Available online at www.sciencedirect.com ScienceDirect The basolateral amygdala and lateral hypothalamus bias learning towards motivationally significant events Ivy B Hoang and Melissa J Sharpe Every day we are faced with a huge amount of new information. best facilitate arrival at our eventual goal. Dysfunction in We can’t learn about everything, we have to select what to learn the balance between learning about proximal and distal about. We have many systems that contribute to learning in predictors of outcomes plays an important role in psycho- different ways, allowing us to select the most relevant logical disorders like anxiety, addiction, and schizophre- information to learn about. This review will focus on one such nia [1,2]. system, comprising the basolateral amygdala and lateral hypothalamus, which we argue works to favor learning about Two regions of the brain that are important for learning information most relevant to current goals. Specifically, we will about motivationally significant outcomes are the lateral discuss work that has revealed the role of the basolateral hypothalamus (LH) and the basolateral amygdala (BLA). amygdala in encoding the sensory-specific aspects of Both structures encode information that is proximal to rewarding information. Then, we discuss new data implicating food (or pain, under some conditions [10 ]), which facil- lateral hypothalamus in biasing learning towards reward- itates the ability to respond appropriately to these pre- predictive cues, and away from information distal to rewards. dictors in the future [3–8,9 ,10 ]. Yet when it comes to Finally, we offer a framework of how these regions learning about the distal predictors of food outcomes, the communicate to relay this information to the midbrain function of these regions diverges. Specifically, the BLA dopamine system, allowing them to bias ongoing learning will only be involved in encoding information about distal towards the best predictors of motivationally relevant predictors if these predictors have already been estab- information. lished as related to something motivationally significant [3,8,9]. For example, the BLA will encode the ice-cream Address truck tune, but only if you know the truck is likely to sell Department of Psychology, University of California, Los Angeles, CA, ice cream. On the other hand, the LH biases learning USA toward proximal predictors and actively opposes learning Corresponding authors: about distal predictors, even if those distal cues are Hoang, Ivy B ([email protected]), Sharpe, Melissa J (melissa.j.shar- related to something motivationally significant. Thus, [email protected]) in contrast to the BLA, the LH will always want to prevent you from encoding the sound of the ice-cream truck tune, even if you’ve bought ice cream from these Current Opinion in Behavioral Sciences 2021, 41:92–97 trucks a hundred times before. Here, we review the This review comes from a themed issue on Cognition and perception function of these regions in the context of Pavlovian – *value-based decision-making* conditioning and discuss potential models of how these Edited by Bernard Balleine and Laura Bradfield regions may interact to facilitate the balance of proximal and distal learning about motivationally significant outcomes. https://doi.org/10.1016/j.cobeha.2021.04.014 2352-1546/ã 2021 Elsevier Ltd. All rights reserved. Basolateral amygdala function Much of the early research on the BLA has centered around the role of this region in fear. The BLA has been shown to be critical for both the acquisition and expres- sion of conditioned fear in rodents, humans, and primates [11,12,13 ]. In a simple fear conditioning task, where Introduction subjects are learning to associate a cue with something Learning about predictors of motivationally significant aversive like a mild foot shock, inhibiting BLA function outcomes, like food or pain, is essential for approaching reduces the subsequent ability of the shock-predictive rewards and avoiding punishments. Some of these pre- cue to elicit fear [14–16,17 ]. Similarly, leaving BLA dictors are proximal to outcomes, like the taste of ice function intact during learning, but disrupting its function cream from your neighborhood’s ice-cream truck. Others in a subsequent test of fear to the shock-paired cue, also are more distal from outcomes, like hearing the nostalgic reduces fear [14–16,18]. These results demonstrate that tune of the ice-cream truck play throughout your neigh- the BLA is necessary for developing and storing fear borhood. We must balance learning about proximal and memories that facilitate appropriate behavior in the pres- distal outcomes, and devote learning to predictors that ence of predictors of aversive outcomes. Current Opinion in Behavioral Sciences 2021, 41:92–97 www.sciencedirect.com BLA and LH balance learning Hoang and Sharpe 93 While most of the work examining the role of the BLA in that the BLA can be engaged to learn about complex learning focuses on predictors of aversive