2009 — 2011 |
Turner, Jill Rebecca |
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. |
Nicotinic Acetylcholine Receptors in Anxiety and Depression @ University of Pennsylvania
DESCRIPTION (provided by candidate): Alterations in nicotinic cholinergic signaling in the brain have been implicated in numerous diseases and disorders, such as Alzheimer's disease (AD), autism, anxiety and depression. In addition, studies using mice lacking specific nicotinic receptor subunits have implicated these receptors in both anxiety and depression. Therefore, nicotine and subtype-specific nicotinic drugs present a rich area for investigation of their therapeutic potential in these mental disorders. However, a dearth of ideal animal models and subtype- selective ligands that easily cross the blood-brain barrier have previously hampered inquiry into this area. Equipped with novel compounds and a variety of behavioral models, this grant aims to examine the behavioral effects of nicotine and the nicotinic partial agonists, varenicline and sazetidine-A, in models of anxiety and depression as well as elucidate the molecular and cellular underpinnings of these behaviors. Initially, the acute and chronic effects of these drugs will be investigated in models of anxiety and depression (e.g., the novelty-induced hypophagia test and the forced swim test). Additionally, the effects of acute and chronic administration of nicotine, varenicline and sazetidine-A on adult neurogenesis, which has been implicated as mechanism for antidepressant action, will be examined using a fluorescently-activated cell sorting (FACS) method to detect BrdU labeled cells in hippocampi from treated animals. Finally, radioligand binding and sequential immunoprecipitation assays will be utilized to determine what nicotinic receptor subtypes are altered by nicotinic ligand administration and, thus, may be responsible for these behavioral and neuronal effects. The goal of this research is to identify new potential therapeutic uses of these drugs for disorders such as anxiety and depression, investigate the molecular correlates underlying the behavioral effects, as well as examine and evaluate the most appropriate behavioral models for use in nicotinic drug discovery. This research may ultimately lead to new therapies for depression and anxiety disorders, as well lay the groundwork for application of nicotinic compounds in the treatment of mental disease and disorders.
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0.951 |
2019 — 2021 |
Turner, Jill R. |
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. |
Dynamic Signaling of Nrg3-Erbb4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes @ University of South Carolina At Columbia
Nearly 80% of smokers attempting to quit, fail. While there is increased appreciation for genetic contributions to this statistic, the molecular mechanism(s) underlying this remain a critical gap in our knowledge. We have previously shown that multiple single-nucleotide polymorphisms (SNPs) across the Neuregulin 3 (NRG3) gene significantly associate with smoking cessation outcomes in two independent cohorts of smokers.104 We now have new evidence that SNPs previously identified to increase NRG3 expression are significantly associated with nicotine withdrawal phenotypes in smokers. Our published murine experiments104 demonstrate that this increased NRG3 expression may be responsible for affective nicotine withdrawal (WD) phenotypes in particular: (1) chronic nicotine and 24hWD increase mRNA and protein expression of NRG3 and it's receptor, ErbB4, in the ventral hippocampus, (2) genetic interruption of NRG3 signaling blocks expression of nicotine WD anxiety-like phenotypes in the Novelty-induced Hypophagia Test, a model shown to be dependent upon ventral hippocampal function, and (3) inhibition of ErbB4, the NRG3 receptor, by Afatinib reduced anxiety-like behaviors during WD in this same behavioral model.While this is persuasive evidence for the role of ventral hippocampal NRG3 signaling in modulating affective nicotine WD phenotypes, little is known regarding the precise mechanisms through which NRG3 and nicotine interact. Therefore, the overall goal of this proposal is to systematically investigate the cell-specific role of the NRG3- ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To accomplish this, we are posing three central questions: 1) Is NRG3-ErbB4 signaling between pyramidal cells and interneurons in the hippocampus necessary for expression of nicotine WD-induced anxiety?, 2) Does the location of nicotinic receptors and NRG3/ErB4 dictate chronic nicotine and 24hWD effects on cellular cascades and glutamatergic input?, and (3) How does nicotine-mediated NRG3-ErbB4 signaling regulate the activity of CCK+ and PV+ cells to influence the dynamic properties of the hippocampal circuit? Our approach is significant because it combines collective genetic information from both human and animal studies to generate a translational, high-impact hypothesis examining the functional role of this signaling pathway within the specific cell-types of the hippocampus during nicotine and withdrawal. Completion of these studies will expand understanding of the complex interplay between genetics, circuit function, and behavior in order to develop better, more specific smoking cessation aids.
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1 |
2021 |
Bardo, Michael T (co-PI) [⬀] Ortinski, Pavel Ivanovich (co-PI) [⬀] Turner, Jill R. |
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. |
Functional and Genomic Signatures of Escalated Fentanyl Use
Project Summary/Abstract Misuse of opioids represents a substantial public and economic burden in the US and worldwide. The existing pharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled with behavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. While individual variability in opioid use have been acknowledged repeatedly in animal behavioral models, the genomic markers linked to neurobiological adaptations underlying such variability are not well understood. We argue that understanding the molecular background of individual differences in behavioral vulnerability to opioid use is critical for development of personalized pharmacogenomic approaches for OUD that may replicate clinical success of personalized cancer treatments. In line with this argument, we hypothesize that individual behavioral variability in escalation of fentanyl use is linked to systems level variability of genomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation of drug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administer opioids under extended access conditions. Based on the published literature and preliminary data, we propose three complementary Aims to monitor development of escalated intake at behavioral, functional cellular/network, and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intake emerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Finding evidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use. Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically, we will evaluate whether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassium channel families and the impact on neuronal output at single cell and network levels. The data collected as part of this aim will establish functional, neuronal drivers of vulnerability to escalated intake. Finally, Aim 3 compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to human opioid use databases. In this aim, we take advantage of cell-type specific RNA sequencing to evaluate both neuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex. This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test the translational relevance of our preclinical findings to a human sample. To characterize interactions at the behavioral, functional, and genomic levels of analysis, a unifying statistical framework is developed based on linear mixed models to examine the strength of bi-directional relationships between behavioral escalation of intake and molecular outcomes.
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0.961 |