Quite A Box of Tricks v1.8-SHOCK serial key or number

Abstract

Introduction

The English word hedonic comes originally from the ancient Greek for pleasure (ἡ ´¿½®; in Latin script: hédoné), in turn derived from the word for sweet (ἡ ´ÍÂ, or h&#x;dús). Today hedonic refers to sensory pleasures as well as many higher types of pleasure (e.g., cognitive, social, aesthetic, and moral).

A goal of affective neuroscience is to understand how brain mechanisms generate pleasures, and also displeasures, and eventually find more effective treatments for affective disorders (Anderson and Adolphs, ; Damasio and Carvalho, ; Haber and Knutson, ; Heller et al., ; Kringelbach and Berridge, ; Panksepp, ). Capacity for normal pleasure is essential to healthy psychological function or well-being. Conversely, affective disorders can induce either the pathological absence of pleasure reactions (as in clinical anhedonia), or the presence of excessive displeasure (dysphoric emotions such as pain, disgust, depression, anxiety, or fear).

But is a neuroscience of pleasure feasible? Doubts that pleasure might be scientifically understood have been expressed for over a century. Early doubts stemmed from behaviorist convictions that only objective behavioral-neural reactions were eligible for scientific study, and never subjective experiences (including the experience of pleasure). However, progress in the past 50 years proves that many complex psychological processes involving subjective experience can be successfully studied and related to underlying brain mechanisms. Still, some objections persist today. For example, LeDoux&#x;s recent recommendation that affective neuroscientists should focus only on behavioral affective reactions, rather than on subjective emotions, shares those earlier concerns (LeDoux, ).

In our view, a neuroscience of pleasure can be pursued as successfully as the neuroscience of perception, learning, cognition or other well-studied psychological functions. The crucial test of this proposition is: can affective neuroscience produce important new conclusions into how brain systems mediate hedonic impact? Evidence in support of this, we think, now exists in the form of recent findings. In this article we discuss some of these new findings, including 1) separation of reward liking, wanting, and learning mechanisms in mesocorticolimbic circuitry; 2) identification of overlap in neural circuitry underlying sensory pleasures and higher pleasures; 3) identification of particular sites in prefrontal limbic cortex that encode pleasure impact; 4) mapping of surprisingly localized causal hedonic hotspots that generate amplifications of pleasure reactions; 5) discovery that nucleus accumbens (NAc) hotspot and coldspot mechanisms are embedded in an anatomically-tuned keyboard organization of generators in nucleus accumbens that extends beyond reward liking and wanting to negative emotions of fear and disgust; and 6) identification of multiple neurochemical modes within NAc mechanisms that can retune keyboard generators into flipping between oppositely-valenced motivations of desire and dread.

A neuroscience of pleasure

In a sense, pleasure can be thought of as evolution&#x;s boldest trick, serving to motivate an individual to pursue rewards necessary for fitness, yet in modern environments of abundance also inducing maladaptive pursuits such as addictions. An important starting point for understanding the underlying circuitry is to recognize that rewards involve a composite of several psychological components: liking (core reactions to hedonic impact), wanting (motivation process of incentive salience), and learning (Pavlovian or instrumental associations and cognitive representations) (Berridge and Robinson, ). These component processes also have discriminable neural mechanisms. The three processes can occur together at any time during the reward-behavior cycle, though wanting processes tend to dominate the initial appetitive phase, while liking processes dominate the subsequent consummatory phase that may lead to satiety. Learning, on the other hand, happens throughout the cycle. A neuroscience of reward seeks to map these components onto necessary and sufficient brain networks (see Figure 1).

Causal hedonic hotspots and coldspots in the brain

A) Top shows positive hedonic orofacial expressions (&#x;liking&#x;) elicited by sucrose taste in rat, orangutan, and newborn human infant. Negative aversive (&#x;disgust&#x;) reactions are elicited by bitter taste. B) shows sagittal view of hedonic hotspots in rat brain containing nucleus accumbens, ventral pallidum, and prefrontal cortex. Hotspots (red) depict sites where opioid stimulation enhances &#x;liking&#x; reactions elicited by sucrose taste. Coldspots (blue) show sites where the same opioid stimulation oppositely suppresses &#x;liking&#x; reactions to sucrose. C) Nucleus accumbens blow-up of medial shell shows effects of opioid microinjections in NAc hotspot and coldspot. (red/orange dots in hotspot = % increases in &#x;liking&#x; reactions; blue dots in coldspot = 50% reductions in &#x;liking&#x; reactions to sucrose). Panels show separate hedonic effects of mu opioid, delta opioid and kappa opioid stimulation via microinjections in NAc shell on sweetness &#x;liking&#x; reactions. Bottom row shows effects of mu, delta or kappa agonist microinjections on establishment of a learned place preference (i.e., red/orange dots in hotspot) or place avoidance (blue dots). Surprisingly similar patterns of anterior hedonic hotspots and posterior suppressive coldspots are seen for all three major types of opioid receptor stimulation. Modified from (Castro and Berridge, ).

