Sorting out dopamine's role in reward

Since the 1970s, neuroscientists have been confident that dopamine plays an essential role in the brain's processing of rewarding experiences. And many researchers used to be fairly certain they knew exactly what that role was. Dopamine was, as the thinking went, the "pleasure neurotransmitter"---the substance responsible for producing sensations of pleasure in the brain, regardless of whether that pleasure comes from enjoying a good meal, having sex, or snorting cocaine. This understanding, according to a 1997 article in Time magazine, made the answers to questions about what causes addiction, "simpler than anyone has dared imagine." The article goes on to claim that dopamine "is not just a chemical that transmits pleasure signals but may, in fact, be the master molecule of addiction."

2-Minute neuroscience video on dopamine.

The popular press was not completely unjustified in making this assumption, as they took their cues from scientists---many of whom had, to some degree, become advocates for the "pleasure neurotransmitter" perspective. For example, well-known dopamine researcher Roy Wise said in a 1980 article that dopamine was involved in creating experiences of "pleasure, euphoria, or 'yumminess'."

This all, of course, was an oversimplification of dopamine's role in reward. Some time (and more research) allowed everyone to recognize that dopamine's contribution to processing rewarding experiences is much more complex than a simple equation where dopamine = pleasure. This realization is now becoming pervasive, and googling "dopamine and addiction" will return almost as many articles on the first page that emphasize the nuances of dopamine function as those that stick to the simplistic dopamine = pleasure formula. Wise eventually changed his mind as well, asserting in the late 1990s that he no longer believed "that the amount of pleasure felt is proportional to the amount of dopamine floating around in the brain."

Today, even those who are only modestly familiar with current hypotheses in neuroscience would likely be able to tell you that dopamine is not the pleasure molecule. Still, they might have a hard time answering the question, "What, then, is its role in reward?" That's partially because no one knows the answer to that question for sure. There are, however, a few popular competing hypotheses that have been proposed in an attempt to elucidate dopamine's reward-related functions.

First, the basics

Dopamine pathways in the brain. The blue lines extend from the ventral tegmental area to the nucleus accumbens (red dot) to illustrate the mesolimbic dopamine pathway. Another blue line extends from the ventral tegmental area to the cerebral cortex, making up the mesocortical dopamine pathway. The purple lines represent the nigrostriatal dopamine pathway, which extends from the subdstantia nigra to the striatum.

The early hypotheses about dopamine's role in reward were formulated based on the evidence that collections of dopamine neurons in the brain tend to be activated in response to the administration of addictive drugs (and other substances generally considered to be rewarding, like sweet foods). Activity in one such collection of neurons in particular, a pathway that stretches from a dopamine-rich area in the midbrain called the ventral tegmental area (VTA) to a nucleus in the forebrain called the nucleus accumbens, has consistently been linked to rewarding events. When someone experiences something rewarding (like snorting a line of cocaine), dopamine neurons in the VTA are activated and send dopamine to the nucleus accumbens, causing dopamine levels in the nucleus accumbens to rise.

This pathway from the VTA to the nucleus accumbens is called the mesolimbic dopamine pathway. It has come to be considered the primary component of what is now known as the reward system, which consists of a group of structures that are activated by rewarding or reinforcing stimuli like addictive drugs. The reward system also includes a number of other structures---as well as other dopamine pathways, such as the mesocortical dopamine pathway, which stretches from the nucleus accumbens to destinations in the cerebral cortex.

The case against dopamine as the "pleasure neurotransmitter"

Although it should be said that there is a great deal of evidence that indicates dopamine release is correlated with pleasure, there is also substantial evidence that suggests dopamine isn't responsible for causing pleasure. 

Much of this evidence comes from animal studies. For example, when researchers damaged dopamine neurons in the brains of rats to the point where dopamine in the nucleus accumbens was depleted by up to 99%, rats still exhibited pleasurable reactions to sweet tastes, indicating some component of pleasure was left intact. In monkeys being trained to obtain juice rewards, once they learned the necessary tasks and could predict exactly when they would receive a reward, their dopamine neurons stopped firing in response to such rewards. Yet, they still seemed to enjoy the rewards, suggesting dopamine may be involved in signals about the predictability of rewards, but not the pleasure linked to them. 

There is also evidence from humans that suggests that dopamine is not the substance that generates pleasure. In one study, for example, researchers found that dopamine levels in the ventral striatum (a region of the brain that contains the nucleus accumbens) correlated better with craving for amphetamine than with the pleasure experienced from taking the drug. In another study, administration of a dopamine antagonist (which blocks dopamine activity) did not prevent participants from experiencing euphoria after amphetamine administration.

