The neural circuitry responsible for memory consists of complex components with dynamic interactions. In hippocampal area CA1, interactions between excitatory pyramidal cells and inhibitory interneurons shape ensemble activity which encodes sequential experience. An extremely diverse set of inhibitory interneurons, with variation in gene expression, synaptic targeting, state-dependent activity, and connectivity, contribute substantially to circuit activity, such as theta and sharp wave-ripple oscillations. The precise roles of each interneuron group is not well understood, though characterization of their activity reveals mechanisms underlying hippocampal circuit computation. In this dissertation, I aim to identify and disrupt interactions between pyramidal cells and local interneurons to clarify their role in shaping cell assembly activity. We characterized axo-axonic cell activity in sharp wave-ripples, and compared their control of pyramidal cell activity and ripple events to parvalbumin expressing neurons. We identified pyramidal cell-interneuron interactions during ripples, suggesting they serve as lateral inhibitors between cell assemblies. We additionally developed and implemented a novel neural device to explore the role of cannabinoid disruption of hippocampal oscillations and organization of assemblies in vivo in awake animals. We demonstrate that cannabinoid receptor type 1 within CA1 is responsible for suppression of theta and SPW-Rs. We also found that cannabinoid activation within CA1 circuitry, regardless of muted input from CA3, was sufficient to disrupt sharp wave-ripples, likely through interference of pyramidal cell-interneuron interactions. The work in this dissertation provides insight suggesting that interneuron activity must be studied at the spiking timescale to characterize their control over cell assembly activity. / Doctor of Philosophy / Understanding how the brain creates memory remains one of the greatest questions in the field of neuroscience. Coordinated brain activity serves to build communication on large and small scales, across brain regions and within circuits consisting of small groups of neurons. Precise coordination of activity and communication across neurons and regions is thought to build salient experience, which is achieved through the timing of neuron action potentials, or spikes. Neurons receive thousands of inputs that control their spiking activity. "Go and stop" signals from excitatory and inhibitory interneurons act to conduct synchronized activity, which is required for proper circuit function. Importantly, coordinated spiking across large groups of neurons is responsible for observed "brain waves", or oscillations, which reflect organized activity. In CA1 of the hippocampus, there are >20 subtypes of interneurons that all make distinct contributions to memory function, and the roles of these interneurons have not been fully studied within behaving animals. As engineers develop new tools, new methods become available to study and classify how unique groups of interneurons play a part in circuit activity. Thus, we sought to characterize the role of axo-axonic cells, a specialized interneuron with strong control over spiking activity, in hippocampal oscillations that are responsible for memory encoding and consolidation. We identified a new role for axo-axonic cells in the regulation of pyramidal cell spiking in sharp wave-ripple oscillations. Additionally, we developed a novel neural device that allowed us to investigate the mechanisms that underlie cannabinoids, molecules found in Cannabis sativa, and memory dysfunction. We leveraged the multifunctionality of our T-DOpE probe to focally deliver synthetic cannabinoid into the hippocampus in combination with optical control of circuits, with simultaneous recording of activity. We found that cannabinoids acting within CA1 sufficiently disrupt hippocampal oscillations, likely through hindering pyramidal cell-interneuron interactions. Together, these findings suggest that the spatial and temporal resolution required to study diverse roles of interneurons is high, and experiments designed to explore interneuron activity should especially emphasize fine time-scales.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/119515 |
| Date | 25 June 2024 |
| Creators | Gilbert, Earl Thomas |
| Contributors | Neuroscience, English, Daniel F., Jayant, Krishna, Olsen, Michelle Lynne, Vijayan, Sujith, McKenzie, Sam, Thompson, Christopher |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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