2-Minute Neuroscience: Amygdala

In this video, I discuss the amygdala. The amygdala is a collection of nuclei found in the temporal lobe; it is best known for its role in fear and threat detection, but its full range of functions is much more diverse. I discuss some of the major nuclei of the amygdala, a common scheme for the anatomical organization of the amygdalar nuclei, and some of the functions that have been associated with the amygdala ranging from threat detection to the processing of positive stimuli.

The amygdala: Beyond fear

The amygdala---or, more appropriately, amygdalae, as there is one in each cerebral hemisphere---was not recognized as a distinct brain region until the 1800s, and it wasn't until the middle of the twentieth century that it began to be considered an especially significant area in mediating emotional responses. Specifics about the role of the amygdala in emotion remained somewhat unclear, however, until the 1970s and 1980s when it was studied in fear conditioning experiments in rodents. A typical fear conditioning experiment in rodents involves pairing an aversive stimulus (e.g. an electrical shock to the feet) with a previously neutral stimulus like an audible tone until the rodent begins to display signs of fear at simply hearing the tone. Using this experimental approach, researchers were able to demonstrate that functioning amygdalae are very important for rodents to learn the fear responses typically seen as a result of fear conditioning.

From this time on, research began to accumulate that identified the amygdala as having an integral role in fear in general. And thus was born the conception of the amygdala as a "threat-detector." According to this view, the amygdala helps us to identify threats in our environment and---if threats are present---to initiate a fight-or-flight response. This basic understanding of the function of the amygdala is repeated in many textbooks and classrooms---and has even found its way into popular culture. The problem is, however, that this is an oversimplified view of the amygdala. Yes, the amygdala seems to play a significant role in fear. But it is also likely involved in a slew of other behaviors and emotional responses.

An intricate structure with manifold connections

The name amygdala comes from the Greek word for almond, and the amygdala earned this designation because it is partially composed of an almond-shaped structure found deep within the temporal lobes. The almond-shaped structure, however, is just one nucleus of the amygdala (the basal nucleus)---for although it is often referred to as one entity, the amygdala is actually made up of a collection of nuclei along with some other distinct cell groups. The nuclei of the amygdala include the basal nucleus, accessory basal nucleus, central nucleus, lateral nucleus, medial nucleus, and cortical nucleus. Each of these nuclei can also be partitioned into a collection of subnuclei (e.g. the lateral nucleus can be divided into the dorsal lateral, ventrolateral, and medial lateral nuclei). 

Exactly how the amygdala should be divided anatomically has been the subject of some debate, and no clear consensus has been reached. Many researchers group the lateral, basal, and accessory basal nuclei together into a structure referred to as the basolateral complex, and sometimes the cortical and medial nuclei are aggregated as the cortico-medial region. However, there is even a lack of consistency in the application of these terms. For example, some investigators use the basolateral designation to refer to the complex mentioned above, while others use it to refer to just the basal nucleus or basolateral nucleus specifically. Thus, the anatomy of the amygdala is much more complex than is often implied in simple descriptions of the structure. Indeed, the complexity is significant enough that neuroanatomists still have a hard time agreeing on how the different components of the amygdala should be categorized.

In addition to its anatomical diversity, the amygdala has abundant connections throughout the brain---connections that are widespread and divergent enough to suggest many functions beyond just threat detection. For example, many areas of the prefrontal cortex as well as sensory areas throughout the brain have bidirectional connections with the amygdala. The amygdala also has projections that extend to the hippocampi, basal ganglia, basal forebrain, hypothalamus, and a variety of other structures.

Evidence for diversity of function

It is true there is ample evidence that suggests the amygdala is important in the processing of fearful emotions and the identification of threatening stimuli. However, there is also a significant amount of evidence pointing to functions for the amygdala beyond simple threat detection. For example, studies have found the amygdala to be active not just during fear conditioning, but also when learning to link a previously neutral stimulus with a positive experience. Indeed, these studies suggest the amygdala may be involved in learning to assign a positive or negative value to a neutral stimulus, suggesting it has a role in assigning value in general and in the formation of positive and negative memories.

Due to its role in assigning value to stimuli and then creating memories about such valuations, it may not be surprising that some have implicated the amygdala in addictive behaviors. The amygdala has been shown to interact with reward areas of the brain like the ventral striatum, and it seems to play an important role in forming memories associated with drug use. Studies have found, for example, that disrupting amygdala function can inhibit the ability of rodents to learn positive associations with drugs like cocaine. Thus, disrupting activity in the amygdala can also disrupt the acquisition of drug-taking behavior in rodents.

Therefore, instead of being involved only with aversive memories and the learning of conditioned responses to fearful stimuli, the amygdala has come to be considered an important region for the consolidation of memories that have any strong emotional component---whether positive or negative. And this is still really only scratching the surface of the function of this complicated structure. Some studies have suggested, for example, that the amygdala plays a key role in social interaction, others have linked it to aggressive tendencies, and still others have indicated that amygdala connectivity may help to predict sexual orientation.

