Date of Award

1-1-2022

Embargo Period

4-22-2022

Document Type

Dissertation

Degree Name

Master of Biomedical Science

Department

Neuroscience

College

College of Graduate Studies

First Advisor

James M. Otis

Second Advisor

Jacqueline F. McGinty

Third Advisor

John J. Woodward

Fourth Advisor

Michael D. Scofield

Abstract

The posterior paraventricular thalamus (pPVT) plays a crucial role in reward-seeking behaviors due to its connectivity with brain structures which are important for reward processing, such as the nucleus accumbens shell (NAcSh). Previous studies have shown that PVT neurons form functional synapses with dopamine 1 receptor- (D1) and dopamine 2 receptor-expressing (D2) medium spiny neurons, as well as parvalbumin (PV) interneurons within NAc; however, how pPVT connections to downstream NAc (pPVT-NAc) neurons contribute to reward-seeking is unclear. While we have recently shown that pPVT-NAc can act to inhibit reward-seeking when it is inappropriate, it is unknown how pPVT downstream targets contribute to this behavioral inhibition. Additionally, I have shown that chronic heroin use causes pPVT-NAc to become dysfunctional by no longer suppressing reward-seeking, yet it remains unknown how chronic heroin use changes pPVT innervation of NAc neurons. This project uses patch-clamp electrophysiology in combination with optogenetics to characterize the innervation of pPVT onto downstream NAc neurons. I hypothesized that pPVT innervation of PV interneurons within the NAc is critical for suppression of reward-seeking behavior and that this synaptic input is inhibited by opioid use. Using D2- and PV-cre transgenic mice, I expressed channelrhodopsin in pPVT projection neurons to the NAc, and patched onto fluorescently tagged D2-, D2+, or PV+ neurons. In naïve animals, I evaluated the innervation of pPVT on each cell type and determined whether calcium-permeable AMPA receptors (CP-AMPARs) were present, to identify the mechanism of excitatory input provided by the pPVT. I found that pPVT forms functional synapses with D1s and D2s and that this innervation does not utilize CP-AMPARs under normal circumstances. The posterior PVT also innervates PVs, and induces CP-AMPAR activation, seen through AMPAR rectification index and CP-AMPAR antagonist (IEM-1460) sensitivity. Next, I measured plasticity in pPVT synaptic inputs to each cell type 24 hrs following the last day of either saline or heroin self-administration, or heroin extinction. I found that the pPVT-NAc pathway undergoes synaptic plasticity following opioid use through a reduction of CP-AMPARs, reducing synaptic input between pPVT and NAc. Results show that pPVT neuronal innervation of PVs within the NAc may play a role in the suppression of reward-seeking behaviors in relation to heroin use and heroin extinction and leads to feedforward inhibition of D1 and D2 neurons. Together, these data reveal that pPVT differentially innervates these cell types, and the synaptic input between pPVT and PVs is inhibited by opioid use. Furthermore, these data aid in the identification of precise circuits that are required for the suppression of reward-seeking and reveal how they are modified in opioid use disorder.

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