanol enhancement of GABAA receptor-mediated synaptic transmission. The results of these experiments will clarify the pharmacological relevance of presynaptic and postsynaptic ethanol actions to its facilitatory effect on GABAA receptor-gated synaptic transmission and identify mechanisms underlying the physiological regulation of ethanol sensitivity at these sites.
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1 |
2003 — 2007 |
Weiner, Jeffrey L. |
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. |
Ethanol and Presynaptic Gaba Beta Receptor Function @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): The cellular mechanisms responsible for ethanol intoxication, reinforcement, and dependence are not fully understood. There is now considerable evidence that ethanol modulates several neurotransmitter systems in the brain to shift the balance between excitatory and inhibitory synaptic transmission in favor of inhibition. For example, a large number of behavioral, neurochemical and electrophysiological studies have shown that ethanol acts, at least in part, by enhancing synaptic inhibition mediated by GABAA receptors. Despite the large volume of evidence linking GABAA receptors and ethanol, the specific mechanism(s) through which ethanol enhances GABAA receptor-mediated synaptic transmission are not clearly understood nor are the factor(s) responsible for regulating the ethanol sensitivity of GABAergic synapses. Based on preliminary studies, we propose that the ethanol sensitivity of GABAergic synapses in the rat hippocampus is regulated by a previously unrecognized presynaptic effect of ethanol on metabotropic GABAB receptors at these synapses. By potentiating GABAB autoreceptor function, ethanol enhances feedback inhibition of GABA release and this mechanism serves to limit the overall potentiating effect of ethanol at these synapses. We hypothesize that this novel presynaptic effect of ethanol contributes to the differential sensitivity of GABAergic synapses that has been noted within and between brain regions. We further propose that differences in presynaptic GABAB receptor function may contribute to differences in the ethanol sensitivity of GABAergic synapses that have been observed between lines of animals bred for differences in behavioral sensitivity to ethanol. The results of these studies will shed new light on a novel presynaptic mechanism that regulates the ethanol sensitivity of GABAergic synapses in the rat hippocampus and determine the extent to which this mechanism contributes to the differential ethanol sensitivity of some GABAergic synapses. Since studies suggest a link between initial ethanol sensitivity and subsequent risk of alcoholism, these studies may reveal novel synaptic gene products that may be associated with alcoholism and may possibly provide new targets for the development of pharmacotherapies to treat this disease.
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0.96 |
2004 — 2006 |
Weiner, Jeffrey L. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Functional Genomics of Excessive Ethanol Self-Administration @ Wake Forest University Health Sciences
Ethanol is thought to act, in part, by enhancing GABAergic inhibitory neurotransmission and by decreasing glutamatergic synaptic excitation in the mammalian CNS. Much evidence also suggests that compensatory changes in these neurotransmitter systems develop in response to repeated ethanol exposure and that this synaptic adaptation contributes to some of the behavioral and cognitive changes associated with alcohol addiction. In this project, we will use in vitro patch clamp electrophysiology methods to study acute and longterm effects of ethanol on GABAergic and glutamatergic synaptic transmission in several brain regions within the meso-cortico-limbic circuitry that is thought to mediate ethanol's reinforcing effects. Aim 1 will test the hypothesis that a novel interaction between ethanol and presynaptic GABAB receptor function, first described in the rat hippocampus, also regulates the ethanol sensitivity of GABAergic synapses in the monkey hippocampus and the rat basolateral nucleus of the amygdala (BLA) and ventral tegmental area (VTA). Aim 2 will examine hippocampal synaptic neuroadaptation in a monkey model of excessive ethanol drinking. We expect that excessive ethanol exposure and withdrawal will result in a downregulation in GABAergic neurotransmission, an upregulation of NMDA-receptor-mediated synaptic excitation, and tolerance to the acute modulatory effects of ethanol on NMDA-, but not GABAA receptor-mediated synaptic responses. Aim 3 will employ a rodent model of excessive ethanol drinking to characterize synaptic adaptation in the hippocampus, BLA, and VTA following long-term ethanol exposure and withdrawal. Results of Aim 3 will permit a systematic comparison of ethanol-induced synaptic adaptation in the rat and monkey hippocampus. This aim will also test the hypothesis that there may be significant brain region differences in synaptic adaptation following ethanol exposure and withdrawal. Integration of the results of these studies with those of other projects within the Center may provide new insight into how synaptic communication in brain regions associated with ethanol self-administration is altered following excessive ethanol drinking. These studies may also identify specific characteristics of brain regions that are most vulnerable to ethanol-induced synaptic adaptation. Such findings may help clarify the neurophysiological mechanisms that contribute to abusive drinking behavior and possibly identify novel targets for the development of pharmacotherapies in the treatment of alcohol addiction.
