Mesolimbic dopamine projections mediate cue-motivated reward seeking but not reward retrieval

Abstract

Efficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.Foraging and other reward-motivated behaviors tend to unfold as a sequence of 1 actions, beginning with a reward-seeking phase and ending with an attempt to retrieve 2 and consume any rewards produced by this activity. Coordinating the discrete reward-3 seeking and reward-retrieval behaviors that make up these action sequences is 4 important for efficient foraging. When rewards are sparse or otherwise difficult to obtain, 5 attempts to retrieve them are often unnecessary and should therefore be withheld to 6 conserve energy and minimize opportunity costs (Stephens and Krebs, 1986; Niv et al., 7 2007). Consistent with this, studies on self-paced instrumental behavior show that the 8 ability to efficiently pattern reward-seeking and -retrieval responses based on task 9 demands (e.g., reinforcement schedule) can strongly impact the rate at which rewards 10

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

“…To elucidate the causal roles of distinct prefronto-subcortical pathways in macaque monkeys, in other words, the pathways from PFC to CD (PFC-CD) and from PFC to MD (PFC-MD), we applied one of the chemogenetic tools, designer receptors exclusively activated by designer drugs (DREADDs). While neuronal silencing can be achieved by activating an inhibitory DREADD (hM4Di) following systemic agonist delivery (24), activating hM4Di expressed at axon terminals through local agonist infusion also leads to suppression of synaptic transmission (25)(26)(27)(28)(29). Here we developed imagingguided chemogenetic synaptic silencing -a methodology for silencing neural pathways selectively with an agonist infused at hM4Di-positive PFC projection sites that are mapped in vivo beforehand by using positron emission tomography (PET) (30).…”

The VTA-BLA-NAc circuit for sex reward inhibited by VTA GABAergic neurons under stress in male mice

“…The mesolimbic system, originating from the ventral tegmental area (VTA) dopaminergic (DA) neurons which project to the nucleus accumbens (NAc), has been extensively involved in regulating motivated behaviors related to reward stimuli and reward-predictive cues (Halbout et al, 2019;Ostlund et al, 2014;Wassum et al, 2013;Yuan et al, 2019), and its abnormalities are associated with Depressive-like behaviors (Krishnan et al, 2007;Chaudhury et al, 2013;Cao et al, 2010). The VTA-NAc pathway does not regulate reward-related behaviors as an independent brain structure, but functions as part of an overlapping and interacting neural circuit.…”

Flexible control of Pavlovian-instrumental transfer based on expected reward value

“…The alpha level for all tests was .05. Sample sizes were not predetermined based on statistical analysis but are similar to those reported in previous publications (Marshall and Ostlund, 2018;Halbout et al, 2019;Marshall et al, 2020). Main effects and interactions are reported as the results of ANOVA F-tests (i.e., whether the coefficients for each fixed effect were significantly different from 0).…”

“…Pre-CS (baseline) data were averaged across all CS trials (within subject). Food-port entry behavior can fall into two categories: spontaneous entries and entries that are performed as part of an instrumental press-entry action sequence (Marshall and Ostlund, 2018;Halbout et al, 2019;Marshall et al, 2020), the latter indicated by an increased likelihood of food-port entry shortly after execution of the lever-press response. To focus our analysis on cue-elicited (and not instrumental) reward-retrieval behavior, we excluded all entries that occurred within a 2.5 sec postlever press period from our analysis, as in our previous studies (Marshall and Ostlund, 2018;Halbout et al, 2019;Marshall et al, 2020)…”

“…However, other findings suggest that the tendency for reward-predictive cues to elicit food-port entries is not mediated by the same motivational process that underlies their ability to facilitate lever pressing. For instance, a growing body of PIT studies have shown that manipulations of the mesolimbic dopamine and cholinergic systems impact cue-motivated lever pressing without affecting cue-elicited food-port entry (Collins et al, 2016;Collins et al, 2019;Halbout et al, 2019). Moreover, previous studies have demonstrated that cue-elicited food-port entry behavior can be attenuated by devaluing the anticipated reward between training and testing (Holland and Rescorla, 1975;Holland, 1998;Keefer et al, 2020), indicating that its expression is mediated by a cognitive representation of the expected reward.…”