Developing a pre-clinical model to study the interaction of female pubertal hormones and early-life stress in vulnerability to anhedonia

2024 Award: $44,577

This preclinical study aims to explore the interaction between chronic stress and reproductive hormones during puberty in females and investigating their role in vulnerability to depression in adulthood. Focusing on anhedonia, or the inability to experience pleasure, we will investigate the impact of these interactions on cortico-striatal circuits, offering insights into potential resilience factors and critical windows of vulnerability, thus advancing our understanding of major depressive disorder in women.

Need/Problem: After puberty, women present twice the prevalence of major depressive disorder than men. The mechanisms by which reproductive hormones shape vulnerability to chronic stress-induced depression during puberty in women remain unexplored.

Grant Summary: We will study how chronic stress interacts with reproductive hormones in females to shape vulnerability to an anhedonic-like phenotype in adulthood. To this end, we will utilize a combination of chronic mild stress and pharmacological puberty blockade in mice. Furthermore, we will also focus on testing the hypothesis that anhedonic-like behaviors emerge from stress-induced impairment on puberty-sensitive cortico-striatal circuits.

Goals and Projected Outcomes: The study will provide data on the role of puberty in shaping vulnerability to anhedonia in female mice. Further, we will test whether estrogen signaling in fronto-striatal circuits is associated to resilience.

Antonio Florido, PhD

Grant Details: Early-life stress has been shown to be an important risk factor for major depressive disorder (MDD). This proposal aims to develop a pre-clinical model of chronic stress during puberty onset early in life that leads to the development of anhedonic-like behaviors in adulthood. To accomplish this, mice will undergo chronic stress exposure before and after puberty, and their responses to a sucrose preference test will be monitored using a custom-made lickometer that will allow us to track licking responses in group-housed mice in their home cage. During puberty, the medial prefrontal cortex undergoes significant development. The emergence of reproductive hormones and exposure to stress have been shown to regulate maturation of fronto-striatal connections. Therefore, we aims to lay the foundation to study the role of medial prefrontal cortical neurons (mPFC) that project to the ventral striatum (VS) that are puberty-sensitive and modulated by chronic early-life stress. By examining these interactions, the project seeks to identify critical windows of vulnerability and resilience in the development of MDD in females.