What is the habenula?

Despite the fact that it is present in almost all vertebrate species, very little was known about the habenula until fairly recently. In the past several years, however, the habenula has received a significant amount of attention for its potential role in both cognition (e.g. reward processing) and disorders like depression. Still, the habenula remains a little-known structure whose functions are yet to be fully elucidated.

Where is the habenula?

The habenula is part of the diencephalon and, together with the pineal gland, makes up a structure called the epithalamus. The pineal gland is found on the posterior side of the thalamus and is attached to the diencephalon by a stalk. At the base of that stalk there are two small swellings (one on each side); these are the habenulae. The habenula is traditionally divided into a lateral and medial section.

What is the habenula and what does it do?

The habenula receives information from the limbic system and basal ganglia through a fiber bundle called the stria medullaris. It sends information to areas of the midbrain that are involved in dopamine release, such as the substantia nigra and ventral tegmental area. The habenula also has neurons that project to areas like the raphe nuclei, which are involved in serotonin release. Thus, the habenula is one of the few known structures in the brain that can exert an influence over large populations of both serotonergic and dopaminergic neurons.

The habenula and reward processing

Dopamine and dopamine-rich areas of the brain like the substantia nigra and ventral tegmental area are thought to be important to processing information related to rewards. When we receive a reward--which could be anything from a slice of cheesecake to a line of cocaine--there is corresponding dopamine activity that seems to be associated with how satisfying we expect the reward to be. If the reward is larger than we expected (e.g. a big slice of cheesecake, topped with syrup and with a side of ice cream), our dopamine neurons get excited with activity that seems to help us remember the details of how we obtained the reward. In this way, our dopamine system helps us to recall how to get the reward again. When this encoding of the details associated with a reward becomes hyperactive, it can result in the obsessive reward-seeking we see in addiction.

But when the reward is smaller than we expected (e.g. a few crumbs of cheesecake on an otherwise empty plate), dopamine activity in the substantia nigra and ventral tegmental area is inhibited. Smaller-than-expected rewards, however, cause increased activity in the habenula, while larger rewards lead to an inhibition of activity there.

Thus, it has been hypothesized that the habenula is involved in encoding information about disappointing (or missing) rewards. The habenula has also been found to be activated in response to punishment (e.g. electric shocks) and stimuli that we have previously associated with negative experiences. Based on all of this information, it is thought the habenula plays an important role in learning from aversive experiences and in making decisions so as to avoid such unpleasant experiences in the future.

The habenula and depression

The habenula has been found to be activated in response to stress, and so it may not be surprising--given the strong relationship between chronic stress and depression--that the habenula is suspected to be involved in the pathophysiology of depression. Habenular neurons are hyperactive in depression; some have suggested this activity may correspond with an increased propensity toward pessimism. Structural abnormalities of the habenula have been found in the brains of patients who suffered from major depressive disorder, and in one case a patient who was not responsive to typical treatments for depression did respond to deep-brain stimulation of her lateral habenula. Regardless, although there are some indications of habenular involvement in depression, the association between the habenula and depression is still unclear. More research will be needed to determine if there is a causative link, and if so what the nature of that link is.

The habenula and sleep

The habenula also seems to play a role in sleep. It has mutual connections with the pineal gland, which secretes melatonin--a hormone important for regulating circadian rhythms and promoting sleep. There is also some evidence that the habenula itself produces melatonin. Lesioning the habenula in experimental animals results in a disruption of rapid eye movement (REM) sleep, and thus the habenula may have role in both promoting sleep and sleep quality. Some have suggested the role of the habenula in sleep may also be related to its role in depression, as depressed individuals often suffer from sleep disorders.

The functions of the habenula are just beginning to be understood. Until fairly recently, our neuroimaging techniques were not even powerful enough to visualize the habenula with adequate resolution. Now that this has changed, the tiny structure is becoming recognized as an important part of the brain. The next decade is likely to reveal some interesting new data about just how important this once-obscure brain region really is.

Hikosaka O (2010). The habenula: from stress evasion to value-based decision-making. Nature reviews. Neuroscience, 11 (7), 503-13 PMID: 20559337

Serotonin, depression, neurogenesis, and the beauty of science

If you asked any self-respecting neuroscientist 25 years ago what causes depression, she would likely have only briefly considered the question before responding that depression is caused by a monoamine deficiency. Specifically, she might have added, in many cases it seems to be caused by low levels of serotonin in the brain. The monoamine hypothesis that she would have been referring to was first formulated in the late 1960s, and at that time was centered primarily around norepinephrine. But in the decades following the birth of the monoamine hypothesis, its focus shifted to serotonin, in part due to the putative success of antidepressant drugs that targeted the serotonin transporter (e.g. selective serotonin reuptake inhibitors, or SSRIs). The monoamine/serotonin hypothesis eventually became generally recognized as viable by the scientific community. Interestingly, it also became widely accepted by the public, who were regularly exposed to television commercials for antidepressant drugs like Prozac, Lexapro, and Celexa--drugs whose commercials specifically mentioned a serotonin imbalance as playing a role in depression.