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0.96 |
2007 — 2008 |
Weiner, Jeffrey L. |
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.) |
Synaptic Correlates of Ethanol-Related Behaviors @ Wake Forest University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): Numerous studies have shown that acute ethanol exposure significantly potentiates GABAA receptor-mediated synaptic transmission in the hippocampus and many other brain regions. These, and other, important findings have led to the popular hypothesis that ethanol's acute facilitatory effects on GABAergic synapses contribute to ethanol drinking, intoxication, and dependence. Although this hypothesis has received considerable indirect support, relatively few studies have demonstrated a relationship between ethanol enhancement of GABAergic synapses and any ethanol-related behaviors. In this pilot project, we seek to build on some recent advances in our understanding of the mechanisms through which ethanol enhances GABAergic synapses in the hippocampus, and the role of the hippocampal GABAergic system in ethanol drinking, to examine the relationship between ethanol drinking-related behaviors and the ethanol sensitivity of hippocampal GABAergic synapses. Rats will be trained to self-administer ethanol or sucrose using a well established limited-access paradigm that permits the discrete assessment of "seeking" and "consummatory" drinking behaviors. Aim 1 will test the hypothesis that this voluntary drinking paradigm engenders sufficient ethanol intake to produce measurable reductions in anxiety-like behaviors in standard Long-Evans rats. In Aim 2, brain slices prepared from ethanol- and sucrose-drinking rats, as well as experience-na[unreadable]ve controls, will be used in whole-cell patchclamp studies to examine the effects of ethanol self-administration on specific physiological and pharmacological properties of hippocampal GABAergic synapses. Based on preliminary findings, we hypothesize that ethanol self-administration will not alter that acute potentiating effect of ethanol on hippocampal GABAA IPSCs, although possible effects of the self-administration regimen on the properties of GABAergic synapses will be carefully examined. Rather, we hypothesize that the ethanol sensitivity of hippocampal GABAergic synapses may be a trait that is positively correlated with appetitive (or seeking), but not consummatory, ethanol drinking-related behaviors. [unreadable] [unreadable] [unreadable]
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0.96 |
2008 — 2012 |
Weiner, Jeffrey L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Translational Centerfor the Neurobehaviral Study of Alcohol @ Wake Forest University Health Sciences
DESCRIPTION: The major goal of this Center is to leverage existing strengths in human, non-human primate, and rodent alcohol research at WFUHS to develop a translational alcohol research program that will successfully compete for a P60 center grant within the next five years. A broad-based Center structure is proposed that will facilitate the integration of institutional expertise in epidemiology and prevention and will bring together faculty from the Departments of Neurobiology and Anatomy, Pediatrics, Physiology and Pharmacology and Public Health Sciences. Infrastructure development activities will include a monthly seminar series, a monthly journal club, and an annual retreat. A workshop series will also be planned and implemented to broaden the base of knowledge and promote the integration of research among participating investigators. The overarching research goal of this Developmental Center is to use human, non-human primate, and rodent models to study the interaction between early-life stressors, behavioral risk factors associated with alcoholism, and binge drinking. These studies will be framed by the working hypothesis that exposure to life stress is associated with increased risk-related behavior (with a focus on impulsivity) and alcohol consumption, and that persistent dysregulation of serotonergic signaling contributes to these environmental and behavioral interactions. These hypotheses will be evaluated in human subjects with and without a history of life stress and/or binge drinking and using established non-human primate and rodent models of early-life stress. A major emphasis will be on the development of non-human primate and rodent models of risk-related behaviors and ethanol self-administration to facilitate integration with human studies. This Developmental P20 center will have an administrative structure, research projects, and training goals that will allow new opportunities at WFU for collaborative translational alcohol research to develop in a manner that maximize the successful transition to a planned P60 Center.
