Brain Plasticity, Extracellular Matrix Molecules, and Advancements in Calcium Imaging of Neural Activity

Abstract

The brain possesses an astounding ability to acquire new memories and retain these memories throughout our lifespan. Consequently, neuronal networks in the brain must exhibit flexibility, or plasticity, adapting and strengthening neuronal connections in response to new learning. Simultaneously, the brain must maintain sufficient stability to solidify the neural connections that underpin long-term memory. The lattice-like structures known as Perineuronal Nets (PNNs), which mainly surround a subset of inhibitory interneurons in the cerebral cortex, are believed to dampen brain plasticity, thus facilitating long-term information retention. In this thesis, I perturb the PNNs by genetically knocking out the PNN component aggrecan solely in these interneurons. Through electrophysiological and behavioral assays and computational modeling, I investigate the potential effects of this perturbation. My findings indicate that while removing aggrecan in developing subjects eliminates PNNs without affecting interneuron function, its removal in adults significantly alters plasticity, suggesting that compensatory mechanisms may mitigate the effect of losing aggrecan and thus PNNs in the germline. These insights shed light on the intricate mechanisms behind memory formation and maintenance in the brain and could contribute to understanding or developing treatments for diseases of the brain, such as Alzheimer's disease. Finally, I develop soma-targeted, genetically-encoded calcium indicator constructs that allow for precise measurement of neuronal activity at the single-cell level in live animals.