Early life stress (ELS) is associated with a significant increase in risk for developing stress-related pathology, including depression, anxiety, and post-traumatic stress disorder (PTSD). However, the mechanisms by which ELS increases the risk for pathologies is not well understood. To study the effects of ELS on postnatal development we take advantage of a well characterized neuronal circuit, the auditory fear circuit. Here we investigate the mechanisms by which early life stress (ELS) alters aversive learning in the developing mouse. We hypothesize that early life stress is accelerating the developmental maturation of the basolateral amygdala (BLA), but not the prelimbic (PL) subregion of the medial prefrontal cortex.
In Aim 1, we demonstrate that early life stress leads to suppression of fear expression during pre-adolescence (postnatal day 21). Our data suggests that ELS accelerates differentiation of parvalbumin positive (PV+) interneurons in the BLA. These neurons could be causing hypoactivation of the BLA, resulting in the observed decreased fear phenotype. Through optogenetic inhibition of PV+ neuron in the BLA we were able to rescue the fear expression deficit in our ELS mice.
In Aim 2, Experiments 2.1 and 2.2, anatomical and functional connectivity of PL to BLA and BLA to PL projections will be assessed. Using retrograde tracer injections and in-vivo electrophysiology during early postnatal development (approx. postnatal days 16-30) we will test how ELS alters this cortico-limbic connectivity. We expect ELS animals to have accelerated anatomical and functional connectivity of BLA to PL projection, but delayed PL to BLA. In Experiment 2.3, we attempt to induce decreased fear expression in unstressed mice through acceleration of PV+ maturation in BLA. Furthermore, we attempt to recover fear expression in stressed mice through a pharmacologically induced acceleration of PL to BLA connectivity.
In Aim 3, we delineate plans for postdoctoral research, including the identification of a postdoctoral fellowship mentor and institution, and the use of calcium- imaging to tract neuronal ensembles during a behavioral assay. During the K00 phase the applicant proposes to acquire the remaining writing, presenting, networking and career skills necessary for a successful transition to an independent researcher. Through the Research and Training Plan, the applicant will deepen her theoretical and conceptual knowledge of developmental, cognitive and neural mechanisms underlying learning and behavior, while acquiring advanced system level techniques, including in-vivo electrophysiology, calcium- imaging, as well as perfecting coding and data analysis. The training acquired through this grant will allow the applicant to use a multilevel approach when addressing developmental questions within the applicant's future lab. Overall the work proposed will add a wealth of knowledge regarding the mechanisms by which early life experiences lead to differences in learning throughout development. It will also provide insight into circuit vulnerabilities that could help explain why early life trauma increases the propensity to emotional disorders.
Acute traumatic events and/or prolonged stress incurred early in life increase the risk of developing anxiety and depressive-like behaviors in both humans and animal models. This project will investigate the effect of early life stress on neural development and their consequences on circuit activation in during early postnatal development (pre-adolescence and early adolescence). Understanding how early life stress is impacting the postnatal developing brain could provide insight into possible biomarkers and predictors of increased risk to psychopathologies.
| Goodwill, Haley L; Manzano-Nieves, Gabriela; LaChance, Patrick et al. (2018) Early Life Stress Drives Sex-Selective Impairment in Reversal Learning by Affecting Parvalbumin Interneurons in Orbitofrontal Cortex of Mice. Cell Rep 25:2299-2307.e4 |