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0.96 |
2008 — 2012 |
Weiner, Jeffrey L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 3 @ Wake Forest University Health Sciences
Acute; Adolescent; Adult; Alcohol consumption; alcohol exposure; alcohol sensitivity; alcohol use disorder; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Behavior; behavior measurement; Behavioral; Behavioral Paradigm; Brain region; cohort; Complex; Data; design; Development; drinking behavior; Environment; Environmental Risk Factor; Ethanol; Etiology; Exhibits; experience; Exposure to; Genetic; Home environment; Housing; Human; Impulsivity; insight; Investigation; Lead; Life Stress; Link; Long-Evans Rats; male; mature animal; Measures; meetings; Modeling; neurobiological mechanism; Neurobiology; nonhuman primate; Outcome; Play; Primates; Principal Investigator; Procedures; programs; Rattus; receptor function; research study; Risk; Risk Factors; Rodent; Rodent Model; Role; Self Administration; Series; Serotonin; serotonin 5 receptor; serotonin receptor; Signal Transduction; Social isolation; Stress; Sucrose; Synapses; synaptic inhibition; Testing
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0.96 |
2009 — 2013 |
Weiner, Jeffrey L. |
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. |
Synaptic Correlates of Ethanol-Mediated Anxiolysis @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): There is a growing body of evidence suggesting that ethanol is used and abused for both its positive and negative reinforcing effects and that ethanol-mediated anxiolysis represents an important element of the negative reinforcement associated with ethanol drinking. Moreover, recent studies have suggested that ethanol's negative reinforcing effects gain salience with repeated ethanol exposure and withdrawal and may play an integral role in the development of, and relapse to, abusive drinking. Although much is known about the neurophysiological mechanisms responsible for the positive reinforcement associated with ethanol consumption, less is known about the neurocircuitry that contributes to many of ethanol's negative reinforcing effects. The overarching goal of this proposal is to integrate electrophysiological and behavioral approaches to begin to examine some of the neurophysiological mechanisms that may contribute to ethanol's anxiolytic effects. Specifically, these experiments will integrate electrophysiological and behavioral approaches to begin to address the central hypothesis that ethanol potentiation of GABAergic inhibition in the basolateral nucleus of the amygdala (BLA) contributes to specific measures of ethanol-mediated anxiolysis. Preliminary and published data suggest that there are two main GABAergic circuits within the BLA that mediate paracapsular, feedforward- and local, feedback-inhibition onto the principal output cells of this nucleus. Aims 1 and 2 will test the working hypothesis that ethanol potentiates both circuits, albeit via distinct mechanisms. We also plan to take advantage of a genetically engineered mouse line with increased sensitivity to some acute anxiolytic effects of ethanol. By combining behavioral and ex vivo electrophysiological studies in these genetically engineered mice (Aim 3) and outbred rats (Aim 4), we will test the working hypothesis that there is a positive relationship between ethanol potentiation of local and/or paracapsular GABAergic inhibition in the BLA and specific measures of ethanol-mediated anxiolysis. Collectively, these studies will identify the mechanisms that mediate and regulate ethanol potentiation of local and paracapsular GABAergic inhibition in the BLA and provide initial insight into some of the synaptic mechanisms that may contribute to ethanol's anxiolytic effects. PUBLIC HEALTH RELEVANCE: The first two aims of this proposal seek to determine how ethanol enhances two distinct inhibitory circuits in the basolateral amygdala (BLA), a brain region that has long been thought to play an integral role in the regulation of anxiety-like behaviors. Aims 3 and 4 outline a novel strategy that integrates behavioral and electrophysiological approaches to begin to assess the relationship between ethanol potentiation of BLA GABAergic inhibition and measures of ethanol-mediated anxiolysis. The results of these studies may lead to a better understanding of some of the neurobiological mechanisms that contribute to ethanol's anxiolytic effects and potentially reveal novel synaptic elements that can be targeted for the development of more effective treatments for alcoholism.
