Book Description

Abstract The effects of early life adversity on the development of circuits that support flexible decision-making by Alaina Wren Thomas Doctor of Philosophy in Neuroscience University of California, Berkeley Professor Linda Wilbrecht, Chair A large proportion of children in the United States experience childhood adversity, with over 50% reporting at least one adverse event. Early life adversity is strongly associated with increased risk for developing a number of physical and mental health disorders, yet the pathways linking childhood adversity to disease are not well understood. This dissertation explores how the early environment can influence developing neural circuits, with a particular focus on neural circuits that support flexible goal-directed decision-making. Cognitive development plays a significant role in mental illness and prospects for recovery. Flexible decision-making is a major cognitive function that is impaired across multiple neuropsychiatric disorders including bipolar disorder and schizophrenia, that is also critical in supporting behavioral change. In Chapter 2, I review my own collaborative work as well as work from others to describe the distinct developmental trajectories of sub-circuits that support flexible decision-making. I focus on frontal cortex dendritic spines and axonal boutons on afferents and efferents of the frontal cortex. These studies are motivated by the idea that identifying when these circuits grow and/or mature at the synaptic level will inform us when connections may be more vulnerable to adverse experiences and/or when interventions may have the greatest impact. I present in vivo imaging data that support previous classic findings that dendritic spines on frontal pyramidal neurons show loss of linear spine density, or in other words “prune,” across the adolescent period. However, I also present evidence that some long range frontal afferent and efferent circuits continue to grow and add synapses during the adolescent period, while others are pruning and stabilizing. These data refute the simple assumption that frontal circuits globally prune during adolescence, and raise questions about why some circuits show delayed growth. Next, in Chapter 3, I explore how maternal separation, a mouse model of early life adversity, affects flexible decision-making across the lifespan. I find that this early life manipulation leads to changes in decision-making specifically at a juvenile, but not adult life stage. I hypothesize that changes in decision-making strategies at the juvenile time point, a point of first independence, may serve as a cognitive adaptation to signals that indicate a harsh environment. Finally, in Chapter 4, I investigate how maternal separation and more specifically variations in maternal care, impact the development of four long range axons (two afferents and two efferents of the frontal cortex) that each play a role in flexible decision-making. I focus on changes at the adolescent life stage, based on differences in flexible decision-making at this age discussed in Chapter 3. I find that dorsomedial prefrontal cortex (dmPFC) axons that descend to target the basolateral amygdala (BLA) are specifically sensitive to the maternal separation manipulation and variations in maternal care, while the other three axons investigated show no relationship with early life care. Specifically, I found higher bouton density and smaller bouton size on dmPFC-BLA axons in maternally separated mice compared to controls. Additionally, bouton density on this projection correlated with maternal care measures, suggesting early maternal care (P1-10) may scale the later growth of this pathway (at P35). Variations in maternal care may serve as an indicator about the type of environment offspring are growing up in. These data support the idea that the brain can sample the statistics from the early environment and tune specific circuits to adapt to that environment. Taken together, this thesis provides new insights about the development of circuits that support flexible decision-making. Importantly, I demonstrate how early life adversity impacts specific circuits at the synaptic level. These experiments provide high-resolution data that aims to help inform intervention and treatment strategies to promote healthy child development.