To study pleasure comprehensively, good human neuroimaging studies are needed to explore correlative encoding of pleasant experiences, and good animal studies are needed to explore causation of underlying hedonic reactions. This two-pronged approach exploits a fundamental duality in hedonic processes, related to the objective versus subjective faces of pleasure (Damasio and Carvalho, ; Kringelbach and Berridge, ; Schooler and Mauss, ; Winkielman et al., ). Pleasure is sometimes assumed to be a purely subjective feeling. But pleasure also has objective features in the form of measurable hedonic reactions, both neural and behavioral, to valenced events. In this review we denote objective hedonic reactions as &#x;liking&#x; reactions (with quotes) to distinguish them from the subjective experience of liking (in the ordinary sense, without quotes). Objective hedonic reactions can be measured in both human and animal neuroscience studies, which together allow some comparisons across species and can lead to a more complete causal picture of how brain systems mediate hedonic impact.

Mapping pleasure in the brain

The experience of one pleasure often seems very different from another. Eating delicious foods, romantic or sexual pleasures, addictive drugs, listening to music, or seeing a loved one: each feels unique. The only psychological feature in common would seem that all are pleasant. However, the difference in one&#x;s subjective experiences is not necessarily a good guide to the underlying neural mechanisms. Those neural mechanisms may overlap to a surprising degree.

Over the last decades, a growing set of results from neuroimaging studies have suggested that many diverse rewards activate a shared or overlapping brain system: a &#x;common currency&#x; reward network of interacting brain regions. Pleasures of food, sex, addictive drugs, friends and loved ones, music, art, and even sustained states of happiness can produce strikingly similar patterns of brain activity (Cacioppo et al., ; Georgiadis and Kringelbach, ; Kringelbach et al., ; Parsons et al., ; Salimpoor et al., ; Vartanian and Skov, ; Veldhuizen et al., ; Vuust and Kringelbach, ; Xu et al., ; Zeki and Romaya, ). These shared reward networks include anatomical regions of prefrontal cortex, including portions of orbitofrontal, insula, and anterior cingulate cortices, as well as often subcortical limbic structures such as nucleus accumbens (NAc), ventral pallidum (VP), and amygdala (shown for rats and humans in Figure 2). An implication of the &#x;common currency&#x; hypothesis is that insights into brain hedonic substrates gained by experiments using one kind of pleasure, such as food &#x;liking&#x;, may apply to many other pleasures too.

Three-dimensional comparison of hedonic sites in rat brain (left) and human brain (right)

A. Rat brain shows hedonic hotspots (red) and coldspots (blue) in coronal, sagittal, horizontal planes and in 3D fronto-lateral perspective view (clockwise from top left). B. Human brain shows extrapolation of rat causal hotspots to analogous human sites in NAc and VP (red), and shows fMRI coding sites for positive affective reactions in green (from text). Human views are also in coronal, sagittal, horizontal and 3D perspective (clockwise from top left of B). The tentative functional networks between the different hotspots and coldspots have been added to give an impression of the topology of a pleasure network. The functional connection lines are not meant to imply direct anatomical projections between two connected structures, but rather a functional network in mediating hedonic &#x;liking&#x; reactions and subjective pleasure ratings. Abbreviations: VP, ventral pallidum; NAc, nucleus accumbens; PBN, parabrachial nucleus; mOFC, medial orbitofrontal cortex; lOFC, lateral orbitofrontal cortex; midOFC, mid-anterior orbitofrontal cortex; dACC, dorsal anterior cingulate cortex; rACC, rostral anterior cingulate cortex; PAG, periaqueductal gray.