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0.96 |
2012 — 2021 |
Weiner, Jeffrey L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core @ Wake Forest University Health Sciences
PROJECT SUMMARY The central goal of the Wake Forest Translational Alcohol Research Center (WF-TARC) is to employ rodent, non-human primate and human subjects to study behavioral and neurobiological substrates associated with vulnerability (and resilience) to alcohol use disorder (AUD). The Administrative Core will provide the organizational infrastructure and support needed to ensure that the WF-TARC functions optimally and accomplishes all its goals and objectives. A strong leadership team will oversee WF-TARC research progress. They will be advised by External and Internal Advisory Boards comprised of outstanding researchers with expertise in translational programmatic alcohol research. The major goals of the Administrative Core will be to promote scientific integration across projects, provide biostatistical support to WF-TARC investigators, enhance scientific rigor and reproducibility, seek out synergistic opportunities with other WFSM addiction- related Centers and promote education and outreach related to the scientific aims of the WF-TARC. These goals will be accomplished through a detailed organizational structure that includes a Steering Committee, a Biostatistical Support Unit, an Education and Outreach Committee, and a highly experienced administrative support team. The Administrative Core will also provide support for a Pilot Project Core that will support new and innovative translational alcohol research initiatives to complement and expand the scope of alcohol research supported by this Center. Collectively, this Core will provide the administrative leadership and infrastructure to best facilitate the integrated translational WF-TARC research projects and pilots, create new translational alcohol research opportunities at WFSM, enhance the translational alcohol research training environment at our institution and support ongoing and new alcohol-related outreach activities throughout the Piedmont Triad region.
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0.96 |
2012 — 2016 |
Weiner, Jeffrey L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Translational Studies On Early-Life Stress and Vulnerability to Alcohol Addiction @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): The major goal of this P01 is to leverage institutional strengths in human, non-human primate, and rodent alcohol research to conduct translational studies directed at understanding the complex relationships between early life stress and vulnerability to alcohol use disorders. This project will take advantage of a highly productive and successful translational alcohol research unit at WFHS that was recently established with NIAAA programmatic grant support. This research unit will employ multidisciplinary approaches to identify enduring behavioral and neurobiological consequences of early life stress, determine how these alterations contribute to excessive alcohol drinking behaviors, and test novel interventional strategies that may be effective at alleviating addiction vulnerability associated with early life stress. The overarching hypothesis is that early life stress results in long lasting behavioral alterations that contribute to an increased risk of alcohol addiction (with a focus on anxiety-like behaviors). It is also hypothesized that these behavioral alterations are mediated, in part, by dysregulatlon of dopamine signaling and glutamate receptor function and plasticity in the nucleus accumbens. Aspects of these hypotheses will be evaluated in human subjects with and without a history of early life stress and with well-established non-human primate and rodent models of early life stress. This P01 will employ a Center-like structure that will include highly integrated rodent, non-human primate, and human projects. An administrative core will provide the infrastructure and support needed to ensure the success of the research. This core will also actively promote new translational alcohol research through a pilot project program and create new translational research training and outreach activities related to the scientific goals of the P01. A major emphasis will be to promote scientific integration across projects to maximize the likelihood of proceeding from benchside discovery to novel treatment strategies for alcohol addiction.
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0.96 |
2014 — 2018 |
Weiner, Jeffrey L |
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. |
Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorders @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): The development and progression of alcohol use disorders is thought to involve adaptive changes in neural circuits that underlie negative affective states, like anxiety. One hypothesis that is garnering increasing support is that these adaptive changes gradually shift motivation for alcohol away from positive reinforcement (e.g. euphoria) toward negative reinforcement (e.g. relief from negative affective states). Although much is known about the neural underpinning of alcohol's positive reinforcing effects, the neural substrates linking negative reinforcement and alcoholism remain less clearly defined. The lateral/basolateral amygdala (BLA) plays a major role in anxiety-like behaviors and alcohol drinking and there is growing evidence that dysregulation of this brain region contributes to the pathophysiology of both anxiety disorders and addiction. Surprisingly, much remains unknown about the intrinsic circuitry of this brain region or the neuromodulatory systems that influence BLA synaptic transmission. During the last funding period, we discovered that beta3-adrenoceptor activation enhances a novel GABA circuit in the BLA and that this effect can decrease anxiety-like behaviors and ethanol seeking behaviors. We have also recently identified powerful effects of the neuromodulator adenosine on BLA synaptic transmission. In other studies, we demonstrated that a rodent early life stress model engenders several behavioral and neurobiological alterations that have also been associated with increased vulnerability to alcoholism. The first two aims of this proposal will determine the neurobiological effects of adenosine A1 and A2a receptor activation on excitatory and inhibitory neurotransmission in the rat basolateral amygdala (BLA) and whether intra-BLA activation of these receptors reduces measures of anxiety-like behavior. Aims 3 and 4 will employ the early life stress model to identify enduring perturbations in norepinephrine and adenosine modulation of BLA synaptic transmission that may contribute to increased vulnerability (and resilience) to excessive alcohol drinking behaviors. Other experiments will determine if pharmacological manipulations that restore normal BLA function can reduce the increases in anxiety-like behavior and ethanol drinking that result from early life stress.
