Date of Award
Summer 8-2-2024
Embargo Period
8-2-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Neuroscience
College
College of Graduate Studies
First Advisor
James Otis
Second Advisor
Peter Kalivas
Third Advisor
Catrina Robinson
Fourth Advisor
Michael Scofield
Fifth Advisor
Takashi Sato
Abstract
External cues can become powerful motivators of behavior when paired with rewarding stimuli, such as natural rewards or drugs of abuse, as is the case in individuals with substance use disorder (SUD). The dorsomedial prefrontal cortex (dmPFC) has been implicated as a neural substrate which encodes cue-reward associations and has been shown to exert top-down control over both natural and drug reward seeking. We and others have shown that activity within the dmPFC is heterogeneous during reward seeking, with some neurons displaying excitatory responses to reward-predictive cues, and others showing inhibitory responses to the same cues. Furthermore, this response heterogeneity cannot be fully explained by the genetic identity or projection targets of the neurons in question. To investigate this, we train mice to perform a head-fixed Pavlovian sucrose seeking task while monitoring dmPFC activity via in vivo two-photon calcium imaging. Using this approach, we identify five non-overlapping dmPFC neuronal ensembles that develop unique cue- and reward-related activity as a function of learning. We find that these ensemble-specific activity patterns are stable after learning occurs, and that each ensemble differentially encodes task-related stimuli and conditioned behavioral responses. To directly probe the function of these ensembles, we utilize two-photon holographic optogenetics to manipulate the activity of these ensembles during sucrose seeking and disrupt conditioned licking responses. Further analysis of dmPFC activity reveals that network dynamics are perturbed following holographic stimulation. Altogether, these findings reveal that functional neuronal ensembles in the dmPFC stably encode learned cue-reward associations and the following behavioral response. Targeted manipulation of dmPFC ensembles is sufficient to disrupt conditioned behavior both during and immediately after stimulation, perhaps by temporarily biasing ensemble output. Future studies that characterize the circuit connectivity, gene expression, and behavioral function of each neuronal ensemble, defined based on in vivo activity dynamics, are essential for understanding the dmPFC circuit contributions to reward-motivated behavior.
Recommended Citation
Grant, Roger Ian, "Prelimbic Neuronal Ensembles in Natural Reward Seeking" (2024). MUSC Theses and Dissertations. 949.
https://medica-musc.researchcommons.org/theses/949
Rights
Copyright is held by the author. All rights reserved.