Goals Unhindered: How spatially selective disinhibition drives new important memories. Restricted; Files Only
Jeong, Nuri (Summer 2023)
Abstract
Animals rely on quickly identifying and remembering the most important locations for successful goal-directed spatial navigation. Developing new spatial memories rapidly requires orchestrated firing activity of excitatory pyramidal cells in the hippocampus, but the mechanisms underlying new goal learning at precise locations are not fully understood. Inhibitory interneurons, including those that directly inhibit the somas of pyramidal cells, are known to modulate excitatory firing but this inhibitory modulation is typically thought to follow and depend on excitatory inputs. According to this view, inhibition supports excitatory reorganization during spatial learning by preventing hyperexcitation and suppressing low-firing activity to increase the signal-to-noise ratio of spatial coding. Distinct from this view, we tested a novel hypothesis that spatially selective reduction in inhibition would drive learning-associated excitatory reorganization at specific locations to serve goal-directed navigation. Spatially selective disinhibition, could drive excitatory reorganization for new learning and therefore gate enhanced information transfer at specific locations most pertinent to learning. We reasoned that such gating would occur at important locations such as rewarded areas. To test our hypothesis, we simultaneously recorded from many single neurons in mouse hippocampal subregion CA3, a region known to be important for developing new spatial memories, during rapid learning of new reward locations in virtual reality environments. We found a spatially selective reduction in firing rates of most interneurons when mice approached learned reward zones. This inhibitory reduction could not be explained by position-related changes in speed or licking behavior, nor was the timing or magnitude of the reduction consistent with simple balancing of changes in excitatory activity. To test the causal role of reductions in interneuron activity in learning, we optogenetically disrupted the normal reduction in inhibition at goal locations in new environments. Consistent with our hypothesis, goal location-specific stimulation of a small subset of CA3 parvalbumin interneurons, which provide perisomatic inhibition onto pyramidal cells, disrupted new goal learning without affecting performance in the familiar environment. Learning impairment was accompanied by deficits in the goal-relevant spatial information and sharp wave ripple activity. These results highlight a novel inhibitory gating mechanism for new goal-specific spatial learning.
Table of Contents
Introduction ......................................................................................................................................................................................................................................................... 1
Chapter 1 ............................................................................................................................................................................................................................................................. 4
Abstract ............................................................................................................................................................................................................................................................... 4
Main Text ............................................................................................................................................................................................................................................................. 4
Figures ............................................................................................................................................................................................................................................................... 16
Chapter 2 ........................................................................................................................................................................................................................................................... 20
Abstract ............................................................................................................................................................................................................................................................. 20
Introduction ....................................................................................................................................................................................................................................................... 20
Results ............................................................................................................................................................................................................................................................... 23
Discussion .......................................................................................................................................................................................................................................................... 36
Materials and Methods ........................................................................................................................................................................................................................................ 39
Figures ............................................................................................................................................................................................................................................................... 52
Supplementary Figures ........................................................................................................................................................................................................................................ 63
Supplementary Text ............................................................................................................................................................................................................................................ 83
Chapter 3 ........................................................................................................................................................................................................................................................... 92
Figure ................................................................................................................................................................................................................................................................ 97
Appendix A BrainWAVE: A Flexible Method for Noninvasive Stimulation of Brain Rhythms across Species ................................................................................................................ 98
Abstract ............................................................................................................................................................................................................................................................. 98
Introduction ....................................................................................................................................................................................................................................................... 99
Results ............................................................................................................................................................................................................................................................. 102
Discussion ........................................................................................................................................................................................................................................................ 106
Materials and Methods ...................................................................................................................................................................................................................................... 110
Figures ............................................................................................................................................................................................................................................................. 119
Extended Data .................................................................................................................................................................................................................................................. 128
Appendix B A rapid and generalizable goal-directed spatial learning paradigm ...................................................................................................................................................... 136
Abstract ........................................................................................................................................................................................................................................................... 136
Introduction ..................................................................................................................................................................................................................................................... 136
Results ............................................................................................................................................................................................................................................................. 137
Discussion ........................................................................................................................................................................................................................................................ 141
Materials and Methods ...................................................................................................................................................................................................................................... 143
Figures ............................................................................................................................................................................................................................................................. 149
References ........................................................................................................................................................................................................................................................ 154
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File download under embargo until 16 August 2025 | 2023-06-26 13:39:08 -0400 | File download under embargo until 16 August 2025 |
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