Maternal Influence Over Prefrontal Cortex and Transition to Independence - Revision - 2

New York University School Of Medicine, New York NY

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Abstract

Abstract Infant attachment occurs in species that require parental care for survival, such as children and rodents, and permits the use of animal models to explore mechanisms for both attachment and attachment dysfunction. Here we propose to use infant rats to understand the brain mechanisms for the attachment figure to reduce fear in the infant (i.e. parent functioning as a safe base). Using an approach involving behavior and brain assessment at the network level (communication between brain areas), circuit level (specific set of neurons) and molecular level (events within neurons) to ask, what is different during learning about a threat when the infant is alone or with the mother? How does the infant’s brain lose the ability to use the mother as a safe base with age or pathology? Since clinical literature shows the parent has limited functions as a safe base when the infant experiences rough treatment from the parent, we ask how is it possible for the brain to lose processing of the parent as a safe base? To address these questions, we use odor-shock fear conditioning because it is a robust neurobehavioral system across children and infant rats, has proven translational value, and the neural network is well-defined. The first five years of this award has shown that, during a sensitive period, maternal cues interface with the threat learning circuit in at least two ways. First, the mother’s presence changes the infant’s network processing of threat by adding in a node (brain area), the ventral tegmental area (VTA), which suppresses another node, the basolateral amygdala (BLA) via dopamine release (DA). Second, the mother’s presence suppresses pups’ immature cascade of intracellular signaling molecules (e.g., ERK) critical for plasticity underlying learning and memory. We expand this research on typical-rearing to infants that have experienced rough maternal care and behaviorally show significant reduction in using the mother as a safe base. We ask how this adversity-reared infant’s brain differs from the typically-reared infant within our behavior-to-neuron-to-molecule approach. In Aim 1 we describe the brain’s global network changes following adversity, while in Aim 2 we describe amygdala’s BLA intracellular molecular cascade. In Aim 3, we focus on causation and chart the VTA-BLA neural circuit using optogenetics to manipulate neurons with a laser light and electrophysiology to record neural activity. This supplement builds on Aim 3 by using transgenic animals (genetic manipulation to permit laser light to manipulate dopamine neurons) that allow direct and specific modulation of dopamine neurons to permit us to precisely define the role of dopamine within the VTA-BLA circuit and used as a format to mentor a postdoctoral fellow. The significance of this research is that it explores network and circuit development, asking how a brain changes to accommodate behavioral transitions required during maturation. We use typical development, but also capitalize on rearing-induced atypical development when circuit transitions are compromised.