Admittedly fMRI measures have limits in spatial and temporal resolution that might miss small or fast differences among neural subsystems that encode particular rewards. It remains possible that more fine-grained spatial and temporal multivariate pattern analysis techniques (Haynes and Rees, ; King and Dehaene, ) will identify subsets of limbic neural circuitry particular to just one type of reward (Chikazoe et al., ). Consistent with this, subtle differences may be found in neuronal firing in animal studies between different sensory rewards, such as tasty foods versus addictive drugs (though some neural differences may be due to accompanying confounds, such as different movements required to obtain the different rewards, or sensory accompaniments, rather than to unique reward encoding per se) (Cameron and Carelli, ). Still, so far, the balance of evidence suggests rather massive overlap between neural systems that mediate rewards of different types. The overlap is far more extensive than many might have expected based on the subjective differences in experiences.

One human brain site that appears especially linked to pleasure in neuroimaging studies is in orbitofrontal cortex, particularly in a mid-anterior subregion (Figures 2 and and3).3). Other medial regions of orbitofrontal cortex, middle anterior regions of insula cortex, and ventromedial regions of prefrontal cortex cortices also correlate with subjective pleasure ratings, but many of these other regions appear to be more concerned with monitoring or predicting reward values than with generating the pleasure per se (Georgiadis and Kringelbach, ; Kahnt et al., ; Kringelbach, ; Kringelbach et al., ; O&#x;Doherty, ; Schoenbaum and Roesch, ; Veldhuizen et al., ; Vuust and Kringelbach, ).

Hedonic coding in the human orbitofrontal cortex (OFC)

In humans, the orbitofrontal cortex is an important hub for pleasure coding, albeit heterogeneous, where different sub-regions are involved in different aspects of hedonic processing. A) Neuroimaging investigations have found differential activity to rewards depending on context in three subregions: the medial OFC (mOFC), mid-anterior OFC (midOFC) and lateral OFC (lOFC). B) A meta-analysis of neuroimaging studies showing task-related activity in the OFC demonstrated different functional roles for these three sub-regions. In particular, the midOFC appears to best code the subjective experience of pleasure such as food and sex (orange), while mOFC monitors the valence, learning and memory of reward values (green area and round blue dots). However, unlike the midOFC, activity in the mOFC is not sensitive to reward devaluation and thus may not so faithfully track pleasure. In contrast, the lOFC region is active when punishers force a behavioural change (purple and orange triangles). Furthermore, the meta-analysis showed a posterior-axis of reward complexity such that more abstract rewards (such as money) will engage more anterior regions to more sensory rewards (such as taste). C) Further investigations into the role of the OFC on the spontaneous dynamics during rest found broadly similar sub-divisions in terms of functional connectivity (Kahnt et al., ) with an optimal hierarchical clustering of four to six OFC regions. This included medial (1), posterior central (2), central (3) and lateral (4&#x;6) clusters with the latter spanning an anterior-posterior gradient (bottom of Fig 3B), and connected to different cortical and subcortical regions (top of Figure 3B). Taken together, both the task-related and resting-state activity provides evidence for a significant role of the OFC in a common currency network. It is also compatible with a relatively simple model where primary sensory areas feed reinforcer identity to the OFC where it is combined to form multi-modal representations and assigned a reward value to help guide adaptive behaviour (Kringelbach and Rolls, ). Images in A are reproduced from (Kringelbach et al., ; Kringelbach et al., ).

It is important to remember that neuroimaging studies are correlational in nature rather than causal, and that the physiological bases of underlying signals (such as the BOLD signal measured with fMRI) are only partly understood (Winawer et al., ). Interpreting correlational signals is complicated. Some correlational neuroimaging activity may of course reflect causal mechanisms for pleasure, while other activity may be a consequence, rather than cause. That is because many brain regions that become active during a normal pleasure may not actually generate that pleasure per se, but rather activate as a step to causally generating their own different functions, such as cognitive appraisal, memory, attention, and decision making about the pleasant event.