Over the years, however, the scientific method quietly and efficiently went to work. Evidence gradually accumulated that indicated that the serotonin hypothesis does a very inadequate job of explaining depression. For example, although SSRIs increase serotonin levels within hours after drug administration, if their administration leads to beneficial effects--a big if--it usually takes 2-4 weeks of daily administration for those effects to appear. One would assume that if serotonin levels were causally linked to depression, then soon after serotonin levels increased, mood would begin to improve. Also, reducing levels of serotonin in the brain does not cause depression. The list of studies that don't fully support the serotonin hypothesis of depression is actually quite lengthy, and most of the scientific community now agrees that the hypothesis is insufficient as a standalone explanation of depression.

In the 1990s another hypothesis, known as the neurogenic hypothesis, was proposed with the hopes of filling in some of the holes in the etiology of depression that the monoamine hypothesis seemed to be unable to fill. The neurogenic hypothesis suggests that depression is at least partially caused by an impairment of the brain's ability to produce new neurons, a process known as neurogenesis. Specifically, researchers have focused on neurogenesis in the hippocampus, one of the only areas in the brain where neurogenesis has been observed in adulthood (the other being the subventricular zone).

The neurogenic hypothesis was formulated based on several observations. First, depressed patients seem to have smaller hippocampi than the general population, and their hippocampi also appear to be smaller during periods of depression than during periods of remission. Second, glucocorticoids like cortisol are elevated in depression, and glucocorticoids appear to inhibit neurogenesis in the hippocampus in rodents and non-human primates. Finally, there is evidence that the chronic administration of antidepressants increases neurogenesis in the hippocampus in rodents.

The neurogenic hypothesis thus suggests that depression is associated with a reduction in the birth of new neurons in the hippocampus, an area of the brain important to stress regulation, cognition, and mood. According to this hypothesis, when someone takes antidepressants, the drugs do raise levels of monoamines like serotonin, but they also enact long-term processes that increase neurogenesis in the hippocampus. This neurogenesis is hypothesized to be a crucial part of the reason antidepressants work, and the fact that it takes some time for hippocampal neurogenesis to return to normal may help to explain why antidepressants take several weeks to have an effect.

This may all sound logical, but the neurogenic hypothesis has its own share of problems. For example, while stress-related impairment of neurogenesis has been observed in rodents, we don't have definitive evidence it occurs in humans. Human studies thus far have relied on comparing the size of the hippocampi in depressed and non-depressed patients. While smaller hippocampi have been observed in depressed individuals, it is not clear that this is due to reduced neurogenesis rather than some other type of structural changes that might have occurred during depression.

Similarly, while the administration of antidepressants has been associated with increased neurogenesis in rodent models of stress, we don't have clear evidence of this in humans. In humans we again have to rely on looking at things like hippocampal size. Because there could be a number of explanations for changes in the size of the hippocampi, we can't assume neurogenesis is the sole factor involved--or that it is involved at all. Additionally, some studies in rodents have found that antidepressants lead to a reduction in anxiety or depressive symptoms in the absence of increased hippocampal neurogenesis.

Another problem is that when neurogenesis is experimentally decreased in rodents, the animals don't usually display depressive symptoms. Experiments of this type haven't been performed with humans or non-human primates, so we don't know if a reduction in neurogenesis in any species is actually sufficient to cause depression. And no studies have found that increasing neurogenesis alone is enough to alleviate depressive-like symptoms.

Of course none of this means the neurogenic hypothesis is incorrect, but it does suggest there is a long way to go before we can feel confident about incorporating it fully into our understanding of depression. In the reluctance of the scientific community to embrace this hypothesis is where I see the beauty of science. Although it took decades of testing and revising before the monoamine hypothesis became a widely accepted explanation for depression, one could argue (based on its now recognized shortcomings) that we accepted it too readily.

However, it seems that many in the scientific community have learned from that mistake. Although there is no shortage of publications whose authors may be too willing to anoint the neurogenic hypothesis as a new unifying theory of depression, overall the tone when speaking of the neurogenic hypothesis seems to be cautious and/or critical. There is also a great deal of discussion now in the literature about the complexity of mood disorders like depression, and how it is unlikely to be able to explain their manifestation in a diverse population of individuals with just one mechanism, whether it be impaired neurogenesis or a serotonin deficiency.

