2011 — 2013 |
Giardino, William J |
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.). |
Edinger-Westphal Urocortin-1 Involvement in Binge Ethanol Intake and Reward @ Oregon Health &Science University
Stress plays a key role in precipitating relapse to excessive ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a role for neural stress networks, such as the corticotropin-releasing factor (CRF) system, in excessive EtOH intake. Unfortunately, the complex neuroanatomical and pharmacological features of the CRF system have hindered our understanding of the roles of its specific components in EtOH-related behaviors. To this end, we have devoted years of study to the examination of Urocortin-1 (Ucn1), an endogenous ligand of the CRF system that is closely related to the prototypical ligand CRF, yet binds to both CRF receptors with higher affinity than CRF itself. While the fields of alcohol abuse and addiction have typically focused on the mesolimbic dopamine pathway and brain structures such as the ventral tegmental area and nucleus accumbens, our laboratory has provided converging lines of evidence to support a role for the centrally-projecting neurons of the Edinger-Westphal nucleus (EWcp) in EtOH intake and sensitivity. The primary site of Ucn1 expression in the brain is within the EWcp, and a relationship between EWcp-Ucn1 expression and a genetic predisposition to excessive EtOH intake has been identified. Further interest in the EWcp as a brain region involved in EtOH intake is based on the observation that in addition to Ucn1, the cocaine- and amphetamine-regulated transcript (CART) neuropeptide, and the ghrelin receptor (Ghsr) are both highly expressed within EWcp. Intriguingly, these proteins have also been implicated in excessive EtOH consumption and EtOH-induced reward, and we have hypothesized that the role of the EWcp in excessive EtOH consumption is dependent on the interactions between Ucn1 and CART, Ghsr, and additional proteins. Thus, Specific Aim 1 of this proposal seeks to use quantitative PCR array technology elucidate interactions between Ucn1 and other EWcp-enriched genes that are relevant for EtOH-related behaviors, and Specific Aim 2 of my proposal seeks to examine well-characterized behavioral models of EtOH binge-drinking and EtOH- induced reward following knockdown of Ucn1 expression within the EWcp, using lentiviral-mediated RNA interference. These highly innovative experiments will not only conclusively determine the importance of EWcp-Ucn1 in two relevant behavioral endophenotypes of alcoholism, but will also use quantitative gene expression analyses to aid in unraveling the complex role that the EWcp plays in excessive EtOH intake.
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2013 — 2016 |
Giardino, William J |
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. |
Optogenetic Studies of Hypocretin in Binge Drinking and Negative Hedonic Valence
DESCRIPTION (provided by applicant): Alcoholism is a chronic disease with severe consequences to society, and stress plays a key role in precipitating relapse of ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a key role for neural stress networks in binge EtOH intake. Therefore, further research is required to advance scientific knowledge of the intricate neurobiology underlying stress-related behavior and excessive EtOH drinking. Indeed, multiple stress neuropeptide systems contribute to EtOH- related behaviors in complex ways. C57BL/6J (B6) mice serve as an ideal for model interrogating the neurobiology of excessive EtOH intake, as they voluntarily consume sufficient quantities of EtOH within discrete periods of the circadian dark cycle to produce blood EtOH concentrations (BECs) that surpass the NIAAA's criteria for binge drinking (80 mg/dL, or .08 percent). This proposal will integrate in vivo optogenetic stimulation/inhibition experiments with models of long-term intermittent binge drinking and aversive place conditioning in order to establish (or refute) causal relationships between the hypothalamic hypocretin system, stress-like states of hyperarousal, and pathological EtOH consumption. In addition, these experiments will use viral tracing and double fluorescent immunohistochemistry to anatomically define the pathways connecting the corticotropin-releasing factor (CRF) and hypocretin systems, and determine how these interactions control the stress response and EtOH drinking behavior. Stress hormone measurements, subtype-specific pharmacology, and transcription factor mapping will provide complementary measures to confirm the findings and further define the precise neural substrates underlying these behaviors. Knowledge gained from the proposed experiments will inform future strategies for mitigation of drug abuse and relapse.
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2018 — 2021 |
Giardino, William J |
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. |
Alcohol-Related Sleep Disturbances and Circuit Dynamics of Arousal Neuropeptides
Project Summary Alcoholism is a chronic disorder with severe consequences to physiology of affected individuals, and far- reaching effects on society in general. In particular, further research is required to advance scientific knowledge of the intricate neurobiology underlying the relationship between excessive alcohol drinking and deficits in sleep, a fundamental component of life. This proposal will integrate in vivo measurements of neural calcium activity with electroencephalogram sleep recordings in animal models of long-term, free-choice intermittent heavy alcohol exposure, in order to establish (or refute) causal relationships between the hypothalamic hypocretin system, extended amygdala corticotropin-releasing factor system, and stress-like states of hyperarousal (disrupted sleep) during alcohol withdrawal. Knowledge gained from the proposed experiments will inform future strategies for mitigation of drug abuse and relapse.
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