However, the mid-anterior subregion of orbitofrontal cortex in particular does appear to track subjective pleasure more accurately than most other limbic regions (Figure 3). One of the strongest tests for pleasure coding is to hold the pleasant stimulus constant across successive exposures, but vary its hedonic impact by altering other input factors such as relevant physiological states. For example, evidence suggests that mid-anterior orbitofrontal activity tracks sensory satiety, involving selective declines in the subjective pleasantness of a given food&#x;s taste after consuming a lot of it, compared to another food which is not devalued (Gottfried et al., ; Kringelbach et al., ). Tracking a change in pleasure of a stimulus is the strongest possible correlational evidence, because it shows the activity is not coding mere sensory features (e.g., sweetness) or other stable confounds. The same region of OFC has also been implicated in the encoding pleasures of sexual orgasm, drugs, and music (Georgiadis and Kringelbach, ; Kringelbach, ; Kringelbach et al., ; Salimpoor et al., ; Veldhuizen et al., ; Vuust and Kringelbach, ). Subcortically, there is evidence from other animals that such selective hedonic changes also may be tracked by activity in nucleus accumbens and ventral pallidum (Krause et al., ; Loriaux et al., ; Roitman et al., ; Tindell et al., ).

Some studies also indicate lateralization of affect representation, often as lateralized hemispheric differences in coding positive versus negative valence. Most notably, the left hemisphere of prefrontal cortex often has been implicated more in positive affect than right hemisphere (Davidson, ). For example, individuals who give higher ratings of subjective well-being may have higher activity in left than right prefrontal cortex, and activity of left subcortical striatum also may be more tightly linked to pleasantness ratings than right-side (Kuhn and Gallinat, ; Lawrence et al., ; Price and Harmon-Jones, ). However, other studies have found more equal or bilateral activity patterns, and so the precise role of lateralization in pleasure still needs further clarification.

An important caveat of human neuroimaging studies is that these have traditionally compared a hedonic activation with a baseline at rest. Recently, it has become clear that the brain is never truly resting but rather spontaneously active and constantly switching between different resting state networks (Cabral et al., ). The switching between different networks depend on the state of the brain, and so one way to think about the pleasure system is to facilitate the state transition between different points in the pleasure cycle to optimize survival. Plausibly, the so-called default mode network may play an essential role in this, and thus problems in orchestrating the state transitions may manifest as anhedonia in affective disorders (Kringelbach and Berridge, ). With advanced computational modelling of human neuroimaging data this is now becoming a testable hypothesis (Cabral et al., ). New efforts have given birth to computational neuropsychiatry as a way to discover novel biomarkers for affective states and in neuropsychiatric disorders, and potentially help rebalance brain networks (Deco and Kringelbach, ).

Mapping brain pleasure generators?

Mapping causal generators of pleasure in the brain is a challenge because it can require invasive brain manipulations, needed to establish evidence for causation, which are ruled out by legitimate ethical constraints in human studies. However, evidence from animal studies is revealing a network of hedonic hotspots that causally enhance &#x;liking&#x; reactions to pleasant stimuli, and coldspots that diminish the &#x;liking&#x; reactions (Figure 2).

A useful starting distinction is between causation of loss versus gain of function. In loss of function, lesions or neural dysfunctions reveal mechanisms that are necessary for normal function. In gain of function, neurobiological stimulations reveal mechanisms that are sufficient to cause higher levels of hedonic impact. While some neural structures mediate both forms of causation for hedonic function, other neural mechanisms may mediate only one: for example, able to produce gains of function that enhance pleasure reactions without being needed for normal pleasure. Brain structures able to cause gains in hedonic function may be more widely distributed than structures needed for normal pleasure reactions, which are more anatomically restricted and subcortically weighted. Further, both forms of causation may be more restricted than the coding activity revealed by neuroimaging correlations with pleasure described above.

As illustration, entire limbic regions of human prefrontal cortex appear surprisingly unnecessary for the causal generation of normal pleasure. For example, the surgical procedure of prefrontal lobotomy, performed on thousands of patients during the s, removed or disconnected most of their prefrontal lobe (Valenstein, ). Yet lobotomy patients retained most hedonic feelings as far as could be discerned (albeit showing impairments in cognitive judgment), as do other human patients with similarly large prefrontal cortex lesions arising from stroke, tumor or injury (Damasio, ; Szczepanski and Knight, ). A dramatic recent report confirmed that even more massive cortical damage, destroying not only prefrontal orbitofrontal and ventromedial cortex but also frontal insula and ventral anterior cingulate cortex (plus hippocampus and amygdala in the rostral temporal lobe), left intact normal behavioral affective reactions to preferred social partners or frightening syringes, and even verbal hedonic reports such as I have a strong feeling of happiness, that we are here together working on these wonderful games (Damasio et al., ).

