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Differentially Modulating the VTA: A Role for delta-mediated GABAA Tonic Inhibition and the Stress Neuropeptide CRF during Ethanol Intake
Başlık:
Differentially Modulating the VTA: A Role for delta-mediated GABAA Tonic Inhibition and the Stress Neuropeptide CRF during Ethanol Intake
Yazar:
Darnieder, Laura M., author.
ISBN:
9780438030909
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (177 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Jamie Maguire; Klaus Miczek Committee members: Joe DeBold; Maribel Rios; Uwe Rudolph.
Özet:
Binge drinking is a prevalent form of short-term alcohol consumption resulting in blood alcohol levels of 0.08 g/dl. Although more frequent in men, binge drinking has become increasingly common in women. To this end, sex-specific changes are evident in underlying mesocorticolimbic circuitry, including the modulation of GABAergic inhibitory neurotransmission. Broadly speaking, extrasynaptic GABAA receptors (GABAARs) incorporating the delta subunit mediate tonic inhibition, while synaptic gamma2-containing GABAARs underlie fast, phasic inhibition. GABAARs incorporating the delta-subunit-containing are sensitive to the low-to-moderate alcohol doses typically found in binge drinking. Critically, they can also be modulated by ovarian-derived hormones, indicating possible sex-specific differences in delta-mediated inhibition. Given this, it was hypothesized that delta-subunit-containing GABAARs would play a sex-specific role in male and female binge-like drinking in a region critical to mesocorticolimbic circuitry---the ventral tegmental area (VTA). Initial qPCR results revealed a nearly two-fold increase in Gabrd transcript levels in female VTA relative to males, but no sex-specific Gabrg2 differences. These baseline differences were also functionally evident, with increased levels of tonic inhibition in female VTA. To determine if Gabrd removal would sex-specifically alter binge-like drinking, both male and female floxed Gabrd and floxed Gabrg2 mice were given bilateral injections into the VTA of either AAV-Cre-GFP or AAV-GFP for Cre-mediated Gabrd or Gabrg2 excision. Mice were subjected to one cycle of a binge-like drinking protocol, with results indicating that female subjects with VTA-specific delta-excision had decreased binge-like alcohol intake. delta-excision had no significant effect on male binge-like drinking and there were no differences in binge-like intake in either male or female gamma2-excised subjects. While the posterior VTA had the highest viral reporter expression and is also known to contain a population of GABAergic interneurons, later cell-type-specific analysis revealed no sex-specific difference in parvalbumin-positive interneurons/delta subunit colocalization. Although these results demonstrate increased baseline delta-mediated tonic inhibition in the VTA of females is asymmetrically important in low-to-moderate binge-like drinking, a better understanding of underlying cell type will be the focus of future work.
Notlar:
School code: 0845
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678049.1) | 678049-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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