Additionally, studies have found that mesolimbic dopamine neurons also can be be activated during experiences that are aversive---which only further complicates any attempt to consider dopamine the "pleasure neurotransmitter."

These are just a handful of examples that contradict the idea that dopamine is the primary pleasure-causing substance in our brains. The whole body of evidence that is at odds with the perspective is much larger, and it is widely accepted in neuroscience today that dopamine's role in reward is more complicated than the "pleasure neurotransmitter" moniker implies.

Other hypotheses: reward learning, reward prediction, and incentive salience

Reward learning

When it became clear to most researchers that dopamine was not responsible for creating sensations of pleasure, new roles were suggested for dopamine. Many scientists, for example, postulated that the neurotransmitter is involved in some aspect of learning about rewards. Along these lines, it has been suggested that dopamine is involved in the process of linking a pleasurable experience to a stimulus that previously had no value----like associating the pleasure of inebriation with alcohol after drinking it for the first time.

When someone experiences something pleasurable, their brain creates a strong association between that experience and whatever is thought to have caused it. Thus, the brain of someone who drinks alcohol for the first time (and enjoys it) will make a strong connection between alcohol and pleasure (previously alcohol would not have had any value to them because they never would have experienced its effects). Dopamine may be responsible for making that connection. 

Similarly, others have proposed that dopamine not only allows for the learning of a new association between some stimulus and pleasure, but that it also is involved in the acquisition of new habits dedicated to obtaining that rewarding stimulus again in the future. In the case of addictive drugs, these habits can become especially persistent, generating patterns of compulsive behavior that persist long after the value of the reward has diminished. 

Reward prediction

Perhaps the most popular hypothesis that posits a role for dopamine in reward learning is the suggestion that dopamine is involved in identifying potentially rewarding stimuli, predicting how valuable those rewards are likely to be, and then responding strongly whenever something turns out to be more rewarding than was originally expected. This type of signaling is often referred to as reward prediction error signaling. 

According to the reward prediction error hypothesis, dopamine neurons are highly active when rewards turn out to be more valuable than predicted and their activity is depressed when a reward is found to be less valuable than expected. This dopamine signaling acts as a mechanism to help us learn what to expect from rewards in the future; in other words, it helps to "train" the brain about what value a potential reward is likely to have. This information can be used to guide behavior, as it can help us determine which rewards are most desirable---and thus which we should pursue.

Additionally, the reward prediction error hypothesis provides us with a way of explaining addiction. According to this hypothesis, addiction can occur when addictive drugs (or other experiences or substances) generate high levels of dopamine release that lead to a reward being overvalued. This causes an individual to develop exceedingly high expectations of the pleasure that will be obtained from the drug reward, which leads to compulsive drug seeking. In essence then, addiction occurs because high levels of dopamine release cause an addict to consistently predict a drug will make them feel better than it really will. This corresponds to anecdotal accounts of drug addiction, where many addicts describe their drug-using experience as a series of failed attempts to recreate the pleasure they felt from their first high.

Incentive salience

Another related, but slightly different perspective asserts that it is critically important to separate behavior surrounding a reward into (at least) two responses that are distinctly different but often confused for one another: "wanting" and "liking." "Liking" refers to the pleasurable response to a reward, while "wanting" refers only to the motivation to obtain a reward.

Think, for example, of a time when you were eating at a delicious restaurant but near the end of the main course you were uncomfortably full. Perhaps the waiter, however, left your plate sitting in front of you for some time (maybe while the rest of your party finished). During that time, you may have continued to occasionally take more bites of the food even though your ability to enjoy it was completely diminished due to your fullness. This could be considered an example of the difference between "liking" and "wanting." You still wanted the food and compulsively took bites of it because your brain had identified it as rewarding, but you no longer really liked the food due to your current state of fullness.

Proponents of the incentive salience hypothesis suggest that dopamine plays a critical role in generating "wanting"---a motivated response to attain rewards based on a previous experience with those rewards in which they were deemed to be valuable. Incentive salience involves "wanting" that is associated with some motivational goal (like obtaining a drug).

According to the incentive salience perspective, when we experience something rewarding, our brains (with the help of dopamine) assign incentive salience not only to whatever directly caused the rewarding experience (e.g. a drug), but also to any other stimuli associated with the reward. In the process, our brains become hypersensitive to the rewarding stimulus and anything we have come to associate with it. This hypersensitivity and increased propensity to generate strong feelings of desire can form the basis of an addiction.

