Separating desire from prediction of outcome value.

Individuals typically want what they expect to like, often based on memories of previous positive experiences. However, in some situations desire can decouple completely from memories and from learned predictions of outcome value. The potential for desire to separate from prediction arises from independent operating rules that control motivational incentive salience. Incentive salience, or 'wanting', is a type of mesolimbic desire that evolved for adaptive goals, but can also generate maladaptive addictions. Two proof-of-principle examples are presented here to show how motivational 'wanting' can soar above memory-based predictions of outcome value: (i) 'wanting what is remembered to be disgusting', and (ii) 'wanting what is predicted to hurt'. Consequently, even outcomes remembered and predicted to be negatively aversive can become positively 'wanted'. Similarly, in human addictions, people may experience powerful cue-triggered cravings for outcomes that are not predicted to be enjoyable.

Corticotropin releasing factor (CRF) systems: Promoting cocaine pursuit without distress via incentive motivation.

Corticotropin releasing factor (CRF) systems in limbic structures are posited to mediate stress-induced relapse in addiction, traditionally by generating distress states that spur drug consumption as attempts at hedonic self-medication. Yet evidence suggests that activating CRF-expressing neurons in the central amygdala (CeA) or nucleus accumbens (NAc) can magnify incentive motivation in absence of distress, at least for sucrose rewards. However, traditional CRF hypotheses in addiction neuroscience are primarily directed toward drug rewards. The question remains open whether CRF systems can similarly act via incentive motivation mechanisms to promote pursuit of drug rewards, such as cocaine. Here we tested whether optogenetic excitation of CRF-containing neurons in either NAc medial shell, lateral CeA, or dorsolateral BNST of transgenic Crh-Cre+ rats would spur preference and pursuit of a particular laser-paired cocaine reward over an alternative cocaine reward, and whether excitation served as a positively-valenced incentive itself, through laser self-stimulation tests. We report that excitation of CRF-containing neurons in either NAc or CeA recruited mesocorticolimbic circuitry to amplify incentive motivation to pursue the laser-paired cocaine: focusing preference on the laser-paired cocaine reward in a two-choice task, and spurred pursuit as doubled breakpoint in a progressive ratio task. Crucially indicating positive-valence, excitation of CRF neurons in NAc and CeA also was actively sought after by most rats in self-stimulation tasks. Conversely, CRF neuronal activation in BNST was never self-stimulated, but failed to enhance cocaine consumption. Collectively, we find that NAc and CeA CRF-containing neurons can amplify pursuit and consumption of cocaine by positively-valenced incentive mechanisms, without any aversive distress.

Liking.

Berridge and Dayan outline the psychological and neural basis of the hedonic concept of 'liking', and its relationship with close, but not always consonant, motivational cousin, 'wanting'.

Incentive motivation: 'wanting' roles of central amygdala circuitry.

The central nucleus of amygdala (CeA) mediates positively-valenced reward motivation as well as negatively-valenced fear. Optogenetic or neurochemical stimulation of CeA circuitry can generate intense incentive motivation to pursue and consume a paired natural food, sex, or addictive drug reward, and even create maladaptive 'wanting what hurts' such as attraction to a shock rod. Evidence indicates CeA stimulations selectively amplify incentive motivation ('wanting') but not hedonic impact ('liking') of the same reward. Further, valence flips can occur for CeA contributions to motivational salience. That is, CeA stimulation can promote either incentive motivation or fearful motivation, even in the same individual, depending on situation. These findings may carry implications for understanding CeA roles in neuropsychiatric disorders involving aberrant motivational salience, ranging from addiction to paranoia and anxiety disorders.

Positive Affect: Nature and brain bases of liking and wanting.

The positive affect of rewards is an important contributor to well-being. Reward involves components of pleasure 'liking', motivation 'wanting', and learning. 'Liking' refers to the hedonic impact of positive events, with underlying mechanisms that include hedonic hotspots in limbic brain structures that amplify 'liking' reactions. 'Wanting' refers to incentive salience, a motivational process that makes reward cues attractive and able to trigger craving for their reward, mediated by larger dopamine-related mesocorticolimbic networks. Under normal conditions, 'liking' and 'wanting' cohere. However, 'liking' and 'wanting' can be dissociated by alterations in neural signaling, either induced in animal neuroscience laboratories or arising spontaneously in addictions and other affective disorders, which can be detrimental to positive well-being.

Activating Corticotropin-Releasing Factor Systems in the Nucleus Accumbens, Amygdala, and Bed Nucleus of Stria Terminalis: Incentive Motivation or Aversive Motivation?

