The lateral hypothalamus and orexinergic transmission in the paraventricular thalamus promote the attribution of incentive salience to reward-associated cues

Abstract

Rationale: Prior research suggests that inputs from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) contribute to the attribution of incentive salience to Pavlovian-conditioned reward cues. However, a causal role for the LHA in this phenomenon has not been demonstrated. In addition, it is unknown which hypothalamic neurotransmitter or peptide system(s) are involved in mediating incentive salience attribution.Objectives: To examine: 1) the role of the LHA in the propensity to attribute incentive salience to reward cues, and 2) the role of orexinergic signaling in the PVT on the expression of Pavlovian conditioned approach (PavCA) behavior, a reflection of incentive salience attribution. Methods: Male Sprague-Dawley rats received bilateral excitotoxic lesions of the LHA prior to the acquisition of Pavlovian conditioned approach (PavCA) behavior. A separate cohort of male rats acquired PavCA behavior and were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their conditioned response. The orexin 1 receptor (OX1r) antagonist SB-334867, or the orexin 2 receptor (OX2r) antagonist TCS-OX2-29, were then administered directly into the PVT to assess the effects of these pharmacological agents on the expression of PavCA behavior and on the conditioned reinforcing properties of the Pavlovian reward cue. Results: Lesions of the LHA before training attenuated the development of leverdirected (sign-tracking) behaviors in the PavCA paradigm, without affecting magazinedirected (goal-tracking) behaviors. In STs, administration of the OX1r antagonist into the PVT reduced lever-directed behaviors and increased magazine-directed behaviors; while administration of the OX2r antagonist only reduced lever-directed behaviors.Further, OX2r, but not OX1r, antagonism was able to reduce the incentive motivational value of the conditioned stimulus on a conditioned reinforcement test in STs. The behavior of GTs was unaffected by orexinergic antagonism in the PVT. Conclusions:The LHA is necessary for the attribution of incentive salience to reward cues and, thereby, the development of a sign-tracking conditioned response..

The Paraventricular Thalamus as a Critical Node of Motivated Behavior via the Hypothalamic-Thalamic-Striatal Circuit

“…To further investigate the role of the LH-PVT pathway in incentive learning, we examined the effects of lesioning the LH and blocking orexinergic activity in the PVT. We found that LH lesions block the development of sign-tracking behavior, and administration of OX-1 or OX-2 antagonists into the PVT attenuates the expression of sign-tracking behavior (Haight et al, 2020). Together, these data led us to develop a neural model of sign-tracking (Figure 2); whereby orexinergic transmission from the LH-PVT encodes the incentive value of cues, altering communication in the PVT-NAcSh pathway, and subsequently, dopamine activity, which we know is critical for incentive learning (Flagel et al, 2011b).…”

Thalamo-Nucleus Accumbens Projections in Motivated Behaviors and Addiction

“…Cue-reward association and salience processing are important components of reward seeking behaviors. PVT neurons are activated in response to cues associated with food reward (Choi et al, 2010;Igelstrom et al, 2010), and influence the attribution of incentive values to reward cues (Haight et al, 2015(Haight et al, , 2017(Haight et al, , 2020Campus et al, 2019). Moreover, both the midline thalamic nuclei (MTN) and the NAc receive prefrontal cortex (PFC) inputs that are able to modulate conditioned reward seeking through divergent cue encoding in PFC neurons (Otis et al, 2017).…”

Orexins (hypocretins): The intersection between homeostatic and hedonic feeding

“…satiety-induced decreases in cue-driven sucrose intake (Meffre et al 2019). Interestingly, administration of an OXR-2 antagonist, TCS-OX2-29, into this area significantly reduces lever responding for sucrose in hungry rats whereas SB-334867 has little effect (Haight et al 2020;Meffre et al 2019), suggesting that OXR-2 in the thalamic paraventricular nucleus play a role in the incentive motivational value of the food cue specifically. In line with this, knocking down OXR-1 signalling in the thalamic paraventricular nucleus did not affect progressive ratio responding for a food reward, but did attenuate unconditioned hedonic feeding where the need for learning and motivation is minimal (Choi et al 2012), highlighting that orexin receptor subtypes may play a distinct role in cue-induced reward processing.…”