Stark examples of subcortical causation of normal hedonic reactions in people also include hydranencephalic children, who essentially lack a telencephalic forebrain and have virtually no cortex, yet may still show complex emotional responses to social caregivers and music. For example, Shewmon et al. described complex behavioral hedonic reactions in hydranencephalic children, such as in a 6-year old boy born with congenital absence of cerebral tissue rostral to the thalamus, except for small mesial temporal-lobe remnants (p. ), who still smiled when spoken to and giggled when played with. These human interactions were much more intense than, and qualitatively different from, his positive reactions to favorite toys and music. (p. ) (Shewmon et al., ). Similarly, Merker reported that other hydranencephalic children "express pleasure by smiling and laughter, and aversion by &#x;fussing&#x;, arching of the back and crying (in many gradations), their faces being animated by these emotional states. A familiar adult can employ this responsiveness to build up play sequences predictably progressing from smiling, through giggling, to laughter and great excitement on the part of the child."(p. 79)(Merker, ). Such cases of human emotional reaction without (hardly any) cortex indicate that subcortical structures may be surprisingly competent to generate many normal hedonic reactions, and are consistent with many animal studies.

Desire to dread: an affective keyboard in NAc shell

The anterior NAc opioid hedonic hotspot and posterior suppressive coldspot fit within a broader anatomical NAc pattern of front-to-back valence organization in shell that generates additional emotions beyond &#x;liking&#x; and &#x;disgust&#x;. This NAc pattern resembles an affective keyboard arranged rostrocaudally within medial shell, which can generate intense desire or even dread as well as hedonic impact (Reynolds and Berridge, ; Richard and Berridge, ) (Figure 4). The keyboard pattern is arranged from anterior to posterior ends of medial shell. At its anterior end, it generates predominantly positive-valenced motivations in response to localized neural events such as microinjections of a GABA agonist (muscimol) or of a glutamate AMPA antagonist (DNQX): eating more than twice normal amounts of food, increasing appetitive seeking for food rewards (Stratford and Kelley, ; Stratford and Wirtshafter, ; Wirtshafter et al., ), inducing a conditioned preference for a place paired with the microinjection, and (for GABA microinjections) even increasing &#x;liking&#x; reactions to sweet tastes (Reynolds and Berridge, ). However, as the microinjection site moves more caudally in NAc shell, appetitive behaviors decline. Instead negative &#x;fearful&#x; behavior becomes increasingly intense, and (for GABA) sweet tastes become also disgusting (Faure et al., ; Ho and Berridge, ; Reynolds and Berridge, ; Richard et al., b).

Affective keyboard in nucleus accumbens for desire and/or dread

Top: A rostrocaudal keyboard pattern of generators in NAc for appetitive versus fearful behaviors, showing consequences of microinjections of either glutamate AMPA antagonist or GABA agonist microinjections at rostrocaudal sites in medial shell. Rostral green sites produced % increases in food consumption (desire only). Caudal red sites generated purely increased fearful reactions at levels up to % over normal (escape attempts, distress calls, defensive bite attempts; spontaneous anti-predator treading/burying e). Photos show examples of antipredator treading/burying behavior elicited by threat stimuli: ground squirrel toward rattlesnake predator, rat toward electric-shock prod in lab. The same antipredator behaviors occurs without any specific threat stimulus after DNQX or muscimol microinjections in posterior NAc: denoted by red dots. Yellow sites released both desire and fearful behaviors in the same rats during the same 1-hr test. Just as a keyboard has many notes, bars reflect the many graded mixtures of affective desire-dread released as microinjection sites move rostrocaudal location in medial shell (appetitive desire to eat at top; fearful dread reactions at bottom). Bottom: Environmental ambience retuned the NAc keyboard. A comfortable &#x;home environment&#x; (the rat&#x;s own home room: dark, quiet, smell and sound of conspecifics in the room) suppressed fearful behaviors, and expanded zone for appetitive behaviors, produced by microinjections that block glutamate AMPA receptors (DNQX). A standard laboratory environment rebalances the keyboard into nearly equal halves for desire versus dread. A stressfully over-stimulating sensory environment (bright lights plus loud rock music) tilted the causal keyboard toward dread, and shrank the zoned that generated appetitive desire. Squirrel photo by Cooke from (Coss and Owings, ). Figure data modified from (Richard et al., a), based on data from (Reynolds and Berridge, ; Richard and Berridge, ).