For example, someone who has never smoked a cigarette likely would find the smell of cigarette smoke to be unpleasant---or at best neither pleasant nor unpleasant. In the brain of a smoker, on the other hand, an association has been made between the smell of cigarette smoke and reward---incentive salience has been attributed to the smoke because the brain has deemed it an important part of the rewarding experience of cigarette smoking. Thus, upon smelling cigarette smoke, the brain will likely stimulate mechanisms that prompt "wanting" of a cigarette, also known as craving.

These associations between "wanting" and smoking-related stimuli can lead to cravings every time a smoker is exposed to a smoking-related stimulus (e.g. the smell of smoke, seeing someone else smoking, etc.)---which can lead to the type of repetitive smoking that has the propensity to precipitate or intensify addiction to nicotine. According to the incentive salience hypothesis, this increased sensitivity to reward-related stimuli can persist for years, which could help to explain why those who develop an addiction often feel as if they are always susceptible to it---even after years of sobriety.

The broad view

These perspectives are not mutually exclusive, and there is clearly some overlap among them. For example, reward prediction and the attribution of incentive salience are both likely to be important aspects of learning about rewards. Thus, it is not improbable that some elements of each hypothesis accurately explain the role of dopamine in reward. 

It's important to remember, too, that there is no contradiction in saying that dopamine may be involved in all of these components of reward processing (as well as with processing aversive experiences). Dopamine, like other neurotransmitters, may exert different actions depending on the subtype of receptors it acts on, the part of the brain its action is occurring in, and even the time course by which it is being released. We must become comfortable giving up our attempts to define neurotransmitters by a short list of actions, as such a simplistic view of neurotransmitter function does not seem to be based in reality.

The consensus, then, is that dopamine is not the substance in our brains that causes pleasure. Instead, it is thought to be involved in some other aspects of reward, but its precise role is still being debated. Regardless, dopamine seems to be more closely associated with reward than most other neurotransmitters, and it is likely to play a paramount role both in processing rewarding experiences and in the pathological states, like addiction, that are linked to faulty reward valuation.

References (in addition to linked text above):

Berridge KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007 Apr;191(3):391-431. Epub 2006 Oct 27.

Further reading:

Know your brain: Reward system

Know your brain: Nucleus accumbens

Know your brain: Locus coeruleus

Where is the locus coeruleus?

The locus coeruleus, which I'll refer to as the LC from here on out to avoid an inevitable misspelling, is a nucleus found in the pons. It is located near the floor of the fourth ventricle.

What is the locus coeruleus and what does it do?

The first descriptions of the LC date back to the late 1700s when French anatomist Félix Vicq d’Azyr detailed a blue-colored area of tissue in the pons. In the early 1800s, the term locus coeruleus, which means "blue spot" in Latin, was used to refer to that pigmented region. It wasn't until the second half of the twentieth century, however, that new techniques allowed scientists to learn that the blue coloring in the LC is caused by the production of a pigment formed by chemical reactions involving the neurotransmitter norepinephrine (also known as noradrenaline).

It is now known that the LC is the primary site of norepinephrine production in the brain. The nucleus sends norepinephrine throughout the cerebral cortex as well as to a variety of other structures including the amygdala, hippocampus, cerebellum, and spinal cord. In fact, the LC sends projections to virtually all brain regions except the basal ganglia, which seems to be lacking noradrenergic (i.e. noradrenaline/norepinephrine-related) input.

Because of the diversity of its projections and the diversity of the actions of norepinephrine as a neurotransmitter, the LC is involved in a long list of functions. It is perhaps most strongly linked, however, to arousal, vigilance, and attention. Neurons in the LC are less active during quiet wakefulness and their activity is even more diminished during sleep (indeed they are completely quiet during rapid eye movement, or REM, sleep), but they display increased activity in response to arousing stimuli. And optimal levels of norepinephrine in areas of the brain involved with attention, like the prefrontal cortex, have been found to be important to the facilitation of attention-related tasks.

Additionally, the LC and the norepinephrine it produces are thought to be integral to a number of higher cognitive functions ranging from motivation to working memory. It also seems to play a role in fine-tuning sensory signals to increase acuity across multiple sense modalities. It should be noted, however, that norepinephrine has wide-ranging actions throughout the brain and any attempt to briefly summarize its functions (or, by extension those of the LC) is an oversimplification.