It may be involved with all of these things. Because the amygdala is a complex structure made up of multiple nuclei, it is unlikely it would serve only one function like "fear detection." Indeed, it is probably unlikely it would even be involved with only one large category of function like emotions. Simplifying the functions of a structure like the amygdala does help to make the brain easier to understand on a superficial level, but it's important to keep in mind that when we do so we are avoiding a more complicated reality in order to make the details of the organ more comprehensible. Although this can be a useful tactic, if we forget we are using it we can hinder the attainment of a more complete understanding of a structure by focusing too much on the simplified model.

LeDoux J. The amygdala. Curr Biol. 2007 Oct 23;17(20):R868-74.


Watch this 2-Minute Neuroscience video to learn more about the amygdala.

Prejudice in the brain

Despite the great strides that have been made toward a more egalitarian society in the United States over the past 50 years, events like what occurred in Ferguson last month are a bleak reminder of the racial tensions that still exist here. Of course, the United States is not alone in this respect; throughout the world we can see abundant examples of strain between different races, as well as between any groups with dissimilar characteristics. In fact, it seems that the quickness with which we form a negative opinion about those who are not members of the same group as us may be characteristic of human nature in general, as its effects have been pervasive throughout history, and it persists even when we attempt fastidiously to stamp it out.

Indeed, it may be that our inclination towards prejudicial thinking has its roots in what was once an adaptive behavior. Some argue that our ancient hominid ancestors may have benefited from living in small groups, as this allowed for joint efforts in gathering and protecting resources. A logical offshoot of the development of group living would have been the emergence of skill in being able to tell members of your group apart from those who were not. It might have paid off to be wary of those who were not part of your group, as they would have been more likely to pose a threat. According to this evolutionary hypothesis, prejudice--which can be defined as an opinion of someone that is formed based on their group membership--may be the result of this strategy being so effective in the past. In essence, we may be saddled with the mindset of our evolutionary ancestors, which makes us more skeptical at first of anyone whom we see as "different" than us.

Prejudice and the amygdala

If prejudice is a deep-seated human behavior, it would not be surprising to find networks in the brain that are selectively activated when someone has xenophobic thoughts. One area of the brain that has been investigated in this context is the amygdala.

The amygdala is often associated with emotion, and is perhaps best known for its role in fear and the recognition of threats. If you were walking in the woods and saw a bear, your amygdalae would immediately become activated, helping to bring about a fear response that would encourage you to run away (or maybe cause you to freeze in place).

Several neuroimaging studies have looked at what happens in the brains of people when they see images of others outside of their racial group (e.g. white people looking at images of black faces). Some findings from these studies include: the amygdala is activated upon seeing such images, amygdala activation is correlated with xenophobic attitudes of the viewer, and amygdala activity in white people is higher when viewing black faces with darker skin tone.

Thus, the amygdala may serve as a threat-detection mechanism that is reflexively activated when we see an outsider. Perhaps because this has been adaptive in the past, it may act to put our brain on alert when someone outside of our racial group is near. In many societies today, however, where we are attempting to make racial divisions less distinct, this knee-jerk reaction seems to be counterproductive.

Prejudice and the insula

Another area of the brain that has been associated with prejudice in neuroimaging studies is the insula. The insula is also involved in processing emotional states, and has been linked to mediating feelings of social disapproval. For example, one study found that the insula and amygdala were activated in individuals while they viewed pictures of of people deemed to be social outcasts, such as homeless people or drug addicts. Because the insula is also activated when viewing pictures of people outside one's racial group, it has been hypothesized that the insula is involved in feelings of distaste that may arise when experiencing prejudicial thoughts.

Prejudice and the striatum

The striatum, a subcortical area thought to play an important role in reward processing, also has been implicated in prejudice--albeit in a very different way than the amygdala and insula. Activity in the striatum correlates with rewarding experiences, and neuroimaging studies have found that the striatum is also activated when looking at pictures of individuals from one's own racial group. When white participants were tested for implicit preferences (i.e. preferences they may not state or even be aware of, but that they still seem to possess) for people of their own race, activity in the striatum was stronger in response to white faces in those who scored higher on the test for implicit preferences.

Thus, there may be activity in the brain that reinforces our tendency toward prejudice in at least two ways: 1) we may be more likely to feel fear and aversion when seeing someone of another race, and 2) we may be more likely to experience positive emotions in response to seeing someone of our own race.

So, if there are structures in our brains that promote prejudice, does it mean attempts to reduce our prejudices--both individually and societally--are a lost cause? Of course not. Just as there are brain structures that may make us more likely to recognize differences, there are also structures (e.g. areas of the frontal cortex) that allow us to exert control over those potentially reflexive reactions.