Of course, several other brain structures, from amygdala to hypothalamus, ventral pallidum or brainstem also known to mediate various aversive emotional reactions, including fear, pain or disgust (Baliki et al., ; LeDoux, ; von dem Hagen et al., ). The amygdala is especially crucial for fear-related learning of passive responses to threats, such as freezing to a Pavlovian cue that predicts footshock (LeDoux, ; Maren et al., ). The posterior NAc instead produces a more active set of fearful coping reactions (Faure et al., ; Reynolds and Berridge, ; Richard et al., b). For example, these include distress calls and frantic escape leaps by a normally tame rat when approached or touched by a human hand, and even defensive bites directed toward the offending hand, as active unconditioned &#x;fearful&#x; responses. Or when left alone after a microinjection, the rat spontaneously often emits &#x;fearful&#x; antipredator reactions that rodents typically use in the wild to defend against natural threats (e.g., defensive burying toward a rattlesnake) (Coss and Owings, ). These defensive reactions are usually targeted toward stimuli the affected rat may perceive as potentially threatening, such as glittering transparent corners of the cage or experimenters visible beyond the transparent wall (Coss and Owings, ; Reynolds and Berridge, ).

Multiple anatomical modules in NAc shell

The number of differently-valenced rostrocaudal keys contained in the nucleus accumbens shell is difficult to estimate, and in practice is defined somewhat arbitrarily by the size of the microinjections used to tap the keyboard. But probably it contains more than two keys corresponding to mere positive vs negative valence: two keys would generate only two outputs, but the NAc shell generates many different incremental outputs of gradual variation depending on precise site. Just as a musical keyboard generates many distinct notes, the rostrocaudal affective keyboard generates multiple distinct quantities of appetitive versus fearful behaviors. For example, as sites move from front to back, intense behaviors become gradually less appetitive, and incrementally more fearful, so that many different ratio mixtures are produced, just as moving a brick along a piano keyboard would generate many different mixtures of notes changing gradually in pitch.

However, a causal caveat may be needed here. To say an appetitive mechanism is densest in the anterior half of NAc shell may really be to say that the anterior half is densest in neural mechanisms which ordinarily inhibit appetitive behavior &#x; and which themselves must be inhibited by the rostral microinjection that produces the intense appetitive behavior. This disinhibition interpretation arises because of the inhibitory nature of the GABA_A agonist or glutamate antagonist microinjections that produce the intense behaviors. The drug microinjections either hyperpolarize NAc neurons (i.e., muscimol stimulates GABA receptors) or at least block excitatory depolarizations of NAc neurons (i.e., via DNQX blocks glutamate AMPA receptors).

Both drugs produce similar motivation keyboard patterns of intense appetitive-fearful behaviors when microinjected in medial shell, and the GABA agonist adds a corresponding hedonic keyboard of &#x;liking-disgust&#x; effects (Faure et al., ; Richard and Berridge, ). A disinhibition interpretation suggests that reduced activity of NAc projection neurons, which themselves release mostly GABA, would release or disinhibit recipient neurons in target structures into relative excitation (e.g., in VP, hypothalamus, or ventral tegmentum) (Carlezon and Thomas, ; Meredith et al., ; Roitman et al., ). Target excitations could be the final active mechanism to produce intense motivations. Output projections from particular rostrocaudal sites in NAc shell appear partly segregated from each other in target structures (Thompson and Swanson, ; Zahm et al., ), which might help tune the valence of intense desire/dread motivations produced at different NAc sites. Although some contrary evidence suggests that local NAc excitations also generate motivated behaviors (Britt et al., ; Taha and Fields, ), this disinhibition hypothesis at least does potentially account for many features of NAc in motivation (Carlezon and Thomas, ), including the NAc keyboard production of &#x;desire&#x; versus &#x;fear&#x;.

