Our Mission
The Bale lab’s research mission is centered on defining the mechanisms involved in how stress increases neuropsychiatric disease risk across the lifespan.
Our Approach
Our preclinical mouse models start with points in the preconception environment when stress alters germ cell maturation and reproductive processes that impact embryonic and fetal development. We have developed in vivo and in vitro models to isolate novel pathways involved in stress transmission, identifying points during gestation when the brain is uniquely vulnerable. Pregnancy itself is a metabolically demanding environment where embryonic and extraembryonic (placental) differentiation occurs at a dynamic rate and where differences in environmental cues can produce significant changes in the wiring and function of the brain.
We emphasize the value of translational research by moving from our preclinical models into human studies, especially focusing on vulnerable populations. This research has deepened our understanding of the long-lasting effects of adverse life experiences and has provided potential biomarkers, extracellular vesicles, for neuropsychiatric disease.
Current Research Areas
Extracellular vesicles as biomarkers of trauma exposure and PTSD risk
These studies are funded by the NIMH (MPI R01, MH129495). Exposure to trauma is linked to long-term mental illness, especially for posttraumatic stress disorder (PTSD) in women. The timing of trauma experienced during development is influential. Our previous studies utilized an unbiased proteomic approach in extracellular vesicles (EV) isolated from adult women and identified a unique EV protein signature linked to a 17q21 gene cluster that was associated with skin keratinocytes, particularly Merkel cells. This change in EV proteins was only detected in the women who had experienced trauma in adolescence. Merkel cells are neuroendocrine cells in the skin that respond to light touch stimuli. The current grant, in collaboration with Dr. Tanja Jovanovic at Wayne State University, will investigate a 30-year prospective longitudinal cohort of Black individuals who have been followed since birth in Detroit. The cohort includes data on trauma experienced during adolescence, allowing us to track their transition into young adulthood and gain insights into the mechanisms and biomarkers associated with PTSD risk.
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The overarching hypothesis is that trauma occurring during the sensitive period of adolescence specifically influences distinct biological pathways along the threat-response axis involving the skin’s Merkel cell-neurite complex. These changes may serve as accessible biomarkers related to PTSD risk. Our studies will examine biomarkers through EV proteomics and investigate Merkel cell involvement in EV production and the alteration of behaviors relevant to PTSD risk using a preclinical mouse model of pubertal multimodal sensory stress.
Key Publications
Stress modeling of the human sperm sncRNA transcriptome and causal importance of dynamic miRNA in reproductive and developmental outcomes
This project, funded by the NICHD (MPI R01, HD105771) in collaboration with Dr. Neill Epperson, aims to investigate the effects of male perceived stress exposures on reproductive outcomes, gestational development, and offspring health and disease. We previously found significant changes in the composition of sperm sncRNA content in a healthy student cohort. Now, we plan to expand our study to a larger and more diverse population and explore the additional influence of adverse childhood experiences (ACEs) on current perceived stress reports associated with changes in sperm sncRNA and changes in sperm physiology, including motility. Using a preclinical mouse model, we will examine the causal importance of the changed specific miRNAs by manipulating their expression in mouse zygotes and examining embryo development, implantation, and brain developmental rates.
Key Publications
Placental epigenetic mechanisms contributing to sex-specific impacts of maternal stress on fetal development
In these studies funded by NICHD (R01 HD097093), we utilize a preclinical mouse model of stress early in pregnancy to investigate sex-specific placental transcriptional regulation. Understanding the mechanisms through which maternal stress during pregnancy influences development in a sex-specific manner is crucial for identifying factors that can predict disease risk or resilience. We hypothesize that sex differences in placental function result in sex-specific transplacental signals that impact the developing fetal brain. These sex differences are attributed to the involvement of sex chromosomes. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causally linked to programming the male-specific stress phenotype by regulating the histone repressive mark H3K27me3. Our research also indicates that similar biochemical and molecular outcomes are predicted by fetal sex in human placental tissue.
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Key Publications
Paternal stress epigenetic programming of offspring neurodevelopment
These studies are funded by the NIMH (R37, MH108286). Parental lifetime exposures to perturbations such as stress have been linked with an increased risk for neurodevelopmental disorders. The mechanisms by which paternal lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. However, the transmission of these epigenetic marks to the next generation can significantly elevate disease risk and, if programmed into the germline, can affect future generations as well.
Using a preclinical mouse model of male stress experience, we can examine molecular mechanisms involved in signals interacting with sperm during maturation, how sperm carry such information to fertilization, and ultimately, what impact this has on embryo and fetal development. These studies are building on our prior scientific accomplishments, including the identification of the epididymal epithelial cell as the reproductive cell type that transmits paternal stress to the sperm, resolving the extracellular vesicle as the secreted signal that impacts embryo development, and the broad conceptualization that the allostatic state of a somatic cell is maintained by epigenetic mechanisms involving the GR and stored in the mitochondria.
Key Publications
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