2002 — 2004 |
Barad, Mark G |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Rodent Models of Anxiety Disorder Treatment @ University of California Los Angeles
DESCRIPTION (provided by applicant): Pavlovian fear conditioning is an important model both of human anxiety disorders and of learning. Extinction, the gradual reversal of fear conditioning, is similarly the explicit model for behavior therapy, one of the most effective treatments in psychiatry. Extinction of fear is also an important paradigm of active inhibitory learning that appears to depend on NMDA receptors in the amygdala. Despite its importance, the molecular and cellular substrates of extinction remain largely unstudied. The goal of this grant is to explore the molecular and physiological bases of the extinction of fear conditioning. I hypothesize that extinction may share many mechanisms with other forms of long-lasting learning and NMDA-receptor dependent synaptic plasticity. However, differences from other forms of learning will be especially informative, since they may suggest mechanisms specific to extinction. My preliminary studies have identified two such differences. First, massed training is more effective in generating extinction than is temporally distributed training. Our data suggest that extinction results from two opposing behavioral processes, a sensitizing effect of reminders, and a weakening effect of longer exposures to the conditional stimulus. We have also found that extinction, but not acquisition or expression, of conditional fear depends on L-type voltage-gated calcium channels (LVGCC). I now propose 1) To optimize protocols in mice to maximally isolate the weakening (extinction) or sensitization of fear conditioning following presentations of unreinforced conditioned stimuli; 2) To dissect these two processes using systemic and intracerebral drug administration; 3) To explore protocols that generate LVGCC-dependent synaptic changes in amygdala; and 4) To use drugs to correlate such LVGCC-LTP with behavioral extinction. In particular, the project will explore the roles of neurotransmitters and second messengers that have already been implicated in the generation extinction, including adrenergic and dopaminergic, cholinergic and GABAergic systems, and MAP kinase. My goal is an academic career in fundamental neuroscience research with potential for rapid translational application to psychiatric treatment. I plan to pursue this goal focusing on the study of extinction of fear conditioning as an important homologous model of psychiatric treatment, and to develop the pharmacological and physiological skills to maximize my ability to perform a molecular and cellular dissection of this phenomenon.
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0.958 |
2004 — 2008 |
Barad, Mark G |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Conference On Childhood, Culture, and Neurodevelopment @ University of California Los Angeles
DESCRIPTION (provided by applicant): Animal and human studies have emphasized the primacy of early life experience on later development. However, much of the existing research on precisely how early life shapes development is founded on studies that rely on mono-theoretical, non-integrated perspectives. Typically, for example, neurobiologists using animal models focus exclusively on the effects of discrete stressors on the subsequent physiological changes and development of the organism, without considering some of the rich and varied contextual factors at play outside the laboratory that may also influence physiology. Likewise, anthropologists focus on culture and meanings with respect to the individual and social group, without considering their impact on neurobiological mechanisms that influence development. As a result, both the biological and social sciences may have, understandably, failed to consider multiple factors that both interact with each other and mutually influence human development, particularly those factors that happen to fall outside their respective disciplines. We propose a conference that seeks to fill this gap by examining how early experiences in the first several years of life contribute to resilience and mental well being or vulnerability to psychopathologies, such as anxiety, depression, and stress-related disorders. In particular, we will look at normative child development from combined neurobiological and cross-cultural perspectives, especially at how socially constructed contexts and normative environments impact physiological, social, and psychological development. The conference will bring together a multi-disciplinary team of researchers and scholars, representing the fields of anthropology, neurobiology, cognitive neuroscience, psychology, and psychiatry. Through presentations and roundtable discussions we want to involve a diverse audience of scholars interested in interactions between biology, psychology, and cultural anthropology that will collectively explore how cultural settings and brain development interact and affect early life experience and development.
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0.958 |
2004 — 2006 |
Barad, Mark G |
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.) |
Translating Extinction of Fear to Anxiety Disorder Treatment @ University of California Los Angeles
DESCRIPTION (provided by applicant): Fear extinction, the reduction of conditional fear by repeated cue (CS) exposure, has long been the explicit model of behavior therapy for human anxiety disorders. The goals of this R21 application are both to strengthen the evidence for this model and to test the translational potential of several recent findings in rodent extinction. In order to better establish the utility of the model of rodent fear extinction, we propose to perform a series of parallel studies in three groups: fear conditioned mice, fear conditioned normal human subjects, and patients with anxiety disorder. We will perform the first comparison to test whether the mechanisms of fear extinction in mice parallel those in fear-conditioned humans. We will perform the second comparison to test whether extinction of conditioned fear in normal human subjects is similar to the extinction of chronic fears in human anxiety disorder patients. We will use this parallel approach in two specific Aims. In Aim 1 we will investigate the role of expectancy in extinction. In fear conditioned humans and mice, we will manipulate the relative lengths of CS used during training and during extinction to create cue presentations that will or will not disconfirm the expectation of an adverse event. In phobic patients, we will use their subjective ratings of expectancy to create such disconfirming or non-disconfirming exposures. Throughout all the human experiments we will monitor both subjective expectancy and physiological variables of heart rate, skin-conductance and eyeblink startle, to seek reliable correlates of disconfirming exposures that effectively generate extinction. In Aim 2 we will investigate the role of excitation in generating extinction. Based on the hypothesis that increased excitation, or fear, during extinction will yield greater extinction, we test both behavioral and pharmacological means of increasing fear. Psychologically, we will increase excitation through compounds of independently conditioned cues in mice and normal human subjects. Pharmacologically, we will use a variety of anxiogenic compounds in mice. Having shown that yohimbine, an anxiogenic alpha2 adrenergic antagonist, accelerates extinction in mice, we will test the effects of yohimbine alone and in combination with the cognitive enhancer, d-cycloserine, in fear-conditioned human beings and anxiety disorder patients. These experiments should help establish the translational validity of the extinction model for anxiety disorder treatment and also may yield potential improvements in current anxiety disorder treatments.
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0.958 |