2005 — 2007 |
Logrip, Marian Lee |
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.). |
Bdnf, Dynorphin and Alcohol Intake @ Ernest Gallo Clinic and Research Center
Alcohol addiction is a widespread problem in our society, yet initial exposure to alcohol does not universally result in addiction. The likely reason for this is varying levels of activity of an endogenous homeostatic mechanism which, when activated by alcohol consumption, reduces further consumption and thus prevents the development of addictive behaviors. The proposed research aims to further elucidate such a homeostatic pathway. Ethanol consumption triggers production of brain-derived neurotrophic factor (BDNF), and reduction of BDNF levels results in higher ethanol consumption. However, the downstream effectors of this ethanol-induced BDNF increase have not been determined. The proposed research will investigate the role of dynorphin, a protein which BDNF signaling can upregulate. First, the molecular connection between ethanol treatment and dynorphin production will be established. The link to ethanol-induced BDNF will be demonstrated both cellularly and behaviorally, by comparing wild type mice to conditional BDNF knockout mice. Finally, the proposed research will investigate the specific brain region in which this homeostasis occurs. These studies will increase our understanding of a brain mechanism for curbing alcohol addiction.
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0.903 |
2009 — 2011 |
Logrip, Marian Lee |
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. |
Stress History Enhances Ethanol Self-Administration: Role of Neuronal Pentraxin 2 @ Scripps Research Institute
DESCRIPTION (provided by applicant): Alcoholism is a pervasive, chronic societal problem, with a high incidence of recidivism despite prolonged sobriety. Thus determination of mechanisms which predispose individuals to development of alcoholism is of great importance for finding new mechanisms of combating this disease. Stress is considered a major risk factor for relapse;stressful experiences can elevate alcohol craving in dependent individuals, even after the cessation of the stress exposure. However, the mechanisms by which stress modulates alcohol (ethanol) drinking remain largely unknown. One means by which stress may elevate ethanol drinking is by triggering the same neuroadaptations caused by chronic alcohol use. The studies in this proposal will investigate one putative common modulator of stress- and ethanol-induced neuroadaptations, amygdalar neuronal pentraxin 2 (NP2), and its ability to regulate operant ethanol self-administration using a novel model of stress exposure prior to the commencement of operant training, which yields marked increases in "relapse" drinking 2 months later. The observed elevation in self-administration after a protracted post-stress period are akin to elevations in alcohol abuse in observed in patients with post-traumatic stress disorder (PTSD). To address the role of NP2 in regulating stress pre-exposure-induced elevation in "relapse" drinking in rats, I will first determine whether NP2 expression in the amygdala is differentially elevated not only immediately after stress experience, but also during periods of withdrawal and during relapse. In addition I will determine whether this is caused by glucocorticoid signaling, which occurs under stressful conditions. Next I will determine whether the proposed elevation in NP2 in the amygdala is responsible for the elevation in "relapse" drinking due to stress pre-exposure 2 months eariier by blocking its expression via RNA interference. Finally, as NP2 has been proposed to increase synaptic complexity via synaptic recruitment of AMPA receptors, I will investigate whether stress pre-exposure alters the synaptic distribution of AMPA receptors and dendritic complexity in the amygdala, and the requirement of NP2 for observed changes. Together these studies will address a novel putative modulator of stress-induced elevations in alcohol intake. Thus the targets identified herein will not only increase our understanding of one mechanism by which stress may increase alcohol intake, but this research may also identify useful new targets for the development of therapies to treat PTSD, alcoholism and other stress-related disorders.
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0.973 |
2013 — 2017 |
Logrip, Marian Lee |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Sex Differences in Stress-Alcohol Interactions Modulating Amygdala Activity @ Scripps Research Institute
DESCRIPTION (provided by applicant): This Pathway to Independence proposal (Sex differences in stress-alcohol interactions modulating amygdala activity) addresses how sex interacts with the stress response system to regulate the development of alcohol dependence and the propensity to relapse. This project will investigate the impact of sexual dimorphism in the amygdala, a stress- and reward-responsive brain region, on the severity of neuroadaptations following stressors (including withdrawal from chronic alcohol). I hypothesize that hyper-activation of the stress axis in females results in enhanced susceptibility to stress-induced neuroadaptations in the amygdala and thus heightened tendency to relapse. This project takes an innovative approach, combining slice electrophysiology (new training to be obtained during the mentored K99 phase of the award) with biochemistry and behavior to answer a pressing question in alcohol research: how does sex impinge on the interaction between stress and alcohol to generate sexually dimorphic neuroadaptations in stress-responsive brain regions thought to underlie alcohol dependence? This proposal will address one possible mechanism, involving the stress hormone corticosterone and the novel putative downstream effector PDE10A. Utilizing electrophysiology, biochemistry and behavioral techniques, I will investigate how these 3 factors (stress, alcohol and sex) interact to modulate transmission in glutamatergic projections from the basolateral (BLA) to the central nucleus (CeA) of the amygdala. I will also test the functionality of identified molecular adaptations in vio to ascertain their involvement in both traditional stress-induced reinstatement and stress history models. Indeed, the stress history model is quite novel, as I developed the paradigm for my postdoctoral NRSA, in order to study the long-term effects of stress history on alcohol self-administration. As female rats have not been studied in these relapse and reinstatement paradigms, this study will be a significant advance for the field of alcohol research even in isolation from delineation of the proposed the molecular mechanism. Together, these studies will integrate my past training in molecular neurobiology and behavior with essential new training in electrophysiology, providing me with the diversity of experience to investigate complete mechanisms underlying alcohol dependence - from molecule to circuit activity to regulation of alcohol intake. In addition, the mentorship I will receive from Drs. Roberto and Koob, as well as myriad career development opportunities, thanks to the excellent environment of TSRI and the greater San Diego scientific community, will greatly facilitate my transition to independence in a timely fashion and enhance my level of productivity as I establish myself as an independent investigator in the R00 phase of the award.
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0.973 |