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0.96 |
2016 — 2017 |
Weiner, Jeffrey L |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
2016 and 2018 Alcohol and the Nervous System Grc @ Gordon Research Conferences
? DESCRIPTION (provided by applicant): This R13 application requests support for the Gordon Research Conference (GRC) on Alcohol and the Nervous System that will take place in February 2016 and 2018 at the historic Hotel Galvez in Galveston, TX. The inaugural GRC on this topic took place in 2014 and was considered a tremendous success by all attendees. This application seeks to build on the success of the first meeting by bringing together young and established alcohol researchers, as well as preeminent scientists from related fields, to discuss the latest groundbreaking developments in neuroscience research on alcohol-related health issues. The central goal will be to foster deep and open discussion of research developments, build new scientific collaborations, and propel the next generation of scientific advances in alcohol neuroscience research. The following four specific aims will ensure that we accomplish this goal: 1) To provide an international forum that promotes open discussion of cutting edge research at the forefront of alcohol effects on the nervous system and related neuroscience areas. 2) To introduce breakthrough neuroscience techniques that facilitate the understanding of brain mechanisms driving alcohol drinking and abuse, as well as mechanisms involved in fetal alcohol spectrum disorders. 3) To promote interaction between young and senior investigators and the exchange of ideas that will shape the future directions of the alcohol neuroscience community. 4) To foster the development of the next generation of alcohol researchers by encouraging the participation of students and postdoctoral fellows, both in alcohol and related research fields. The Alcohol and the Nervous System GRC will focus on presentations and discussions at the forefront of our field. The scope of the research presented will be restricted to basic and clinical studies involving alcohol and the nervous system as well as groundbreaking new neuroscience techniques that can be brought to bear on the greatest challenges facing our field. Talks will address questions centered on the neural substrates that contribute to alcohol-related health disorders across the entire lifespan. The unique GRC format is ideal for breaking down barriers to progress and includes formal talks interspersed with ample discussion time, poster sessions, and informal discussion periods designed to stimulate communication, planning, and collaboration. To foster the growth of the next generation of alcohol researchers, we will put concerted efforts into encouraging and supporting participation of students, postdoctoral fellows and young investigators. Thus, this R13 will foster communication of frontier alcohol research, opportunities for cutting edge scientific collaboration, and entry of new and younger investigators into the alcohol research field. We envision the GRC on Alcohol and the Nervous System will significantly advance our current understanding of the neurobiology of alcohol addiction and stimulate the development of effective therapeutic approaches for the treatment of alcohol use disorders.
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0.903 |
2017 — 2021 |
Weiner, Jeffrey L |
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. |
Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder @ Wake Forest University Health Sciences
Summary Although alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, little is known about the neural substrates that contribute to this comorbidity. Moreover, despite the frequent co- occurrence of AUD and PTSD, there is marked variability in the likelihood of developing these disorders and even less is known about the neural substrates that might confer vulnerability or resilience to AUD and PTSD. The scientific premise of this application is that a better understanding of the circuitry and neurobiology that differentiate these vulnerable and resilient populations may reveal novel targets for the development of more effective treatments for individuals suffering from the comorbid condition. To address this challenge, we have extensively characterized a rodent model of early life stress, adolescent social isolation (aSI), and have generated encouraging support for the face, construct and predictive validity of aSI as a model of vulnerability to AUD and PTSD. For example, relative to rats group-housed throughout adolescence (aGH), aSI rats exhibit many behaviors linked with heightened risk of AUD and PTSD, including deficits in fear extinction and enduring increases in ethanol drinking behaviors. Notably, a relatively mild fear conditioning procedure significantly increased ethanol self-administration in aSI rats for at least 8 weeks while having no effect on ethanol drinking in aGH subjects. Published and ongoing neurobiological studies have identified profound adaptations that may contribute to these behavioral phenotypes, including increased measures of excitability within the basolateral amygdala (BLA) and ventral hippocampus (vHC), two highly interconnected brain regions that play an integral role in many of the emotional behaviors that are disrupted in AUD and PTSD. Based on these findings, the studies outlined in this application will employ a multidisciplinary experimental design to determine if the fear conditioning procedure leads to the expression of core behavioral symptoms of AUD and PTSD in aSI rats and whether aGH subjects will be resilient to this stressor. Neurobiological studies will determine if the fear conditioning procedure exacerbates aSI-associated neurobiological adaptations in the BLA and vHC, and specifically within the BLA-vHC circuit, and whether a strengthening of this circuit plays a causal role in AUD/PTSD-like behavioral phenotypes promoted by this model. Additional studies will test a novel therapeutic strategy to reverse the maladaptive behaviors promoted by aSI + fear conditioning. Based on other emerging findings, these studies will also test the innovative hypothesis that aSI + fear conditioning promotes similar neural adaptations in male and female rats but that the behavioral phenotypes engendered by these stressors may be sexually dimorphic. Collectively, these studies will further strengthen the validity of aSI as a model of heightened vulnerability to comorbid AUD and PTSD and potentially lead to the identification of novel neurobiological targets for the development of much needed treatments for the comorbid condition.