Aging is associated with a significant loss of neurons in the LC, and a number of disorders---including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy---are linked to deficits in the number of LC neurons. In fact, in Alzheimer's disease the number of LC neurons lost exceeds the number of acetylcholine neurons lost in the nucleus basalis and in Parkinson's disease the number of LC neurons lost exceeds the number of dopamine neurons lost in the substantia nigra. This is notable because neuronal loss in the nucleus basalis and substantia nigra are considered hallmark signs of Alzheimer's disease and Parkinson's disease, respectively. Although the impact of LC loss in these diseases is not fully understood, it is thought to contribute significantly to the pathology of these conditions.

References:

Counts SE, Mufson EJ. Locus Coeruleus. JK Mai and G Paxinos (Eds.). 2012; Elsevier, New York.

Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009 Mar;10(3):211-23. doi: 10.1038/nrn2573.

2-Minute Neuroscience: Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the most widely-used treatment for depression, and have been since their introduction to the market in the late 1980s. They were formulated based on the hypothesis that depression is caused by low levels of the neurotransmitter serotonin. In this video, I discuss how SSRIs work along with some questions that have been raised about the serotonin hypothesis since the introduction of SSRIs.

Know your brain: Inferior colliculus

Where is the inferior colliculus?

INFERIOR COLLICULI AS SEEN WHEN LOOKING AT THE POSTERIOR SIDE OF THE BRAINSTEM.

There are two inferior colliculi in the midbrain. They are symmetrically positioned, one on either side of the midline of the brainstem, and they form two bumps on the posterior surface of the brainstem just below the superior colliculi. The inferior colliculus is often subdivided into three regions: a central nucleus, dorsal cortex, and external cortex. The names of these last two regions are not completely consistent (e.g. some sources refer to the dorsal cortex as the pericentral nucleus and the external cortex as the lateral nucleus). The dorsal cortex and external cortex surround the central nucleus.

What is the inferior colliculus and what does it do?

The inferior colliculus is best known for its role in hearing. It is the largest nucleus of the auditory system in humans, and it is the point in the brainstem where all auditory pathways traveling through the brainstem converge. It is also the point from which auditory pathways branch out to carry auditory information on to other areas of the brain like the superior colliculus or thalamus.

The central nucleus of the inferior colliculus receives information from a number of auditory regions, including the cochlea itself as well as other areas like the superior olivary nuclei. The central nucleus also extends neuronal fibers to the medial geniculate nucleus of the thalamus, another important nucleus in the auditory pathway. From there, information travels to the cerebral cortex. Thus, the inferior colliculus acts as an important relay station for auditory information.

It's also thought, however, that the inferior colliculus plays important roles in integrating auditory information from various auditory nuclei, as well as in fine-tuning that information. The cells of the central nucleus of the inferior colliculus are organized tonotopically, meaning that different neurons respond preferentially to different frequencies of sound. Activation of neurons linked to a particular frequency, along with the inhibition of those that respond to different frequencies, may help to sharpen the perception of sound.

Additionally, neurons in the inferior colliculus are specialized to respond to cues (e.g. intensity, the difference in arrival time of a sound to both ears, etc.) that allow for the localization of sound, or the determination of where in space sound is coming from. This information is transmitted to the superior colliculus, which is involved with movement (e.g. of the head and eyes) in response to visual and auditory cues in the environment. There are also direct connections between the inferior colliculus and cortical areas involved in the control of gaze, perhaps to facilitate complex tasks of gaze control that involve aspects of memory, recognition, and other more sophisticated types of cognition.

These functions are all attributable to the central nucleus. The roles of the external and dorsal cortices are not as well understood. Although the external cortex receives input from auditory areas, it also receives information regarding bodily sensations, and is hypothesized to play a role in the representation of bodily position in respect to sounds in the environment. Damage to the dorsal cortex has been found to produce greater deficits in attention and vigilance than hearing, but its role is still in need of further clarification. 

Thus, more work needs to be done to completely understand the functions of the inferior colliculus, but at this point it is clear that the structure is an important component of the auditory pathway. It is involved in fine-tuning and integrating auditory sensations from a variety of other auditory regions, and sending that information on to the thalamus and cerebral cortex. It also is important to identifying the location of sound in space and orienting the body towards such sounds. Its other functions will likely become clearer with future research.

Oertel D, Doupe AJ. 2000. The Auditory Central Nervous System. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science, 5th ed. New York: McGraw-Hill.

