Lillian Brady, Ph.D., has received a 2023 NARSAD Young Investigator Grant for her study, “Estradiol regulation of dopamine release dynamics through subunit-specific nicotinic receptor activation underlying sex-specific behavior.”
This study explores the mechanisms by which estradiol influences dopamine release patterns, specifically examining subunit-specific nicotinic acetylcholine receptor (nAChR) activation.
The goal is to understand how these processes relate to sex-specific behavioral responses in the context of substance use disorder (SUD).
“The experiments proposed within this grant will help me to establish my independent research program and follow up on preliminary data that suggests that cholinergic interneuron regulation of dopamine release in the NAc is sex-specific and may underlie sex differences in motivated behavior,” says Brady.
The Heersink communications team sat with Brady to learn more about her research and how these findings contribute to our understanding of sex-specific behavioral responses in substance use disorder.
Q: What motivated you to pursue this specific research topic, and what are the project's main objectives?
The significant difference in the occurrence and outlook of substance use disorder in females, coupled with the lack of information about the distinct neural pathways contributing to gender differences in SUD, highlights the critical need for investigating dysregulated neural reward circuits in female subjects.
To fully understand the mechanism by which estradiol influences neurotransmission via nAChRs and its relevance to substance use disorder, this proposal aims to address the following specific objectives:
1. To test the hypothesis that extracellular calcium levels contribute to estradiol potentiation of dopamine release through nAChR activation. Utilizing pharmacology combined with ex-vivo fast-scan cyclic voltammetry and optogenetics, we will investigate sex differences and estradiol regulation of extracellular calcium effects on endogenous and exogenous nAChR activation.
2. To test the hypothesis that estradiol potentiation of dopamine release alters sex-specific behavioral responses to sensory reinforcement through α4-nAChRs. Using operant conditioning in male, naturally cycling, and ovariectomized α4 knockout mice, we will examine sex differences in the effects of nicotine on dopamine release underlying reinforcement learning.
Q: How do you envision the outcomes of your research benefiting the field?
Collectively, this project will define how sexual dimorphism in the regulation and function of the dopamine system contributes to variations in reward learning. This work will expand our understanding of sex differences in the neural control of motivation - which is dysregulated across a wide range of psychiatric disease states - and provide targets to correct deficits in this system in both male and female subjects. Understanding the regulation of these processes in both sexes is critical to improving treatment outcomes and the overall quality of life for individuals living with SUD.
Q: Could you share any insights into how the grant will be allocated and utilized to support your research?
Securing funding through the NARSAD Young Investigator Award Grant is crucial for the success of this project, providing essential support for the proposed research. The allocated funds from the Brain and Behavior Research Foundation (BBRF), amounting to $35,000 per year, will play a pivotal role in covering expenses associated with outsourcing the production of specialized AAV vectors outlined in the proposal. Additionally, these funds will be utilized for acquiring and breeding transgenic/mutant mice, as well as covering costs related to necessary equipment, reagents, and supplies.