Abstract

The mesolimbic dopamine (DA) system contributes to reward and reinforcement learning for ethanol (EtOH). The nucleus accumbens (NAc) receives DA input from the ventral tegmental area (VTA) encoding rewarding information. Acute EtOH increases NAc DA levels, and this DA response is attenuated with chronic EtOH exposure. Furthermore, chronic EtOH results in reduced DA release, increased DA clearance and presynaptic D2-type auto-receptor sensitization. Further research into EtOH-induced neural adaptations that modulate NAc DA release is explored herein, including changes in cholinergic interneurons (CIN), which are known regulators of DA transmission. One potential class of regulators are immune related cytokines, that can be initiated by peripheral and central changes in inflammation, induced by EtOH interactions with peripheral immune cells. One cytokine that is known to regulate DA release is granulocyte colony stimulating factor (G-CSF), which is a glycoprotein growth factor associated with neutrophil progenitor proliferation. G-CSF but also known to influence dopamine release and reward behavior. The mechanism for G-CSF DA enhancement is unknown and investigated in the present work. Further, the projects examines adaptations in this system from chronic intermittent ethanol (CIE) exposure in mice. G-CSF enhanced NAc DA release, which is consistent with prior studies. The G-CSF receptor was observed in DA and GABA neurons of the VTA, but also in CINs in the NAc. Next, G-CSF was applied while recording firing of each of these neuronal subtypes. No clear consistent effect on firing was observed, though increases in DA firing were observed in some cells, suggesting that DA responsivity may be in specific subpopulations. Importantly, we observed increased fluorescent calcium signals after G-CSF in GCaMP labeled terminals from the VTA (putative DA terminals), which were attenuated by nAChR blockade. Also, nAChR blockade resulted in a lack of G-CSF effect on DA terminals. These results suggest that G-CSF acts to enhance nAChR effects, perhaps through enhanced acetylcholine release, to drive DA potentiation. Last, CIE resulted in exacerbated G-CSF effects in female mice, and attenuated G-CSF effects in male mice. Future studies will benefit from examining sex dependent differences in G-CSF on DA terminals that underlie this adaptation.

Degree

MS

College and Department

Life Sciences; Cell Biology and Physiology

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2025-07-18

Document Type

Thesis

Keywords

alcohol, dopamine, G-CSF, cholinergic interneuron, nucleus accumbens, ventral tegmental area

Language

english

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