Abstract

The hippocampus relies on a diverse network of regulatory components for memory formation. Neuromodulators and inhibitory interneurons act in concert with excitatory neurons to control learning. Even within one of these components there is a vast diversity of genetic or chemical composition that may come from unique sources at uniquely timed intervals or events. The goal of this dissertation is to identify specific functional-behavioral attributes of two such examples: parvalbumin (PV)-expressing interneurons and the neuromodulator dopamine, in hippocampal CA1. In separate experiments, I used two-photon microscopy of the calcium sensor, GCaMP, which measures neuronal activity, and GRAB-DA, which reports levels of dopamine, in mice as they performed tasks in a virtual reality (VR) environment. Our inhibitory interneuron experiments focused on PV interneurons that provide fast, somatic inhibition. Here I found a subpopulation of these neurons whose activity was strongly suppressed in new environments and also shared high activity correlation in familiar environments. Highly suppressed neurons and less suppressed neurons also differed in several coding properties. Our results identify two inhibitory subnetworks that either provide stable inhibition in new environments or decrease inhibition to favor plasticity, suggesting downstream targeting of vii distinct excitatory circuits. For dopamine, contrary to expectation, we identified release in two closely apposed spatial domains. In Pavlovian conditioning, dopamine transients appeared at rewards in the "deep" domain of CA1 (basal dendritic layer). Surprisingly these transients did not encode reward but were an action signal corresponding to reward consumption. Similarly, hippocampal dopamine transients showed no reward prediction error. In a spatial goal-directed task, deep dopamine domain transients at rewards persisted but dopamine ramps now appeared, ramping up in the superficial domain (cell body and apical dendrites) during reward approach while ramping down in the deep domain. Our results reveal anatomically segregated hippocampal dopamine release domains with dynamic signaling that is distinct from striatal dopamine. Rather than a unitary volume and function of dopamine, we identify multiple spatial domains and functional signals that likely play distinct and dissociable roles in hippocampal dependent learning and memory. Together, these results reveal previously hidden hippocampal structures that indicate specialized circuits regulated by distinct forms of functional inhibition or neuromodulation by dopamine. This specialization of hippocampal circuitry could be useful for future studies targeting memory impairment in neurodegenerative diseases such as Alzheimer’s.

Committee Chair

Edward Han

Committee Members

Alexxai Kravitz; Andreas Burkhalter; Barani Raman; Edward Han; Gaia Tavoni

Degree

Doctor of Philosophy (PhD)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

4-29-2026

Language

English (en)

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