BACKGROUND: Corticotropin-releasing factor (CRF) neural systems are important stress mechanisms in the central amygdala (CeA), bed nucleus of stria terminalis (BNST), nucleus accumbens (NAc), and related structures. CRF-containing neural systems are traditionally posited to generate aversive distress states that motivate overconsumption of rewards and relapse in addiction. However, CRF-containing systems may alternatively promote incentive motivation to increase reward pursuit and consumption without requiring aversive states. METHODS: We optogenetically stimulated CRF-expressing neurons in the CeA, BNST, or NAc using Crh-Cre+ rats (n = 37 female, n = 34 male) to investigate roles in incentive motivation versus aversive motivation. We paired CRF-expressing neuronal stimulations with earning sucrose rewards in two-choice and progressive ratio tasks and investigated recruitment of distributed limbic circuitry. We further assessed valence with CRF-containing neuron laser self-stimulation tasks. RESULTS: Channelrhodopsin excitation of CRF-containing neurons in the CeA and NAc amplified and focused incentive motivation and recruited activation of mesocorticolimbic reward circuitry. CRF systems in both the CeA and NAc supported laser self-stimulation, amplified incentive motivation for sucrose in a breakpoint test, and focused "wanting" on laser-paired sucrose over a sucrose alternative in a two-choice test. Conversely, stimulation of CRF-containing neurons in the BNST produced negative valence or aversive effects and recruited distress-related circuitry, as stimulation was avoided and suppressed motivation for sucrose. CONCLUSIONS: CRF-containing systems in the NAc and CeA can promote reward consumption by increasing incentive motivation without involving aversion. In contrast, stimulation of CRF-containing systems in the BNST is aversive but suppresses sucrose reward pursuit and consumption rather than increase, as predicted by traditional hedonic self-medication hypotheses.

'Liking' and 'wanting' in eating and food reward: Brain mechanisms and clinical implications.

It is becoming clearer how neurobiological mechanisms generate 'liking' and 'wanting' components of food reward. Mesocorticolimbic mechanisms that enhance 'liking' include brain hedonic hotspots, which are specialized subregions that are uniquely able to causally amplify the hedonic impact of palatable tastes. Hedonic hotspots are found in nucleus accumbens medial shell, ventral pallidum, orbitofrontal cortex, insula cortex, and brainstem. In turn, a much larger mesocorticolimbic circuitry generates 'wanting' or incentive motivation to obtain and consume food rewards. Hedonic and motivational circuitry interact together and with hypothalamic homeostatic circuitry, allowing relevant physiological hunger and satiety states to modulate 'liking' and 'wanting' for food rewards. In some conditions such as drug addiction, 'wanting' is known to dramatically detach from 'liking' for the same reward, and this may also occur in over-eating disorders. Via incentive sensitization, 'wanting' selectively becomes higher, especially when triggered by reward cues when encountered in vulnerable states of stress, etc. Emerging evidence suggests that some cases of obesity and binge eating disorders may reflect an incentive-sensitization brain signature of cue hyper-reactivity, causing excessive 'wanting' to eat. Future findings on the neurobiological bases of 'liking' and 'wanting' can continue to improve understanding of both normal food reward and causes of clinical eating disorders.

The central amygdala recruits mesocorticolimbic circuitry for pursuit of reward or pain.

How do brain mechanisms create maladaptive attractions? Here intense maladaptive attractions are created in laboratory rats by pairing optogenetic channelrhodopsin (ChR2) stimulation of central nucleus of amygdala (CeA) in rats with encountering either sucrose, cocaine, or a painful shock-delivering object. We find that pairings make the respective rats pursue either sucrose exclusively, or cocaine exclusively, or repeatedly self-inflict shocks. CeA-induced maladaptive attractions, even to the painful shock-rod, recruit mesocorticolimbic incentive-related circuitry. Shock-associated cues also gain positive incentive value and are pursued. Yet the motivational effects of paired CeA stimulation can be reversed to negative valence in a Pavlovian fear learning situation, where CeA ChR2 pairing increases defensive reactions. Finally, CeA ChR2 valence can be switched to neutral by pairing with innocuous stimuli. These results reveal valence plasticity and multiple modes for motivation via mesocorticolimbic circuitry under the control of CeA activation.

Desire or Dread from Nucleus Accumbens Inhibitions: Reversed by Same-Site Optogenetic Excitations.

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.

Optogenetic mapping of feeding and self-stimulation within the lateral hypothalamus of the rat.

