The Paraventricular Thalamus is a Critical Mediator of Top-down Control of Cue-motivated Behavior in Rats

Abstract

Stimuli or cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the signtracker/goal-tracker animal model. Goal-trackers attribute predictive value to rewardcues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goaltrackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction. independent delivery of food-US, distinct conditioned responses emerge. Some rats, goal-trackers (GTs), approach the location of impending food delivery upon the lever-CS presentation, while others, sign-trackers (STs), approach and interact with the lever-CS itself. For both GTs and STs the lever-CS acquires predictive value and elicits a conditioned response, but for STs, the CS also acquires incentive value. This animal model, therefore, provides a unique platform to investigate the neurobiological determinants of individual differences in the propensity to attribute incentive salience to reward-cues.Previous studies suggest that sign-tracking behavior results from enhanced activity in subcortical brain circuits known to mediate motivated behaviors, including the striatal dopamine system, the amygdala, and the hypothalamus 22,23,28-31 . In addition, relative to GTs, STs appear to have deficits in top-down cognitive control originating in the prefrontal cortex 32 . Thus, we hypothesize that sign-tracking behavior arises from an imbalance between top-down cognitive control and bottom-up motivational processes.One brain region that is ideally situated to act as a fulcrum between cortical, limbic and homeostatic circuits is the paraventricular nucleus of the thalamus (PVT). The PVT has, in fact, come to be known as the "thalamic gateway" 33 for appetitive motivation; acting to integrate cognitive, emotional, motivational and viscerosensitive information, and, in turn, guide behavioral responses 33,34 . Consistent with this view, the PVT has been implicated in the propensity to attribute incentive motivational value to reward-cues [35][36][37] .The functional connectivity of the PVT in response to cue-induced neuronal activity differentiates STs from GTs 28,29,35 . In STs, cue-induced activity in the PVT is correlated with activity in subcortical areas, including the nucleus accumbens (NAc); whereas in GTs, cue-...

Inhibition of a cortico-thalamic circuit attenuates cue-induced reinstatement of drug-seeking behavior in “relapse prone” male rats

“…While the PrL-PVT pathway has been implicated in cue-reward learning [45,[55][56][57], the present study assessed the role of this pathway in mediating individual variation in cue-induced and cocaine-primed reinstatement of drug-seeking behavior. Sign-tracker and goal-tracker rats, categorized based on their propensity to attribute incentive salience to reward-paired cues, did not differ in behavior during cocaine self-administration [19][20][21]44] or extinction training prior to the reinstatement tests [19,22,44,58,59].…”

“…The reported results challenge our hypothesis that the PrL-PVT pathway inhibits the incentive motivational value of reward cues. This hypothesis is based on our previous work that assessed the role of this pathway during Pavlovian learning [45], whereas the current study utilized an instrumental procedure. The neural circuitry mediating these two forms of associative learning are different [62][63][64][65]; thus, it is possible that the PrL-PVT pathway plays a distinct role in each of these forms of learning.…”

“…The PVT receives dense projections from the prelimbic (PrL) cortex, and both phenotypes engage this "top-down" pathway in response to a food cue, suggesting that it mediates the predictive value of a Pavlovian reward cue [32]. Recently, however, we have found that activation of the PrL-PVT pathway in STs decreases the incentive value of a food cue and the tendency to sign-track, while inhibition of the same pathway in GTs permits the attribution of incentive value to a food cue and increases the tendency to sign-track [45]. These results suggest that the PrL-PVT pathway acts to suppress the incentive motivational value of a food cue.…”

An arbiter model of motivational selection

“…PVT has been implicated in a remarkably diverse range of functions including arousal (Colavito et al, 2015), stress (Bhatnagar, 2003;Bhatnagar and Dallman, 1999;Bhatnagar et al, 2002;Hsu et al, 2014), fear (Beas et al, 2018;Do-Monte et al, 2015;Penzo et al, 2015;Zhu et al, 2018), appetitive learning (Otis et al, 2017;Otis et al, 2019;Zhu et al, 2018), incentive salience (Campus et al, 2019;Haight and Flagel, 2014;Haight et al, 2015;Haight et al, 2017), relapse to drug seeking (Dayas et al, 2007;Dayas et al, 2008;Hamlin et al, 2009;James et al, 2011;James et al, 2010;James and Dayas, 2013;Marchant et al, 2010;Martin-Fardon and Boutrel, 2012;Matzeu et al, 2017;Matzeu et al, 2015), opiate withdrawal (Zhu et al, 2016) , drinking and feeding (Barson et al, 2015;Barson et al, 2017;Ong et al, 2017). We argue that PVT is implicated in these diverse functions because they have in common the need for motivational selection and PVT is a key component of the circuitry arbitrating this selection.…”

“…As noted above, PVT is not necessary for approach to a lever or magazine (Choi et al, 2019;Choi and McNally, 2017;Do-Monte et al, 2017); but, when these behaviors compete with each other such as during sign-tracking, PVT is critical to selection between them. Under these conditions, PVT, and PL inputs to PVT, suppress approach to the lever (sign tracking) enabling approach to the magazine (goal tracking) (Campus et al, 2019;Haight et al, 2015). Flagel (Flagel et al, 2011;Haight and Flagel, 2014;Haight et al, 2017) has hypothesized that the opposite would be observed for hypothalamic inputs to PVT (i.e.…”