Early life stress impacts molecular and network properties that bias the recruitment of pro-stress BLA circuits

Tufts University Boston, Boston MA

Investigators

Abstract

Emotional stress is a substantial risk factor for numerous psychiatric illnesses, and distressing events during adolescence are particularly salient. Adverse childhood experiences (ACEs) negatively impact mental and physical health and drive maladaptive behaviors, however the neural mechanisms underlying these outcomes are not comprehensively understood. Many of the disorders associated with ACEs involve altered activity within brain regions involved in emotional processing, corresponding with aberrant behaviors. To better understand how networks become dysfunctional and impair emotional processing, this proposal aims to investigate the impact of early life stress (ELS) on adult local field potential (LFP) network states relating to valence assignment and stress-associated emotional processing, and to reveal the underlying molecular mechanisms and circuitry. We hypothesize that ELS results in divergent network states corresponding with the recruitment of negative valence pathways through a mechanism involving BLA PV interneuron dysfunction. Opposing network states govern different behavioral outcomes, and our lab has demonstrated that divergent behavioral states involve selective activation of unique downstream pathways. Fear and safety are associated with distinct LFP network states, and our lab has shown that manipulating the activity of a fractional population of GABAergic parvalbumin (PV) interneurons is sufficient to entrain these conflicting states. Our preliminary data suggests that ELS alters the development and function of PV interneurons in this region, the basolateral amygdala (BLA), which is critical for valence processing and emotional regulation. Further, ELS induces divergent social behavior and LFP network states associated with predatory stress. The goal of the current proposal is to investigate the mechanisms mediating the impact of ELS on BLA network and behavioral states. This project will build on our novel preliminary data to investigate the effects of ELS on valence processing. To observe how these changes in LFP network state impact information routing through the BLA at the cellular level, the membrane and synaptic properties of PV interneurons and projection-specific principal neurons will be monitored using whole cell patch clamp, retrograde tracing, and optogenetics. To observe how ELS impacts information routing through the BLA at the network level, calcium imaging of BLA projectors from separate pathways associated with positive and negative valence will be performed in vivo during pro-stress paradigms. This project will advance our understanding of how developmental stress impacts the routing of emotional information through the brain, with the potential to advance the development of novel, targeted therapies for the treatment of psychiatric disorders in adults who have experienced ACEs. This project is sponsored by four experts who will each provide guidance interpreting results and designing experiments relating to their specialties and the project as a whole, in addition to providing career advice. We have developed a tailored training plan to assist with achieving my research goals and to ideally position me for a career in academic research.