Chemogenetic Inhibition of Lateral Hypothalamus Inputs to the Paraventricular Thalamus Reduces Goal-Tracking in a Behaviorally Flexible Subgroup of Male Rats

Abstract

The paraventricular nucleus of the thalamus (PVT) has emerged as an important node in circuits regulating motivated behavior. The neuronal pathway from the lateral hypothalamus (LH) to the PVT has specifically been shown to regulate arousal, feeding, and reward seeking. However, the involvement of the LH-PVT pathway in individual differences in cue-motivated behavior remains unclear. During a Pavlovian conditioned approach paradigm, when a reward is repeatedly preceded by the presentation of a cue, rats come to exhibit a conditioned response to the cue. One extreme of the population, sign-trackers (STs), approach and interact with the cue itself; while the other extreme, goal-trackers (GTs), approach the location of reward delivery. Intermediate responders (IRs) approach and interact with both the cue and reward location, without a clear preference. We utilized a Pavlovian conditioned approach paradigm to examine the effects of LH-PVT pathway inhibition on individual differences in cue-motivated behavior. A dual-vector approach was used to selectively express inhibitory chemogenetic receptors in the LH-PVT pathway. We found that inhibition of the LH-PVT pathway selectively attenuates the expression of goal-tracking behavior, without affecting sign-tracking. This effect is driven primarily by IR rats, as inhibition of LH-PVT neurons attenuates goal-tracking behavior in IRs, without impacting the response of STs or GTs. We speculate that the flexibility of responding in IR rats made them especially vulnerable to this manipulation. These findings identify the LH-PVT pathway as a selective contributor to reward-directed conditioned responding and a circuit substrate for behavioral flexibility. Significance StatementIndividuals differ in how reward-predictive cues motivate behavior, a feature linked to vulnerability and resilience to maladaptive reward seeking. The paraventricular thalamus (PVT), a midline hub with broad limbic connectivity, and its input from the lateral hypothalamus (LH) influences arousal, feeding, and reward seeking, but the role of the LH-PVT pathway in individual variability in cue-motivated behavior is unclear. We used chemogenetics to selectively suppress LH-PVT neurons during a Pavlovian conditioned approach paradigm. Inhibiting this projection reduced goal-tracking without altering sign-tracking, and this effect was driven primarily by intermediate responders, a phenotype characterized by behavioral flexibility. These results implicate LH-PVT signaling in reward-directed conditioned responding and suggest that this pathway contributes to flexible cue-motivated behavior.