outcomes, the sensory-specific associations that are distal from out- BLA is also critical for learning about the predictors of comes, but only if that information is motivationally rewards [3–7,19,20]. However, its contribution to reward significant at the time of encoding. learning is more nuanced, such that inhibiting BLA function does not abolish learning or responding to cues The importance of the BLA in prioritizing encoding of that predict rewarding outcomes, like it does during fear information that is motivationally significant is also conditioning [19,20]. Instead, appetitive learning studies indexed by the pattern of cue-evoked firing seen in have revealed that the BLA is important for encoding the electrophysiological studies. In one study, rats were sensory-specific representation of the reward, demon- trained to discriminate responding to two different odors strated by using Pavlovian-to-instrumental Transfer predictive of either a rewarding sucrose solution or an (PIT) and devaluation studies [3–6]. For example, during aversive quinine solution [23]. Neurons in the BLA were PIT, subjects first learn that two cues (e.g. light or tone) recorded in these rats during a reversal of these contin- lead to two different rewards (e.g. pellets or sucrose). gencies. This revealed that neuronal populations in the Then, subjects learn to make two actions (e.g. lever press BLA switch their firing preference to follow their pre- or chain pull) to receive the two outcomes. Finally, ferred outcome. That is, after a reversal, the same neuron subjects are given a test where the cues are played and that was once firing to an odor predictive of sucrose will either action can be made (in the absence of reward). now preferentially fire for that opposite odor that is now Encoding of the sensory-specific representation of these predictive of sucrose. Thus, these neurons change selec- rewards is revealed when subjects make the action that tivity to follow the reward and not the odor. Similarly, in leads to the reward congruent with that predicted by the another study, BLA neurons increased firing rate with an current cue being played (e.g. sucrose action made during unexpected change in reward magnitude or delay, exhi- sucrose cue). However, lesions of the BLA impair the biting a short burst of increased activity whether these specific PIT effect, characterized by indistinguishable changes meant more or less reward, or delivered over a action selections in the presence of either cue, despite shorter or longer timescale [24]. This is reminiscent of an the ability of the cues to generally invigorate motivated unsigned attentional signal [24], strengthening the idea responding remaining intact [6]. These findings demon- that BLA is concerned with the specific outcomes pre- strate that the BLA is necessary for encoding the rela- dicted by environmental stimuli and their motivational tionship between cues and a sensory-specific representa- significance [24,25]. Altogether, these studies provide tion of rewards [4–6]. evidence to support the BLA as an associative structure important for learning about motivationally significant Interestingly, this role of the BLA in learning about cues events by encoding sensory-specific information about that predict either rewarding or aversive outcomes can these events, including their current predictive status. extend to learning about information that is distal to these outcomes. However, this only occurs if the information being learned carries motivational significance at the time Lateral hypothalamus function these relationships are encoded. For example, the BLA is While the BLA has been known to be critical for associa- not involved in sensory preconditioning [8,9,21,22]. In tive learning for some time, it is only recently that the LH this procedure, two neutral cues are first paired together, has been conclusively shown to be necessary for rein- where neither carry any motivational significance (e.g. A forcement learning [10 ,26–28,29 ,30,31]. Before this, ! B). The next day, cue B is paired with a motivationally the function of the LH was relatively restricted to pro- significant outcome (e.g. B ! shock), endowing this cue moting approach to food and its consumption (but see: with motivational significance. After this training, when Castro et al. [32]; Petrovich [33 ]). For example, early cue A is presented alone, rats will freeze because it leads studies demonstrated that lesions made in the LH would to B, which they learned predicts shock. Inhibition of reduce spontaneous feeding behavior, suggesting the BLA function during initial A ! B learning has no impact necessity for this region for food consumption and the on the later ability of A to elicit freezing after B is paired prevention of starvation [34]. Similarly, electrical stimu- with shock, demonstrating that the BLA is not involved in lation of the LH was shown to increase food intake in learning the initial A ! B association [8,9]. However, the sated rats [34–36].