Elucidating the Role of Subcortical Circuitry in Cue-Motivated Behaviors

Abstract

Environmental cues can influence behavior in an adaptive manner by signaling the availability of valuable resources. For some individuals, however, such cues can attain inordinate control and promote maladaptive behavior. That is, when cues are attributed with incentive motivational properties, they become incentive stimuli that gain the power to evoke complex emotional states and subsequently influence behavioral responding. The propensity to attribute incentive motivational value to such cues is also an indicator of behavioral traits that can render one vulnerable to cue-influenced psychopathologies (e.g. substance abuse disorder). We can study these phenomena through an animal model, the sign-tracker (ST)/goal-tracker (GT) model, through a behavioral task termed Pavlovian conditioned approach (PavCA). In PavCA training, presentation of a neutral cue is followed by delivery of a food reward, and after repeated cue-reward pairings, distinct behavioral phenotypes emerge –sign-trackers (STs), goal-trackers (GTs), and intermediate responders (IRs). While both GTs and STs attribute predictive value to the cue, STs also attribute incentive motivational value to the cue, which leads to greater engagement with the cue. IRs show both sign-tracking and goal-tracking conditioned responses, with no clear predominance of either. These differential responses in the Pavlovian conditioned approach task have been associated with distinct neurobiological mechanisms. An investigation of the subcortical neural systems that subserve these behaviors will be the focus of this dissertation. Dopamine has long been implicated in reward and motivated processes, and prior work suggests that the behavior of sign-trackers is dopamine-dependent. In Chapter 2, we addressed a gap in the literature regarding the temporal dynamics of dopamine and sign-tracking. Using optogenetics we disrupted cue-elicited dopamine neural activity in the ventral tegmental area. We found that sign-tracking does not develop without cue-paired dopamine activity due to disrupted incentive salience attribution, but that sign-tracking behavior subsequently emerges with intact dopamine signaling (i.e. when laser inhibition is terminated). Another subcortical system of interest is the paraventricular nucleus of the thalamus (PVT) to the lateral hypothalamus (LH) pathway. The PVT has emerged as a neural hub that mediates the characteristic differences in associative learning captured in the ST/GT model. Prior findings have led us to postulate that bottom-up projections from the lateral hypothalamus (LH) to the PVT relay the incentive value of reward-associated cues. In Chapter 3 we utilized chemogenetics to inhibit the LH-PVT pathway and found that this manipulation attenuated goal-directed behavior and that this effect was apparent in IR rats, but not STs and GTs. In Chapter 4, we utilized a novel tissue multiplexing technology to label cue-elicited neuronal activity simultaneously with neuronal identity and projection specificity. We found that, in response to a Pavlovian food-cue, STs have more active orexinergic neurons that project from the LH to the PVT, relative to GTs. Collectively, these studies illuminate the contributions of multiple subcortical systems in the acquisition and expression of behavioral responses that emerge through cue-reward learning. Regarding the dopaminergic system, we add to a body of literature suggesting that incentive value attribution, and by proxy sign-tracking behavior, is dopamine-dependent. For the LH-PVT pathway and orexinergic system, we open a line of questions to further investigate what role these subcortical targets play in individual differences in cue-reward learning. In all, this research teased apart some of the neurobiological factors that contribute to divergent cue-influenced behaviors, which is of relevance to understanding multiple neuropsychiatric disorders.