The lateral hypothalamus (LH) includes several anatomical subregions involved in eating and reward motivation. This study explored localization of function across different LH subregions in controlling food intake stimulated by optogenetic channelrhodopsin excitation, and in supporting laser self-stimulation. We particularly compared the tuberal LH subregion, the posterior LH subregion, and the lateral preoptic area. Local diameters of tissue optogenetically stimulated within the LH were assessed by measuring laser-induced Fos plumes and Jun plumes via immunofluorescence surrounding optic fiber tips. Those plume diameters were used to map localization of function for behavioral effects elicited by LH optogenetic stimulation. Optogenetic stimulation of the tuberal subsection of the LH produced the most robust eating behavior and food intake initially, but produced only mild laser self-stimulation in the same rats. However, after repeated exposures to optogenetic stimulation, tuberal LH behavioral profiles shifted toward more self-stimulation and less food intake. By contrast, stimulation of the lateral preoptic area produced relatively little food intake or self-stimulation, either initially or after extended stimulation experience. Stimulation in the posterior LH subregion supported moderate self-stimulation, but not food intake, and at higher laser intensity shifted valence to evoke escape behaviors. We conclude that the tuberal LH subregion may best mediate stimulation-bound increases in food intake stimulated by optogenetic excitation. However, incentive motivational effects of tuberal LH stimulation may shift toward self-stimulation behavior after repeated stimulation. By contrast, the lateral preoptic area and posterior LH do not as readily elicit either eating behavior or laser self-stimulation, and may be more prone to higher-intensity aversive effects.

Mapping excessive "disgust" in the brain: Ventral pallidum inactivation recruits distributed circuitry to make sweetness "disgusting".

The ventral pallidum (VP) is an important structure in processing reward. The VP may be the only brain structure where localized lesions in rats replace normal facial "liking" expressions to sweetness with excessive "disgust" reactions, such as gapes and chin rubs, that are normally reserved for unpalatable tastes. The posterior half of the VP (pVP) contains a hedonic hot spot where opioid or related neurochemical stimulations can amplify positive "liking" reactions to sweet taste. This is the same site where lesions or pharmacological inactivations replace positive hedonic reactions to sucrose with intense negative "disgust." In the present study, we aimed to identify brain networks recruited by pVP inactivation to generate excessive "disgust," using neuronal Fos expression as a marker of neurobiological activation. Microinjections in pVP of inhibitory GABAA/B agonists (muscimol and baclofen) caused rats to exhibit excessive "disgust" reactions to sucrose. Excessive "disgust" was accompanied by recruitment of neural Fos activation in several subcortical structures, including the posterior medial shell of nucleus accumbens (which also contains another GABAergic "disgust"-inducing "hedonic cold spot"), the bed nucleus of stria terminalis, lateral habenula, hypothalamus, and midbrain ventral tegmentum. Fos suppression was found in cortical limbic regions, including previously identified hedonic hot spots in the anteromedial orbitofrontal cortex and posterior insula. Finally, in addition to inducing excessive "disgust," pVP inactivation abolished motivational "wanting" to eat palatable food, reduced positive social interactions, and reordered sensorimotor relations. Our findings identify potential "disgust" generators in the brain that are released into excitation by pVP inhibition and may serve as targets for future research.

A Neurobehavioral Approach to Addiction: Implications for the Opioid Epidemic and the Psychology of Addiction.

Two major questions about addictive behaviors need to be explained by any worthwhile neurobiological theory. First, why do people seek drugs in the first place? Second, why do some people who use drugs seem to eventually become unable to resist drug temptation and so become "addicted"? We will review the theories of addiction that address negative-reinforcement views of drug use (i.e., taking opioids to alleviate distress or withdrawal), positive-reinforcement views (i.e., taking drugs for euphoria), habit views (i.e., growth of automatic drug-use routines), incentive-sensitization views (i.e., growth of excessive "wanting" to take drugs as a result of dopamine-related sensitization), and cognitive-dysfunction views (i.e., impaired prefrontal top-down control), including those involving competing neurobehavioral decision systems (CNDS), and the role of the insula in modulating addictive drug craving. In the special case of opioids, particular attention is paid to whether their analgesic effects overlap with their reinforcing effects and whether the perceived low risk of taking legal medicinal opioids, which are often prescribed by a health professional, could play a role in the decision to use. Specifically, we will address the issue of predisposition or vulnerability to becoming addicted to drugs (i.e., the question of why some people who experiment with drugs develop an addiction, while others do not). Finally, we review attempts to develop novel therapeutic strategies and policy ideas that could help prevent opioid and other substance abuse.

Affective valence in the brain: modules or modes?

How do brain systems evaluate the affective valence of a stimulus - that is, its quality of being good or bad? One possibility is that a neural subsystem, or 'module' (such as a subregion of the brain, a projection pathway, a neuronal population or an individual neuron), is permanently dedicated to mediate only one affective function, or at least only one specific valence - an idea that is termed here the 'affective modules' hypothesis. An alternative possibility is that a given neural module can exist in multiple neurobiological states that give it different affective functions - an idea termed here the 'affective modes' hypothesis. This suggests that the affective function or valence mediated by a neural module need not remain permanently stable but rather can change dynamically across different situations. An evaluation of evidence for the 'affective modules' versus 'affective modes' hypotheses may be useful for advancing understanding of the affective organization of limbic circuitry.

