Sculpting Amygdala-Prefrontal connectivity and adult emotional cognition by Amygdala perturbation during adolescence – Sculpt-Amy

Emotional cognition, based on learning about significant events, their temporal relationship, and predictive values is fundamental for adaptive behavior, and relies critically on a reciprocally connected network formed by basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Developmental perturbations of this network, e.g. in adolescence, can predispose to neuropsychiatric, emotion-related disorders later in life. The amygdala as an early maturing brain structure is in a key position to influence the ongoing maturation of, and its connectivity with, the late-maturing mPFC. Whether the amygdalar functioning in adolescence can sculpt BLA-mPFC interconnectivity and its ability to support appropriate emotional-cognitive behavior in adulthood is an open question. To pinpoint the amygdala’s role, we used an amygdala-restricted manipulation of tuberous sclerosis complex 2 (Tsc2), a risk gene for neuropsychiatric disorders, with ascribed roles in shaping synaptic function and plasticity, excitatory/inhibitory (E/I) balance, and emotional and social behaviors. Our finding that Tsc2-knockdown (kd) in BLA from early adolescence onwards alters fear regulation and increases basal mPFC activity in adult rodents strongly supports such an instructive role of the amygdala. To go further, we will address the following questions: Does transient BLA Tsc2-kd during adolescence define a critical period for the wiring of BLA-mPFC connectivity? How does it affect BLA microcircuitry and functional long-range connectivity? How do these alterations modify emotional cognition later in life, and does this differ between sexes, given the peripubertal character of adolescence? We will employ a state-of-the art strategy for temporally restricting Tsc2-kd during adolescence and follow its impact into adulthood. Our complementary expertise enables multimodal analyses in rodents. At the cellular level, we will investigate synaptic and circuit functions, signaling components, excitatory/inhibitory balance, and functional properties of micro- and long-range circuits in BLA-mPFC networks. At the systems level, we will longitudinally track connectivity in large-scale circuits using functional MRI, and correlate this with structural connectivity from diffusion MRI. We will also comprehensively assess adult behaviors, including fear generalization, extinction, and temporal expectancy of fearful events and their neural correlates. Immediate early gene mapping will identify alterations in fear memory allocation.BLA-mPFC functional connectivity will be analyzed though coherence of neural oscillations in behaving animals and will be correlated with fMRI. By providing novel mechanistic insights on how amygdala perturbations during adolescence influence wiring of maturing networks to shape adult emotional behavior, our work can inform critical period interventions to alleviate psychopathological alterations later in life.