Winer JA, Schreiner CH. 2005. The Central Auditory System: A Functional Analysis. In: Winer JA, Schreiner CH, eds. The Inferior Colliculus. New York: Springer Science + Business Media, Inc. 

Know your brain: Wernicke's area

Where is Wernicke's area?

approximate location of wernicke's area

Although the location of Wernicke's area is often presented in images and texts as definitive, there is some controversy about the exact location of the region. Typically, however, Wernicke's area is considered to reside in the cortex of the left cerebral hemisphere, surrounding a large groove called the lateral sulcus or Sylvian fissure, near the junction between the parietal and temporal lobes.

What is Wernicke's area and what does it do?

In the second half of the 19th century, neuroscientists were trying to come to grips with a new perspective on the brain that suggested that the two cerebral hemispheres were not completely equivalent in terms of function. The most convincing evidence to support this perspective at that point had been offered up by the famous physician Paul Broca, who had identified a number of cases where damage to the left hemisphere produced deficits in language---whereas damage to the right hemisphere was much less likely to do so. These observations coincided with Broca's identification of what would come to be known as Broca's area---a brain region typically found in the left hemisphere that is thought to be important to the production of speech (see this article for more about Broca's area).

This idea that one hemisphere could be more responsible for a behavior than the other---and in this case that the left hemisphere was dominant when it came to language---was mostly foreign to neuroscientists before Broca (although not completely unheard of as it had previously been proposed by the physician Marc Dax). Many were hesitant to accept it.

Left hemispheric dominance for language got some additional support, however, from the German physician Carl Wernicke in 1874. Wernicke reported that damage to a certain region in the left hemisphere often resulted in a speech deficit where patients were able to produce speech sounds that resembled fluent language, but actually were meaningless. These patients would string together incongruous syllables, neologisms, similar-sounding words substituted for one another, and so on, to produce speech that made little sense. Patients with this disorder, which would come to be known as Wernicke's aphasia, usually also suffer from a deficiency in their ability to understand language. You can see an example of Wernicke's aphasia in the video above.

Wernicke's aphasia contrasted with the syndrome Broca had observed after damage to Broca's area (that syndrome is known as Broca's aphasia). Patients with Broca's aphasia generally have difficulty producing the sounds necessary for speech. Often a patient with Broca's aphasia knows what he or she wants to say, but can't get the words out. Comprehension of language generally remains intact. You can see an example of Broca's aphasia in the video to the right. 

Because Wernicke's area seemed to play an important role in language comprehension and the production of language that was intelligible, Wernicke proposed a model for language that involved both his area and Broca's area. Wernicke's area, according to this model, generates plans for meaningful speech. Broca's area, on the other hand, is responsible for taking these plans and generating the movements (e.g. of the tongue,  mouth, etc.) required to turn them into vocalizations. To do so, Broca's area sends information about intended speech to the motor cortex, which then signals the muscles involved in speech production to create the vocalizations. Thus, according to this view, Wernicke's area makes sure that language makes sense, while Broca's area helps bring about the muscle movements necessary to actually produce the sounds.This model was later expanded upon by neurologist Norman Geschwind, and it eventually became known as the Wernicke-Geschwind model.

It is now thought, however, that this model is too simplistic. Language is a complex behavior made possible by a list of individual functions---ranging from the retrieval of particular phonemes to the adding of intonation and rhythm---that each likely involves widespread networks; it cannot simply be boiled down to a connection between two brain regions. Additionally, later studies have found that the functions of Broca's and Wernicke's areas are not as circumscribed as once thought. For example, Wernicke's area seems to play a role in speech production and Broca's area contributes to language comprehension. And damage to what is considered Wernicke's area does not always disrupt comprehension, which suggests Wernicke's area is just one component in a larger network involved in understanding language. 

Wernicke's area is thus not as anatomically well defined nor functionally well understood as many textbooks would lead you to think. It is thought to be important to language, but researchers are still trying to work out exactly what its role is. It's likely that it functions as part of a larger network, which---when fully understood---might allow us to appreciate the network as the important functional unit for language, rather than focusing so much on the individual brain regions that make up the network.

References:

Binder, JR. The Wernicke area: Modern evidence and a reinterpretation. Neurology. 2015; 85(24): 2170-2175.

Breedlove SM, Watson NV. Biological Psychology. 7th ed. Sunderland, MA: Sinauer Associates, Inc.; 2013.