Optogenetic self-stimulation in the nucleus accumbens: D1 reward versus D2 ambivalence.

The nucleus accumbens (NAc) contains multiple subpopulations of medium spiny neurons (MSNs). One subpopulation expresses D1-type dopamine receptors, another expresses D2-type receptors, and a third expresses both. The relative roles in NAc of D1 neurons versus D2 neurons in appetitive motivation were assessed here. Specifically, we asked whether D1-Cre mice would instrumentally seek optogenetic self-stimulation specifically targeted at D1 MSNs in NAc, and similarly if D2-Cre mice would self-stimulate D2 neurons in NAc. Mice were implanted with Cre-targeted channelrhodopsin (ChR2) virus and optic fibers in NAc. Subsequently, mice could earn brief NAc laser illuminations by actively touching a metal spout in one task, or by going to a particular location in a separate task. Results indicated that D1 neuronal excitation in NAc supported intense self-stimulation in both tasks. D1-Cre mice earned hundreds to thousands of spout-touches per half-hour session, and also sought out locations that delivered NAc laser to excite D1 MSNs. By comparison, D2 ChR2 mice showed lower but still positive levels of self-stimulation in the spout-touch task, earning dozens to hundreds of NAc laser illuminations. However, in the location task, D2 mice failed to show positive self-stimulation. If anything, a few D2 individuals gradually avoided the laser location. Brain-wide measures indicated that D1 and D2 stimulations in NAc recruited heavily overlapping patterns of Fos activation in distant limbic structures. These results confirm that excitation of D1 MSNs in NAc supports strong incentive motivation to self-stimulate. They also suggest that excitation of D2 neurons in NAc supports self-stimulation under some conditions, but fails under others and possibly may even shift to negative avoidance.

Evolving Concepts of Emotion and Motivation.

This review takes a historical perspective on concepts in the psychology of motivation and emotion, and surveys recent developments, debates and applications. Old debates over emotion have recently risen again. For example, are emotions necessarily subjective feelings? Do animals have emotions? I review evidence that emotions exist as core psychological processes, which have objectively detectable features, and which can occur either with subjective feelings or without them. Evidence is offered also that studies of emotion in animals can give new insights into human emotions. Beyond emotion, motivation concepts have changed over decades too, and debates still continue. Motivation was once thought in terms of aversive drives, and reward was thought of in terms of drive reduction. Motivation-as-drive concepts were largely replaced by motivation-as-incentive concepts, yet aversive drive concepts still occasionally surface in reward neuroscience today. Among incentive concepts, incentive salience is a core motivation process, mediated by brain mesocorticolimbic systems (dopamine-related systems) and sometimes called 'wanting' (in quotation marks), to distinguish it from cognitive forms of desire (wanting without quotation marks). Incentive salience as 'wanting' is separable also from pleasure 'liking' for the same reward, which has important implications for several human clinical disorders. Ordinarily, incentive salience adds motivational urgency to cognitive desires, but 'wanting' and cognitive desires can dissociate in some conditions. Excessive incentive salience can cause addictions, in which excessive 'wanting' can diverge from cognitive desires. Conversely, lack of incentive salience may cause motivational forms of anhedonia in depression or schizophrenia, whereas a negatively-valenced form of 'fearful salience' may contribute to paranoia. Finally, negative 'fear' and 'disgust' have both partial overlap but also important neural differences.

Endocannabinoid-Enhanced "Liking" in Nucleus Accumbens Shell Hedonic Hotspot Requires Endogenous Opioid Signals.

Introduction: Stimulating either endogenous cannabinoids or opioids within a restricted dorsomedial "hedonic hotspot" in nucleus accumbens (NAc) shell enhances hedonic impact, or "liking" reactions to sweet tastes. In this study, we probed within this hotspot the relationship between endocannabinoid and opioid signals in hedonic enhancement. Materials and Methods: Specifically, we asked whether enhancement of sucrose "liking" by intra-NAc microinjections of the endocannabinoid anandamide requires concurrent endogenous opioid signaling. Results: Co-administration of the opioid antagonist naloxone in the same NAc microinjections with anandamide prevented the endocannabinoid from enhancing orofacial "liking" reactions to sucrose. Since intra-NAc hotspot naloxone injection alone failed to affect hedonics, reversal of anandamide-induced "liking" by opioid blockade reveals an interdependence of opioid and cannabinoid signaling in enhancing taste hedonic impact. Conclusions: These results elaborate our understanding of the mechanisms of hedonic processing of food rewards, and may also carry implications more generally for how opioid and cannabinoid drugs interact to generate natural pleasures, or drug-induced euphoria.