MIT: Eating a slice of chocolate cake or spending time with a friend
usually stimulates positive feelings, while getting in a car accident or
anticipating a difficult exam is more likely to generate a fearful or
anxious response. An almond-shaped brain structure called the amygdala is believed to
be responsible for assigning these emotional reactions. Neuroscientists
from MIT’s Picower Institute for Learning and Memory have now identified
two populations of neurons in the amygdala that process positive and
negative emotions. These neurons then relay the information to other
brain regions that initiate the appropriate behavioral response. The study, which appears in the April 29 issue of Nature,
represents a significant step in understanding how the brain assigns
emotions to different experiences.
“How do we tell if something is good or bad? Even though that seems
like a very simple question, we really don’t know how that process
works,” Tye says. “This study tells us that streams of information are
hard-wired and are separated into good and bad at the level of the
amygdala.”
The findings could also help scientists to better understand how
mental illnesses such as depression arise, she says. Many psychiatric
symptoms may reflect impairments in emotional processing. For example,
people who are depressed do not find positive experiences rewarding, and
people who suffer from addiction are not deterred by the negative
outcomes of their behavior.
Graduate student Praneeth Namburi and postdoc Anna Beyeler are the paper’s lead authors.
The good, the bad, and the amygdala
For many years neuroscientists viewed the amygdala — and in
particular, a subregion known as the basolateral amygdala — as a
processing center for fear. However, more recent studies, including work
that Tye did as a graduate student at the University of California at
San Francisco, have highlighted the importance of the amygdala in
processing reward.
Those findings raised the question of how the same structure could
respond to both positive and negative inputs and initiate the
appropriate behavioral response. The neurons of the basolateral amygdala
are intermingled, making it difficult to distinguish which populations
might be involved in different functions.
Tye and colleagues suspected they might be able to distinguish
populations of neurons that respond to different emotions based on their
targets elsewhere in the brain. Previous studies had suggested that
some of these neurons project to the nucleus accumbens, which plays a
role in reward learning, while others send information to another part
of the amygdala known as the centromedial amygdala.
To identify these populations, the researchers delivered green and
red fluorescent microspheres called retrobeads to the target cells in
the nucleus accumbens and centromedial amygdala, respectively. These
spheres traveled backwards until they reached the neurons of the
basolateral amygdala, clearly marking two distinct populations.
After labeling these neurons, the researchers analyzed amygdala
activity as the mice learned either a fear-conditioning task or a reward
task. In the fear-conditioning task, the mice learned to associate a
tone with a foot shock, and in the reward task the tone was paired with a
drink of sugary water.
The next day, the researchers measured the strength of the
connections coming into the two populations, which carry sensory
information to the amygdala. They found that basolateral amygdala
neurons that connect to the nucleus accumbens receive stronger input
after reward learning, but their inputs are weakened after fear
learning. Neurons that connect to the centromedial amygdala show the
opposite response.
The results suggest that these two populations essentially function
as a gate for sensory information coming into the amygdala, Namburi
says. “There are sensory inputs coming in to either of these
populations, and once learning happens, you’re shifting the flood onto
one population or the other,” he says.
The researchers then found that by shutting down the pathway to the
fear circuit, they not only impaired fear learning, but also enhanced
reward learning.
“This was exciting because it suggests that these populations engage
in a push-pull interaction with each other, which makes sense as seeking
rewards and avoiding threats are often behaviors that present opposing
forces,” Tye says. “Just as you might expect someone to lose their
appetite if gunshots were fired, the activation of the fear circuit
could suppress reward-related behaviors.”
Sheena Josselyn, an associate professor of psychology and physiology
at the University of Toronto, describes the paper as “a huge advance in
our understanding of how the brain processes different emotions.”
“Everyone knows that we can learn about both positive and negative
experiences, but it has never been shown how one structure can
contribute to encoding two diametrically opposed emotional outcomes,”
says Josselyn, who was not involved in the research. “This work showed
that where each cell projects determines whether it encodes a positive
or a negative memory. Just looking at the cell doesn’t reveal its
identity, one must consider the cell in the context of a broader
circuit.”
Distinguishing traits
Once the researchers defined the functions of each cell population,
they set out to identify other distinguishing characteristics. They
found only minor differences in shape and in the electrophysiological
properties of the neurons, but they did detect some intriguing
differences in gene expression. Some of the genes that were more active
in one cell type than the other encode receptors that sit on cell
surfaces and bind to incoming neurotransmitters, which help transmit
sensory information to the amygdala.
The researchers are particularly interested in one of these
receptors, which interacts with a small protein called neurotensin. This
protein helps to regulate the cells’ response to glutamate, one of the
major neurotransmitters required to strengthen connections between
neurons. In follow-up studies, they are now investigating the role
neurotensin may play in reward- and fear-learning in the amydgala.
“This represents a new paradigm for therapeutic development,” Tye
says. “‘Circuit-based drug discovery’ relies on first identifying how
different components of the circuit work and then identifying what
targets might control them.”