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0.96 |
2018 — 2021 |
Weiner, Jeffrey L |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Project 4: Adolescent Social Isolation Increases Vulnerability to the Behavioral and Neurobiological Consequences of Chronic Ethanol Exposure in Male and Female Rats @ Wake Forest University Health Sciences
PROJECT SUMMARY Individuals diagnosed with anxiety disorders are 2-4 times more likely to develop AUD and this comorbid diagnosis is associated with a telescoped progression of AUD and a much worse prognosis in recovery. Despite the clinical significance of this problem, we still lack a full understanding of the neurobiological substrates responsible for the frequent co-occurrence of these disorders. One major obstacle has been the lack of well-validated animal models that reliably engender a behavioral profile that may be indicative of a heightened risk of developing these diseases. To that end, we have re-examined a common rodent model of early-life stress, adolescent social isolation (aSI) and in a series of studies, have generated strong data supporting the face, predictive and construct validity of aSI as a model of vulnerability to anxiety disorders and AUD in male rats, and have used this model to identified profound adaptations in mesolimbic circuits that may contribute to the ?AUD vulnerable phenotype? engendered by this model, including enduring alterations in catecholamine release dynamics in the nucleus accumbens and increased intrinsic excitability in the basolateral amygdala. Despite the promise of this model, several key gaps in our knowledge remain. First, this model has not been carefully validated in female rats. Our preliminary data suggest that it may promote a vulnerable phenotype in females but that this phenotype may be sexually dimorphic. Experiments in Aim 1 will therefore conduct behavioral and neurobiological studies to further validate the utility of the aSI model in females. Second, although aSI alters many behaviors linked with increased risk of AUD, it is not known if aSI actually increases vulnerability in a rodent model of ethanol dependence. Aim 2 will integrate aSI and a well- established rodent model of ethanol dependence (chronic intermittent ethanol vapor, CIE) to test the hypothesis that aSI increases sensitivity to the behavioral consequences of CIE. Complementary neurobiological studies will determine if CIE exacerbates neurobiological adaptations engendered by aSI and test the causal role of these adaptations using pharmacological and chemogenetic interventions. Collectively, these studies will further validate aSI as a model of vulnerability to comorbid AUD and anxiety disorders in male and female rats and may facilitate the discovery of novel treatment strategies that may be particularly effective for individuals suffering from comorbid AUD and anxiety disorders.
