Date of Award

Summer 6-14-2023

Embargo Period

6-30-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Peter W. Kalivas

Second Advisor

James M. Otis

Third Advisor

Thomas Jhou

Fourth Advisor

Nathan C. Rownlad

Fifth Advisor

Adviye Ergul

Sixth Advisor

Veronica A. Alvarez

Abstract

The nucleus accumbens core (NAc) represents a major neural substrate of reward encoding that has been found to play a role in differentially regulating natural and drug rewards, including cocaine. Its constituent D1- and D2- receptor expressing medium spiny neurons (MSN) are alternatively hypothesized to have either opposing effects on reward seeking or a shared role in forming encoding “ensembles” – a sparsely activated population of neurons that encode reward associations- that coordinate behavioral responding to rewards and cues predicting reward availability. Previous methods used to study these neuronal populations failed to temporal quantify the cell-type specific activity in reward seeking tasks.

To conjoin the functional dichotomy and ensemble hypotheses, we leveraged the use of single-cell calcium imaging of D1- and D2-MSN in freely behaving mice during active sucrose and cocaine self-administration, cued seeking and extinction. In the first part of the dissertation, we show that reinforced cocaine and sucrose seeking are associated with the recruitment of time-locked excitatory and inhibitory ensembles from both cell types. The seeking ensemble of excited D1-MSN showed high stability within- and across- multiple sessions for both reward types, while the stable recruitment of D2-MSN was only identified with cocaine self-administration. The balance between stability and dynamicity of D1- and D2-MSN ensembles, respectively, may be a consequential aspect of how NAcore encodes natural reward seeking.

The second part of my dissertation aimed to determine if D1- and D2-MSN differentially encode cocaine seeking and sucrose seeking behavior in cued non-reinforced seeking tasks. Previous reports have shown drug-specific synaptic potentiation of the nucleus accumbens core associated with cued seeking after abstinence that is not seen with natural reward seeking. We show that D1-MSN, but not D2-MSN, were found to differentially encode cocaine seeking over sucrose seeking through stable and consistently recruited excitatory ensembles during cued seeking after forced abstinence or extinction training. Interestingly, I show that different ensembles are recruited during cued seeking before and after extinction. Together, my data reveal a unique neuronal signature of D1-MSN associated with relapse to cocaine.

Rights

Copyright is held by the author. All rights reserved.

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