Date on Master's Thesis/Doctoral Dissertation

5-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

McGee, Aaron

Committee Co-Chair (if applicable)

Guido, William

Committee Member

Guido, William

Committee Member

Bickford, Martha

Committee Member

Samuelsen, Chad

Committee Member

Hetman, Michal

Author's Keywords

Aggrecan; NGR1; parvalbumin; chondroitin sulfate proteoglycans; experience dependent plasticity

Abstract

In the developing visual system, a transient critical period demarcates when neural circuits are most sensitive to visual experience. In the mouse, the critical period occurs between approximately postnatal day(P) 19 to 32. Closing one eye (monocular deprivation, MD) within the critical period shifts ocular dominance (OD) to be more responsive to the open eye. Nogo-66 Receptor 1 (NGR1) limits OD plasticity to the critical period yet it remains unknown how OD plasticity propagates through primary visual cortex or by which mechanisms NGR1 utilizes to confine said plasticity. In primary studies, NGR1 was selectively deleted in different cortical layers to investigate the characteristics of OD plasticity. From these studies, we conclude that L4 regulates intracortical disinhibition to gate OD plasticity in visual cortex. First, I determined that OD plasticity advances faster in L4 than L2/3 or L5 but does not rely on a canonical cortical microcircuit for expression. Second, I examined the signaling mechanisms for NGR1. I determined that NGR1 does not operate through the TROY or LINGO coreceptors. Third, I focused on the maturation of perineuronal nets (PNNs), which contain ligands for NGR1, and for which there is substantial evidence that they are involved in the closure of the critical period. These extracellular structures are enriched in chondroitin sulfate proteoglycans (CSPGs) and predominantly ensheath inhibitory interneurons expressing parvalbumin (PV). Recent work has revealed that the gene for aggrecan (acan), a principal neuronal CSPG, is essential for the formation of PNNs and required to close the critical period for OD plasticity. We performed a genetic dissection of the requirement of acan to close this critical period by combining the conditional allele for the gene with different yet overlapping drivers for expression of Cre recombinase. Drivers that eliminated acan only in inhibitory neurons were not sufficient to sustain plasticity in adulthood but deletion of acan in all neurons permitted OD plasticity after the closure of the critical period. Therefore, I conclude that PNNs are not required to close the critical period.

Download

Share

COinS