Retuning the affective keyboard

Strikingly, the valence of desire-dread motivations generated by the NAc keyboard is not necessarily fixed by anatomical location, but can be powerfully retuned psychologically for many sites by emotional factors such as the valenced ambience of an environment (Figure 4). At least, dramatic psychological retuning occurs for the glutamate-related DNQX gradient that merely blocks local NAc excitation (Reynolds and Berridge, ; Richard and Berridge, ). By comparison, the GABA-related muscimol gradient is more resistant to retuning, perhaps because it involves stronger neuronal NAc hyperpolarization (Richard et al., b). Retuning can completely reverse the valence generated at a site from desire to dread, or back from dread to desire. For example, the fear-generating zone of caudal shell expands in a stressfully bright and loud environment to invade rostral shell, while simultaneously shrinking the desire-generating zone to only the far-rostral tip of medial shell (Reynolds and Berridge, ; Richard and Berridge, ). Conversely, a quiet home-like environment (which rats prefer) causes the NAc keyboard to expand its rostral desire-generating zone into the caudal half of shell, and shrink the fear-generating zone into merely the far-caudal tip. Such remapping can actually flip many intermediate sites of shell into releasing opposite motivations in the different environments.

Speculatively, it can be hypothesized that some pathological human conditions might induce more permanent retuning of NAc valence generators. For example, post-traumatic stress disorder might persistently retune NAc generation in a fearful direction in human patients, similarly to a stressful ambience. Conversely, human addiction and mesolimbic sensitization might retune NAc generators in an appetitive direction, potentiating desire for addicted rewards. These possibilities could be explored by future research.

For the glutamatergic keyboard in rats, the neurobiological mechanism of psychological retuning appears to rewire local neurobiological modes of neurochemical activation within the local NAc microdomain. For example, generation of &#x;fear&#x; behaviors by NAc AMPA blockade requires endogenous dopamine activity at both D1 and D2 receptors simultaneously within the local microinjection site; the defensive motivation can be prevented by adding an antagonist for either dopamine receptor to the eliciting DNQX microinjection (Faure et al., ; Richard and Berridge, ). By contrast, generation of appetitive desire, even at the same NAc site, requires only D1 activity &#x; not D2 activity (Richard and Berridge, ). That pattern suggests that direct and indirect output paths of NAc may have different roles in this desire-dread generation. Dopamine D1 receptors occur mostly on NAc neurons belonging to the &#x;direct&#x; output path that includes a projection directly to ventral tegmentum, whereas D2 receptors occur mostly on neurons belonging to the &#x;indirect&#x; output path that projects only to VP and hypothalamus (Humphries and Prescott, ). Thus both paths may be equally important in producing the intense &#x;fearful&#x; reaction, whereas positive &#x;desire&#x; generation may be dominated by the direct path (Richard and Berridge, ). If so, that would be consistent with suggestions from others that a NAc D1 direct path dominates in appetitive motivation (Xiu et al., ).

Finally, NAc keyboard tuning is regulated by corticolimbic top-down inputs from prefrontal limbic cortex (Richard and Berridge, ). For example, raising local cortical excitations in infralimbic cortex, a medial prefrontal region homologous to human subgenual anterior cingulate cortex (Area 25), broadly suppressed the intensity of motivations otherwise produced by simultaneous NAc microinjections, regardless of valence (Richard and Berridge, ). By comparison, excitation of the orbitofrontal cortex tilted valence in a positive desire direction: at least in the sense of expanding the appetitive zone that generates eating into caudal areas of NAc that otherwise produce negative &#x;fear&#x; reactions (Richard and Berridge, ). Thus corticolimbic regulation adjusts both the intensity and valence of motivations produced by NAc circuitry.

Pruning false candidates: Mesolimbic dopamine and &#x;pleasure electrodes&#x;?

Beyond identifying brain mechanisms that cause subjective feelings of pleasure or objective hedonic reactions, progress in affective neuroscience is also aided by pruning away previous candidates for pleasure generators that have failed to live up to their initial hedonic promise. In our view, two of the most famous brain candidates for pleasure mechanisms featured in textbooks of the past few decades turn out in the end to lack sufficient evidence needed to maintain their hedonic claim: 1) mesolimbic dopamine systems that are activated by many reward-related stimuli, and 2) most so-called &#x;pleasure electrodes&#x; for deep brain stimulation that supported behavioral self-administration (i.e., animals or people were willing to work to stimulate the electrodes, such as by pressing a button). As discussed next, our view is that neither dopamine nor most &#x;pleasure electrodes&#x; actually caused hedonic reactions or pleasure after all, but rather more specifically increased motivation components of reward such as incentive salience, producing &#x;wanting&#x;, without causing &#x;liking&#x; or true hedonic impact.