Neuronal innervation dynamics in uterine function and maternal age-associated miscarriage

The global trend toward delayed motherhood has led to a decline in birth rate and significantly increases the
chance of obstetric complications including miscarriage and pre-term birth. Traditionally, age-related miscarriages have been ascribed to oocyte chromosomal abnormalities. However, evolving research underscores the influence of oocyte-independent factors in reproductive aging. A majority of miscarriages, exceeding 80%, occur in the first trimester, stemming from intricate challenges in embryo implantation and placental development.

Central to successful pregnancy is innervation of the uterus, which undergoes significant transformation across
the menstrual cycle and pregnancy. Neuronal innervation plays a pivotal role in reshaping the uterine milieu by
signaling to diverse endometrial and immune cell types. Ablating uterus-innervating neurons causes infertility,
underscoring the importance of these neurons in supporting pregnancy. Yet, the impact of advanced maternal
age on uterine neuronal innervation and its ramifications for miscarriage rates, alongside other pregnancy
complications, remains enigmatic. This proposal addresses three interconnected, yet independent aims focused
on the neural mechanisms implicated in age-associated miscarriages. First, the proposal aims to construct a
comprehensive neuro-uterine atlas delineating neuronal subtypes innervating the uterus, elucidating how innervation patterns and transcriptome profiles evolve with age. Second, the proposal aims to implement cutting-edge tissue clearing techniques on extracted uteri to discern alterations in uterine innervation patterns and signaling across the rodent estrous cycle and the first trimester of pregnancy. Finally, the proposal aims to
manipulate uterine innervation from peripheral sensory neurons to impair or rejuvenate reproductive function in
young and aged mice, respectively. This interdisciplinary proposal will comprehensively explore the intricate
relationship between maternal age, neuronal innervation dynamics, and obstetric outcomes. By delving into the
neural underpinnings of age-associated miscarriage, the proposal aspires to produce crucial mechanistic insights that hold promise for enhancing our understanding of reproductive challenges associated with advancing maternal age.