It's possible that the recognition of deep-seated mechanisms for prejudice could help us to understand racism a little better. It could, for example, provide insight into why people in high-stress situations may be more likely to see things as divided down racial lines. For, if their brains are already inclined to see people of another race as more threatening and they are in a stressful situation, they may be quicker to identify someone of a different race as the threat.

However, the extent to which such innate responses to outsiders affects our behavior is still somewhat unclear, and the hypothesis that such responses are remnants of once-adaptive behavior is just that: a hypothesis. For practical purposes, it may not matter exactly what the basis of prejudicial thinking is, as we are certain it's a thought pattern that doesn't have much remaining value in today's world. However, being open to the idea that we have some inclinations toward prejudicial thinking may help us to be able to train people to more mindfully deal with high-stress interactions with people of another race. For, instead of pretending these prejudicial thoughts don't (or shouldn't) happen, it would allow us to focus more on ways to mitigate the damage that might occur when they do.

Amodio DM (2014). The neuroscience of prejudice and stereotyping. Nature reviews. Neuroscience PMID: 25186236

Optogenetics, memories, and mind control

Optics

A few years ago (2010), the journal Nature Methods chose optogenetics as its "method of the year." The fact that optogenetics, in 2010, was already considered a viable approach to studying the brain is impressive in and of itself, considering that all of the seminal work with optogenetics has been done since the year 2000. Because the method is still a relatively recent development, however, it is probably true that the most intriguing work with optogenetics has yet to be done.

What is optogenetics?

Optogenetics incorporates methodology from the fields of optics and genetics in attempting to understand the activity of neurons. Specifically, optogenetic methods can be used to selectively activate individual neurons. This allows researchers to gain a better understanding of the function of these neurons by observing the effects of their activation.

There have been a few different approaches developed to activate neurons; one of the more common approaches was realized with the help of green algae. Green algae possess an ion channel that opens in response to light. When the channel is exposed to light it opens, allowing ions to rush into the cell and potentially causing an action potential to occur. The channel is called channelrhodopsin-2 (ChR2), and algae use its light sensitivity to grow towards sources of light.

Researchers in the early 2000s realized if they could get neurons to express light-sensitive ion channels like ChR2, then they could potentially control the activation of those neurons using pulses of light. So, they packaged the genes that encode for ChR2 into a viral vector and used it to infect neurons. The viral vector carries ChR2 genes into susceptible cells and "infects" them, causing the target cells to express the genes.

Once the genes for a light-sensitive ion channel become incorporated into a neuron, researchers can use light to activate that neuron. They can do this by inserting optical fibers into the brains of animals and using lasers or light emitting diodes (LEDs) to expose neurons to light. You can see this in action in the video below, which shows a mouse that (after being injected with a viral vector containing ChR2 genes) expresses ChR2 in its motor cortex. When researchers apply a burst of blue light to the mouse's brain, this causes a distinct pattern of movement.

What is optogenetics used for?

Optogenetics provides neuroscientists with a method to turn on specific neurons and then observe the effects. This gives researchers a way to make a strong connection between the activity of individual neurons and behavior. In other words, if researchers stimulate a particular area of the motor cortex (as seen in the video above) and this causes a mouse to move counterclockwise in circles, then we can hypothesize that the region stimulated plays a large role in that type of movement. Understanding the role of individual neuronal populations is crucial to understanding behavior and disease.

A study published this month in Nature provides a good example of influential optogenetics research. In the study, researchers (Nabavi et al.) used optogenetic methods to examine the behavior of neurons involved in conditioning fear responses. Normally, when you take a rodent and play a specific tone right before it receives an uncomfortable electric shock, it will begin to associate the tone with the shock; quickly it will come to fear the tone itself. In other words, it forms a memory of what normally follows the tone (a shock) and begins to anticipate it immediately upon hearing the tone.

It is thought that the mechanism of fear conditioning involves the amygdala, a region of the brain that plays an important role in fear processing of all kinds. In the case of associating fear with an auditory signal, the lateral amygdala receives auditory information from the thalamus. When there is an aversive stimulus associated with that auditory information, some neurons in the amygdala may undergo a process known as long-term potentiation, which is a term for the enhancement of synaptic communication thought to underlie memory formation (for more on this process, see this article). This enhancement allows those neurons in the amygdala to "remember" that the auditory information was followed by something aversive, and promotes avoidance behavior upon simply hearing the tone in the future.

Nabavi et al. injected a virus that expressed a variant of ChR2 into the brains of rats, and then waited until it was expressed in neurons of the lateral amygdala. Then, instead of pairing the shock with an auditory tone, they paired it with a burst of light that would hypothetically activate the same neurons in the amygdala that would be activated by a tone. This created a fear response that was similar to what was seen in rats who had the shock paired with a tone. So, the investigators essentially created a memory for an auditory stimulus in these rats, even though there was no auditory stimulus present.

