UCLA

Neural computations rely on the complex spatiotemporal dynamics that emerge from ensembles of interconnected neurons in neocortical microcircuits. It is widely accepted that experience—more precisely, previous patterns of neural activity—shapes neural circuits through activity-dependent modifications of synaptic strength. A key feature defining the behavior of any given neural circuit is the pattern of synaptic weights that connect the individual neurons that comprise the circuit. Yet it remains poorly understood how cortical microcircuits learn to perform different computations and how various interacting forms of plasticity contribute to this experience-dependent reorganization. In the current dissertation, I examine some of the cellular, synaptic, and network mechanisms that underlie experience-dependent cortical reorganization. Combining, in vitro neural recordings, optogenetics, pharmacology, and computational modeling, the studies presented here describe various interacting forms of plasticity in isolated cortical microcircuits, as well as the associated changes that indicate learning. First, in Chapter 1, I review relevant background on neocortical organization, fundamental forms of neural plasticity, and examples of learning in cortical microcircuits, laying the groundwork for the original research presented in later chapters. Chapter 2 presents research examining the cellular and synaptic mechanisms underlying cortical ensemble formation by investigating how simple forms of chronic external input can reshape cortical microcircuits. Next, Chapter 3 investigates the ability of cortical circuits to learn different temporal intervals and generate timed predictions. Using organotypic slice cultures, this study demonstrates that timing is a computational primitive of neocortical microcircuits, specifically, that neural mechanisms are in place to allow isolated cortical circuits to autonomously learn the temporal structure of external stimuli and generate internal predictions. Finally, Chapter 4 presents a collaborative translational study led by Dr. Nazim Kourdougli and the Portera-Cailliau lab, utilizing a pharmacological rescue strategy for cortical network dysfunction in a mouse model of Fragile X Syndrome. Taken together, the results presented in this dissertation provide novel insights into the various mechanisms that cortical circuits engage to implement experience-dependent changes, perform temporal processing, and inform future studies linking neural dynamics with behavioral outcomes in normal and pathological conditions.