UC Irvine

Spaced training is a powerful behavioral method for enhancing long-term memory. Despite decades of observational study of this phenomenon, a precise neurobiological mechanism remains unknown. Memory consolidation literature describes both synaptic and systems-level changes that accompany the stabilization of memory traces; the aim of the present work was to determine at which level spaced training operates. A specific spaced training schedule in the object location memory (OLM) task has been shown to dramatically lower the threshold to long-term memory in mice. Here we compare this paradigm to the standard, single-trial, “massed” schedule of training on a number of neurobiological outcomes. First we assayed, across the entire mouse brain, patterns of neuronal activation as reflected by Fos immunoreactivity. This analysis revealed a distinct network difference between spaced and massed training; specifically, the orbitofrontal cortex (OFC) showed significantly different activity. Next we chemogenetically inactivated OFC during massed and spaced training and found that it was necessary for spaced, but not massed, OLM learning. In Chapter 3 we assayed patterns of synaptic modification in hippocampus after massed and spaced OLM training. This analysis did not significantly distinguish between the training schedules. The studies in Chapters 4 and 5 depart from the spaced vs. massed question, and instead venture into territory of intellectual disability. The Fmr1-KO mouse is a commonly-used model of Fragile-X Syndrome, the most common form of inherited intellectual disability in humans. Here we show that these mice fail to exhibit social recognition, and that this deficit is corrected with treatments which enhance TrkB signaling. In Chapter 5, we apply behavioral pattern analysis (Markov sequences) to WT vs. KO exploratory patterns, and then to behavioral tasks discussed in Chapters 1-3 (including spaced vs. massed training and OFC inactivation). The main takeaway of this ethological analysis was that exploratory patterns vary more with environmental novelty than with any other factor. Together the studies in this dissertation support a systems-level effect of spaced training upon long-term memory, which may or may not be related to the difference in exploratory movement patterns.