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0.96 |
2018 — 2019 |
Almonte, Antoine Gabriel (co-PI) [⬀] Weiner, Jeffrey L |
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.) |
The Role of the Bla-Ventral Hippocampal Circuit in Ethanol Withdrawal-Related Behaviors @ Wake Forest University Health Sciences
Summary Although considerable progress has been made in identifying brain regions and neural substrates that contribute to the etiology of alcohol use disorder (AUD), translating these discoveries into effective treatments has proven difficult. Recent methodological advances in the field of neuroscience have revealed that many of the brain regions that contribute to AUD are not comprised of homogenous neuronal populations but, instead, contain distinct subpopulations of neurons with unique afferent and efferent connections. The overarching scientific premise of this application is that a better understanding of the specific neural pathways that are dysregulated in AUD may lead to the identification of better targets for the development of more effective treatments for this disorder. The basolateral amygdala (BLA) is a brain region that is known to play an integral role in AUD. Although considerable evidence suggests that chronic ethanol leads to BLA hyperexcitability and that this increased excitability contributes to elements of the negative affective state that develops in withdrawal (e.g. anxiogenesis), the specific BLA circuits responsible for these maladaptive behaviors are not fully understood. Preliminary rodent data from our lab demonstrate that chemogenetic silencing of an excitatory projection from the BLA to the ventral hippocampus (vHC) reduces anxiety-like behaviors and ethanol drinking and that withdrawal following a well-established rodent model of ethanol dependence (chronic intermittent ethanol vapor, CIE) promotes increases in synaptic excitability in the vHC. Based on these recent findings, the experiments in this application will integrate chemogenetic, optogenetic, electrophysiological and behavioral approaches to test the hypothesis that CIE promotes increases in BLA-vHC excitability and that this adaptation contributes to the negative affective state that manifests in withdrawal. A secondary hypothesis, based on emerging literature, will determine if females are less sensitive to the behavioral and neurobiological consequences of CIE. Collectively, these pilot studies will provide a critical foundation for a comprehensive study that will more fully characterize the role of the BLA-vHC in the negative affective state that develops following CIE, identify neurobiological mechanisms through which CIE promotes increases in BLA-vHC excitability, and seek to develop novel pharmacotherapies that can reverse these maladaptive CIE-associated alterations.
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0.96 |
2018 — 2021 |
Weiner, Jeffrey L |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Wake Forest Translational Alcohol Research Center (Wf-Tarc) @ Wake Forest University Health Sciences
PROJECT SUMMARY The central goal of the Wake Forest Translational Alcohol Research Center (WF-TARC) is to employ animal models and human subjects research to study behavioral and neurobiological substrates associated with vulnerability (and resilience) to alcohol use disorder (AUD). This Center builds on a highly productive translational alcohol research program at WFSM that was recently established with NIAAA developmental program project (P01) support. The WF-TARC will have four research projects and two cores. An administrative core will provide the leadership and infrastructure needed to ensure integration across all research projects, provide biostatistical support, and promote interactions and communication between this Center and the many other addiction- related research and educational programs at Wake Forest School of Medicine (WFSM). A pilot project core will be established to advance the goals and objectives of the WF-TARC. This core will fund four projects each year to attract new investigators to bring their talent and expertise to the study of AUD vulnerability. The unifying research focus of the WF-TARC will be to leverage the strengths and advantages of animal models and human subjects research to study behavioral correlates of AUD vulnerability and identify neurobiological adaptations that contribute to this heightened risk of developing AUD. Studies will employ cutting-edge, multidisciplinary experimental approaches spanning molecular, cellular, circuit, and whole-brain analyses. Importantly, each project will evaluate novel interventions targeted at the reversing the maladaptive neural adaptations that promote AUD vulnerability. The highly-integrated conceptual framework and research design will facilitate backward and forward interactions between the projects, facilitating the rapid translation of therapeutic discoveries from animals to humans. The WF-TARC takes advantage of a well-established, extremely collaborative translational alcohol research program at WFSM and will benefit from a strong and growing institutional focus on alcohol and drug addiction research. This Center will further enhance the outstanding educational environment at our institution, providing unique training opportunities for the students and postdoctoral who will become the next generation of translational alcohol researchers. Finally, the innovative research that will be supported by the WF-TARC may lead to better evidence-based therapies for individuals who are at greatest risk of developing AUD, individuals who are particularly ill-served by current AUD treatment options.