The researchers went on to demonstrate that the memory formation was likely due to long-term potentiation. One way they did this was to use a method of optical stimulation thought to induce long-term depression, which is in some ways the opposite of LTP, as it acts to weaken the connection between synapses. By doing this, Nabavi et al. were able to abolish the memory. Amazingly, they were then able to reactivate it simply by re-stimulating the amygdala with light (foot shock was not needed again).

This experiment demonstrates how optogenetics can be used to activate specific neurons to help us to understand their role in behavior. In this case, researchers activated neurons in the amygdala to show how they are involved in fear conditioning, and expanded upon this by verifying that LTP is important to the fear conditioning process.

Optogenetics and mind control

While optogenetics gives us the ability to explore the functions of individual neurons, at the same time it provides us with the ability to modify the activity of those neurons. In this way, we can influence behavior, as can be seen in the video above when the mouse is prompted to move in a specific direction after optogenetic stimulation. Although tethering an animal to a cable for experimentation would seem to limit the possibilities that could be explored in terms of behavior, wireless optogenetic methods have already been introduced; their use will remove some of these limitations.

But how far can this technology go? Would it be possible to express ion channels sensitive to different wavelengths of light in different areas of the brain, thus giving scientists the capability of controlling a whole panoply of behavior? Indeed, work has already started to move in this direction. Will optogenetic technology one day be able to be applied to humans to influence things like addictive behavior or to treat disorders like depression, essentially modifying peoples' thought patterns in the process? Although this is not right around the corner, it is conceivable, and it is not a far stretch from approaches like deep-brain stimulation that are already being explored for these purposes. Thus, using optogenetics to exert some sort of control over the mind, albeit not of the devious sort that the phrase "mind control" seems to imply (hopefully), may be a distinct possibility at some point in the future.

Nabavi, S., Fox, R., Proulx, C., Lin, J., Tsien, R., & Malinow, R. (2014). Engineering a memory with LTD and LTP Nature DOI: 10.1038/nature13294

Magic mushrooms and the amygdala

Magic mushrooms

People have been eating psychedelic mushrooms since ancient times. There are even indications--although they are impossible to verify--that psychedelic mushrooms played an important role in cultures like the Mayan civilizations of South America thousands of years ago. Of course, the use of "magic" mushrooms has continued into the present day, but it wasn't until 1958 that Albert Hofmann (the discoverer of LSD) isolated psilocybin as the active hallucinogenic compound in psychedelic mushrooms.

Recently, psilocybin has also received some recognition as a potential treatment for anxiety. For example, a pilot study conducted in 2011 explored the ability of psilocybin to reduce anxiety in individuals with advanced stage cancer. Although it was a small study and only exploratory in nature, it suggested that psilocybin could have some benefit in reducing anxiety and improving mood in patients with a terminal illness.

In a study due to be published soon in Biological Psychiatry, a research group in Switzerland explored a potential mechanism for reduced anxiety after psilocybin administration. The authors, Kraehenmann et al., administered psilocybin or placebo to a group of participants. Then, they monitored the participants' brain activity using functional magnetic resonance imaging (fMRI) while the subjects completed a task that generally increases activation in an area of the brain called the amygdala. The task involved viewing a series of pictures; half of the pictures presented negative stimuli like a car accident, and the other half presented neutral pictures like everyday objects or scenes from daily life.

The amygdala is an almond-shaped collection of nuclei in the temporal lobe (there are actually two amygdalae--one in each hemisphere). Increased activity in the amygdala has been associated with emotional reactions, and especially with fear and anxiety. Hyperactivity in the amygdala has also been observed in depressed patients, and treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to reduce that hyperactivity. This suggests that increased activity in the amygdala may also play a role in symptoms of depression.

Kraehenmann et al. found that psilocybin administration improved mood and decreased anxiety, which was to be expected (magic mushrooms acquired their moniker for a reason). The study, however, also offered some insight into what might be causing that reduction in anxiety. After taking psilocybin (as compared to placebo), activity in the right amygdala was reduced while viewing negative images, and activity in the left amygdala was decreased in response to both negative and neutral images.

Psilocybin is thought to act as an agonist at serotonin receptors, meaning it increases serotonin transmission. Thus, it may be that antidepressants like SSRIs that act on serotonin--at least as part of their mechanism--have something in common with psilocybin. And, it suggests that perhaps psilocybin should continue to be investigated for its antidepressant and anxiolytic (anti-anxiety) properties.

Kraehenmann, R., Preller, K., Scheidegger, M., Pokorny, T., Bosch, O., Seifritz, E., & Vollenweider, F. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers Biological Psychiatry DOI: 10.1016/j.biopsych.2014.04.010