The paraventricular thalamic nucleus and its projections in regulating reward and context associations.

Abstract

The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse) are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, whole-cell brain slice electrophysiology recordings on PVT neurons that project to the NAcSh showed that bath perfusion of morphine (10 μM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath perfused morphine (10 μM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1-receptor and D2-receptor expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP. Together, these results provide valuable insights into the intricate interplay between the PVT and reward-related behaviors.

Significance Statement This study investigates the direct impact of paraventricular thalamic nucleus (PVT) inhibition on reward-related behaviors, employing manipulations related to drugs of abuse, specifically morphine, as well as employing chemogenetic approaches that replicate the inhibitory effects induced by morphine. Our findings reveal that morphine exerts an inhibitory effect on PVT neurons projecting to the nucleus accumbens shell (NAcSh). Furthermore, local administration of morphine within the PVT elicits reward-related behaviors, a response mimicked by the inhibition of PVT neurons projecting to the NAcSh. These results firmly establish the PVT as an integral component of a complex neurocircuit involved in the acquisition of associations with opioid-related contexts. Additionally, these results provide compelling evidence linking the inhibition of PVT neurons to reward processes.