Developmental and Sex-Dependent Targets for Prevention after Early Life Stress

点击翻译按钮获取中文摘要

This project aims to elucidate developmental neurocircuitry effects of early life stress (ELS) in an animal model. Growing clinical evidence suggests that many ELS-attributable mental illnesses manifest in adolescence after an apparent latent period, and are unresponsive to traditional therapies. Our lab and others have further shown that these ELS-attributable effects follow a different time-course in males and females. Therefore, there is a need to understand aberrant developmental mechanisms that likely require targeted intervention and treatments in ELS-exposed individuals. Our recent studies revealed that ELS causes overexpression of the glutamatergic NMDA receptor subunit NR2A in the prefrontal cortex (PFC) of male adolescents. Importantly, targeted manipulation of NR2A protected ELS-exposed males from behavioral deficits such as increased anxiety-like behavior. Our preliminary data further suggests that NMDAR changes and increased anxiety appear earlier in development in ELS-exposed females, compared to ELS-exposed males. Understanding the developmental trajectory between ELS exposure and altered PFC receptivity is necessary to effectively intervene with preventative treatments. PFC receptivity is largely driven by glutamate activity in the PFC from limbic inputs, therefore the impact of ELS on corticolimbic connectivity requires delineation. The proposed project aims to target developmental origins of PFC dysfunction in ELS-exposed males and females. The central hypothesis is that ELS alters development of PFC innervation and glutamate receptivity in a sex-specific manner. These studies will first reveal sex-specific ELS effects on corticolimbic connectivity (Aim 1) and innervation (Aim 2) throughout development. Effects of ELS on PFC connectivity will provide translational data that can be juxtaposed with recent clinical findings in ELS-exposed boys and girls and will elucidate a likely mechanism behind how ELS leads to receptor alterations later in life. Aim 3 will investigate the developmental trajectory of post-synaptic NMDA receptor subunit changes after ELS. We will also determine critical periods when deactivating PFC NR2A function can prevent ELS-induced behavioral deficits later in life. Since recent evidence suggests that females show earlier ELS-attributable changes than males, we will determine whether females require an earlier intervention than males to prevent ELS-induced behavioral dysfunction. Together, these studies will fill critical gaps in knowledge about the developmental and sex-specific nature of ELS effects on PFC circuitry and are expected to have significant impact on the development of specific targets for prevention in ELS-exposed populations.