Extrinsic and Intrinsic Factors Impacting Local Circuit Inhibition in the Neocortex

Abstract

Neuronal circuits controlling our perception and behaviors are radically shaped by experiences during early critical periods. For example, early life stress (ELS) has been linked to enduring negative behavioral consequences in humans and compromised structure/function of the prefrontal cortex (PFC). Parvalbumin (PV) expressing interneurons are particularly vulnerable to genetic and environmental insults associated with cognitive disorders. The maturation of PV inhibition is also pivotal for initiating critical periods in primary sensory cortices. The goal of this thesis is to examine how the functional maturation of PV inhibition is affected by intrinsic and extrinsic factors with a particular focus on the developing mouse medial PFC (mPFC). First, I examined cell-intrinsic and extrinsic factors that might regulate the maturation and organization of local circuit inhibition. Assisting Yohei Kobayashi, we demonstrated that PV cell-intrinsic Clock genes underlie the maturational trajectory of PV cell-mediated inhibition and hence critical period timing. In collaboration with Mohammed A. Mostajo-Radji from Paola Arlotta’s lab, using the approach of in vivo reprogramming of cortical pyramidal neurons, we showed that postsynaptic projection neuron identity instructs afferent connectivity from inhibitory PV inputs in a pyramidal class-specific manner. Next, I established models for studying the impact of ELS in both C57BL/6J and monogamous, bi-parental wild mice (Peromyscus polionotus). Based on anatomical and physiological results, we discovered sex-specific effects of poor parental care on PV interneurons in the mPFC, and their potential involvement in regulating anxiety behaviors in females. Our lab had previously defined a critical period for the anxiolytic benefits of acquiring an acoustic preference in the mPFC upon early music exposure. Here, I found the emergence of PV-cells in the mPFC normally matches this critical period window. Finally, I tested whether PV-cell maturation controls such critical period plasticity in the mPFC by examining acoustic preference formation in two genetic models (Otx2, BDNF Val/Met) exhibiting delayed developmental trajectories. In contrast, the anxiolytic window for early music exposure was shifted earlier in females experiencing ELS. Notably, this effect was replicated in both mice and humans, suggesting a conserved mechanism and potential opportunity for therapeutic intervention after ELS.