Thus, the neurogenic hypothesis will require much more testing before we can consider it an important piece in the puzzle of depression. Even if further testing supports it, however, it will likely be considered just that--a piece in the puzzle, instead of an overarching explanation of the disorder. And that circumspect approach to explaining depression represents an important advancement in the way we look at psychiatric disorders.

See also: http://www.neuroscientificallychallenged.com/blog/2008/04/serotonin-hypothesis-and-neurogenesis

Miller, B., & Hen, R. (2015). The current state of the neurogenic theory of depression and anxiety Current Opinion in Neurobiology, 30, 51-58 DOI: 10.1016/j.conb.2014.08.012

Know your brain: Brainstem

Where is the brainstem?

The brainstem is composed of the three highlighted structures above: the midbrain, pons, and medulla. Image courtesy of OpenStax College - Anatomy & Physiology, Connexions Web site.

The brainstem is composed of the three highlighted structures above: the midbrain, pons, and medulla. Image courtesy of OpenStax College - Anatomy & Physiology, Connexions Web site.

The spinal cord enters the skull through an opening known as the foramen magnum. At about this point, the cord merges with the medulla oblongata, which is the lowest part of the brainstem. The brainstem is thus the stalk that extends from the brain to meet the spinal cord, and is clearly visible when looking at the brain from any perspective that allows the base of the brain to be seen. The brainstem is made up of 3 major structures: the medulla oblongata (usually just called the medulla), the pons, and the midbrain.

What is the brainstem and what does it do?

In addition to connecting the brain to the rest of the nervous system, the brainstem has a number of essential functions. To simplify things, I'll discuss some of the functions associated with each of the three major regions of the brainstem. It should be noted, however, that the organization of the brainstem is very complex and this is just an overview.


In addition to being the point where the brainstem connects to the spinal cord, the medulla contains a nucleus called the nucleus of the solitary tract that is crucial for our survival. The nucleus of the solitary tract receives information about blood flow, along with information about levels of oxygen and carbon dioxide in the blood, from the heart and major blood vessels. When this information suggests a discordance with bodily needs (e.g. blood pressure is too low), there are reflexive actions initiated in the nucleus of the solitary tract to bring things back to within the desired range.

Thus, the medulla is essential to our survival because it ensures vital systems like the cardiovascular and respiratory systems are working properly. Additionally, the medulla is responsible for a number of reflexive actions, including vomiting, swallowing, coughing, and sneezing. Several cranial nerves also exit the brainstem at the level of the medulla.


The next structure on our way up the brainstem is the pons. The pons is hard to miss; it is a large, rounded, and bulging structure just above the medulla. The word "pons" means bridge in Latin, and it resembles a rounded bridge that connects the medulla and the midbrain.

The pons is an important pathway for tracts that run from the cerebrum down to the medulla and spinal cord, as well as for tracts that travel up into the brain. It also forms important connections with the cerebellum via fiber bundles known as the cerebellar peduncles.

The pons is home to a number of nuclei for cranial nerves. Nerves that carry information about sensations of touch, pain, and temperature from the face and head synapse in a nucleus in the pons. Motor commands dealing with eye movement, chewing, and facial expressions also originate in the pons. Additionally, cranial nerve nuclei in the pons are involved in a number of other functions, including swallowing, tear production, hearing, and maintaining balance/equilibrium.


The final branch of the brainstem as we move toward the cerebrum is called the midbrain. The midbrain contains a number of important tracts running to and from the cerebrum and cerebellum, as well as some key nuclei.

The upper posterior (i.e. rear) portion of the midbrain is called the tectum, which means "roof." The surface of the tectum is covered with four bumps representing two paired structures: the superior and inferior colliculi. The superior colliculi are involved in eye movements and visual processing, while the inferior colliculi are involved in auditory processing.

At about the level of the superior colliculi, but located more anteriorly (i.e. toward the front) is another important nucleus called the substantia nigra. The substantia nigra, which literally means "black substance," was so named because it appears very dark in an unstained piece of tissue. The substantia nigra is rich in dopamine neurons and is considered part of the basal ganglia, which is a collection of nuclei that are crucial to normal motor movement. In patients who are suffering from Parkinson's disease, neurodegeneration occurs in the substantia nigra, and this neurodegeneration is associated with the hallmark movement dysfunction we see in Parkinson's.


Although it is the most evolutionarily ancient part of our brain, the brainstem is still very complex and has a long list of roles that haven't been included here. The brainstem may not provide us with the higher intelligence we normally associate with being human, but it does carry all of the information to and from those areas we do associate with higher intelligence. And, just as importantly (if not more so), it ensures the vital functions necessary to support those areas continue uninterrupted.