As the population ages, memory dysfunction is an increasingly prevalent issue resulting from neurodegenerative diseases such as Alzheimer’s disease and dementia. Despite the resulting decline in quality of life, current treatment options remain limited for this patient population. These treatment options do not target specific neural circuits, remaining agnostic to the cognitive processes underlying memory. To increase therapeutic specificity for neurodegenerative diseases, a fundamental understanding of memory processes is required. Memory recall is traditionally induced by external stimuli, though recent advances have allowed for memory reactivation through neural stimulation. The network effects of stimulation induced memory reactivation remain unknown because the dynamics resultant of such stimulation have not been well studied.
In this work I first increase the fidelity of recording from multiple neuronal populations before developing novel methods for stimulating memory associated neurons and apply these techniques to investigate the downstream dynamics during induced memory reactivation. Investigation of expressing multiple fluorophores resulted in significantly improved co-expression over previously established methods, thus enabling high fidelity dual color imaging. After optimizing fluorophore expression for imaging, I next developed a novel method to conduct induced memory recall. Previously, only the blue-light activated channelrhodopsin had been used for induced memory reactivation, thus limiting experimental designs to those compatible with blue light stimulation. This work demonstrates the potential of ChrimsonR, a red-shifted opsin, to induce memory recall and shows that ChrimsonR induced memory recall can take place in both open field and head-fixed experimental paradigms. These results enable calcium imaging during induced memory recall, allowing for all-optical stimulation and recording of memory-associated neuron activity.
Having developed the tools for observing neural activity during induced memory recall, I then applied this approach to observe the downstream network dynamics during upstream memory-associated neuron stimulation. This investigation uncovered the inhibitory mechanism responsible for reducing the firing of downstream non memory-associated cells during stimulation. This mechanism provides novel insight into the neural basis of induced memory recall. Additionally, this demonstration of calcium imaging during induced memory recall provides a proof of concept for future investigation of the dynamics of individual memories throughout the brain. / 2025-01-17T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47941 |
| Date | 18 January 2024 |
| Creators | Norman, Jacob Frederick |
| Contributors | White, John |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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