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0.96 |
2019 — 2021 |
Weiner, Jeffrey L |
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. |
Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder @ Wake Forest University Health Sciences
Although individuals with anxiety disorders are more likely to develop alcohol use disorder (AUD) than healthy controls, the neural substrates responsible for this heightened risk are poorly understood. These dual diagnoses are also associated with greater symptom severity of both disorders and poor treatment outcomes. The central goal of this project is to employ neurobiological and behavioral approaches in rodent models to identify neural circuit adaptations that play a causal role in promoting increased risk of developing AUD and anxiety disorders. To that end, we have established a rodent adolescent social isolation model (aSI) that engenders many behaviors associated with greater risk of developing AUD and anxiety disorders. Relative to rats reared in groups throughout adolescence (aGH), aSI rats exhibit increases in anxiety-like behaviors, novelty responding, impulsivity, and aggression in adulthood. aSI rats also display impaired fear extinction and long-lasting increases in voluntary ethanol drinking. Neurobiological studies revealed that aSI promotes increases in the excitability of glutamatergic projection neurons in the basolateral amygdala (BLA), a brain region integral to anxiety-like and motivated behaviors, as well as increased synaptic activity in areas that receive dense innervation from the BLA. It has also recently been discovered that BLA projection neurons are not homogenous. Rather, these cells are distributed into two distinct clusters along the anterior- posterior axis and form largely non-overlapping circuits in downstream brain regions. Activation of anterior BLA (aBLA) circuits promotes aversion/anxiogenesis whereas activation of posterior BLA (pBLA) circuits elicits rewarding/anxiolytic behaviors. Based on these findings, this project will test the hypothesis that aSI shifts the excitatory/inhibitory balance between these opposing amygdala circuits, leading to excessive excitability within aBLA pathways, and that these maladaptive changes play a causal role in the ?addiction vulnerable? phenotypes promoted by aSI. A secondary hypothesis to be investigated is that aSI promotes similar adaptations in male and female rats but that the behavioral phenotypes that emerge are sexually dimorphic. Additional studies will also seek to identify novel pharmacological approaches to restore normal aBLA/pBLA excitability. Collectively, this project will provide critical new insight into the circuitry underlying vulnerability to AUD and anxiety disorders and potentially lead to the identification of novel and much needed treatments for individuals suffering from these frequently co-occurring diseases. RELEVANCE (See instructions): These studies will employ a rodent model that promotes an ?addiction vulnerable? phenotype to identify circuit-specific neural adaptations responsible for these behaviors. Studies will also seek to identify novel interventions to reverse these maladaptive changes. Collectively, these studies will help to identify specific neural pathways associated with AUD and comorbid anxiety disorders and potentially identify novel treatments for individuals afflicted with these diseases.
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0.96 |
2020 |
Weiner, Jeffrey L |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Wake Forest Translational Alcohol Research Center @ Wake Forest University Health Sciences
PROJECT SUMMARY As the most common form of dementia, Alzheimer?s disease (AD) is a neurodegenerative disorder that affects approximately 30 million people worldwide. AD is characterized by the aggregation of extracellular amyloid ? (A?) into amyloid plaques and intracellular tau into neurofibrillary tangles (NFTs), both of which begin to accumulate ~15 years before cognitive decline. Alcohol is among the most widely abused drugs in the world and problems arising from alcohol use disorder (AUD) represent a major public health concern. Epidemiological studies consistently identify AUD as a significant and independent predictor of AD in older adults. Heavy drinking in AD patients is associated with faster cognitive decline, suggesting that alcohol consumption may contribute to AD progression. However, it is unknown how alcohol intake during the pre- symptomatic period drives the AD pathogenesis, specifically, the production, clearance, and aggregation of A? and tau, the two pathological hallmarks of AD. In humans, monkeys, and rodents, the hippocampus is a brain area critical for memory formation and encoding and is especially vulnerable to the neurodegenerative processes and cognitive impairments associated with AD. The hippocampus is also compromised in AUD, with multiple lines of evidence suggesting that maladaptive changes in hippocampus-containing brain circuits leads to increases in fear- and anxiety-like behaviors and decreases in cognitive performance. Despite the availability of rodent models for alcohol dependence and mouse models for AD, very few studies have investigated the effects of alcohol exposure in AD mouse models. The central hypothesis of this proposal is that aberrant hippocampal excitatory synaptic function arising from ethanol exposure promotes the onset and progression of neuropathology and impairments in behavior and synaptic plasticity associated with AD. Toward this end, the work described in this proposal capitalizes on the research strengths of investigators in the Wake Forest Translational Alcohol Research Center and the Wake Forest Alzheimer?s Disease Research Center. We will combine a well-established model of ethanol dependence and a widely used AD mouse model to elucidate the interaction between AUD and AD at the molecular, behavioral, and synaptic levels. In addition, we will take advantage of an established cohort of monkeys undergoing a longitudinal study of ethanol consumption to determine if AD biomarkers correlate with ethanol intake. Collectively, these experiments will provide critically needed insight into the relationship of AUD and AD at the molecular, cellular, circuit, and whole-brain levels across animal models (rodents and non-human primates) and human subjects.
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0.96 |