Thursday, November 21, 2024
11/21/2024
Abstract There are reported sex differences in both the propensity to develop nicotine addiction and the efficacy of treatment interventions pointing to women as a particularly vulnerable population. Thus, understanding how sex differences in nicotine effects on the brain arise is a critical unanswered question in addiction neuroscience. Dopamine signaling within the nucleus accumbens is involved in initiation and maintenance of nicotine addiction, and dopamine release is sensitive to heavy modulation by acetylcholine through nicotinic receptors located on dopamine axons. Acetylcholine modulation of dopamine release at distal axon terminals is discussed extensively, and better understanding this interaction has driven experimentation across fields - critically, we find that this interaction is not present in adult intact females. However, our preliminary data show that this effect is rescued in females after ovariectomy, suggesting that ovarian hormones play a critical role in modulating acetylcholine effects on dopamine release; the goal of this proposal is to define where this modulation occurs and how this influences nicotine effects on this system. This proposal is guided by the overarching hypothesis that estradiol acts acutely through estrogen receptors located within acetylcholine interneurons in the nucleus accumbens core to strengthen acetylcholine effects on dopamine release. However, in intact females, long-term estrogen modulation of this interaction leads to an inability of modulators – such as nicotine – to further enhance dopamine release. This is supported by robust preliminary data showing that in males and ovariectomized females estradiol effects on dopamine release can be blocked via nicotinic receptor antagonism. In intact females, estradiol effects on dopamine release are blunted and insensitive to nicotinic receptor agonists and antagonists. This fellowship application describes a robust training plan to investigate the microcircuitry of how ovarian hormones mediate dopamine-acetylcholine interactions and the role that this plays in attributing motivational value to nicotine-associated cues. Aim 1 will define the estrogen receptor subtypes contributing to estrogen effects on acetylcholine-dopamine interactions. Aim 2 will determine how estrogen receptors regulate acetylcholine release using optical acetylcholine sensors. Aim 3 will use genetic approaches to knock out estrogen receptors from acetylcholine interneurons and determine how this affects the ability of dopamine to respond to nicotine and nicotine-associated cues in operant tasks. This plan expands on my current electrophysiology expertise to train me on optogenetic tools and optical imaging and gives me the career development opportunities necessary to propel me to a successful placement in a tenure-track position at a respected institution. Together, the results of this project will critically inform the addiction field on the effects of ovarian hormones on dopamine interactions in the nucleus accumbens core, providing new directions for more effective treatment of addiction. .
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