Timing Is Everything: How the Brain Links Memories of
Sequential Events
Suppose
you heard the sound of skidding tires, followed by a car crash. The next time
you heard such a skid, you might cringe in fear, expecting a crash to follow --
suggesting that somehow, your brain had linked those two memories so that a
fairly innocuous sound provokes dread.
MIT neuroscientists
have now discovered how two neural circuits in the brain work together to
control the formation of such time-linked memories. This is a critical ability
that helps the brain to determine when it needs to take action to defend
against a potential threat, says Susumu Tonegawa, the Picower Professor of
Biology and Neuroscience and senior author of a paper describing the findings
in the Jan. 23 issue of Science.
"It's important
for us to be able to associate things that happen with some temporal gap,"
says Tonegawa, who is a member of MIT's Picower Institute for Learning and
Memory. "For animals it is very useful to know what events they should
associate, and what not to associate."
The interaction of
these two circuits allows the brain to maintain a balance between becoming too
easily paralyzed with fear and being too careless, which could result in being
caught off guard by a predator or other threat.
The paper's lead
authors are Picower Institute postdocs Takashi Kitamura and Michele Pignatelli.
Linking memories
Memories of events,
known as episodic memories, always contain three elements -- what, where, and
when. Those memories are created in a brain structure called the hippocampus,
which must coordinate each of these three elements.
To form episodic
memories, the hippocampus also communicates with the region of the cerebral
cortex just outside the hippocampus, known as the entorhinal cortex. The
entorhinal cortex, which has several layers, receives sensory information, such
as sights and sounds, from sensory processing areas of the brain and sends the
information on to the hippocampus.
Previous research has
revealed a great deal about how the brain links the place and object components
of memory. Certain neurons in the hippocampus, known as place cells, are
specialized to fire when an animal is in a specific location, and also when the
animal is remembering that location. However, when it comes to associating
objects and time, "our understanding has fallen behind," Tonegawa
says. "Something is known, but relatively little compared to the
object-place mechanism."
The new Science paper
builds on a 2011 study from Tonegawa's lab in which he identified a brain
circuit necessary for mice to link memories of two events -- a tone and a mild
electric shock -- that occur up to 20 seconds apart. This circuit connects
layer 3 of the entorhinal cortex to the CA1 region of the hippocampus. When that
circuit, known as the monosynaptic circuit, was disrupted, the animals did not
learn to fear the tone.
In the new paper, the
researchers report the discovery of a previously unknown circuit that
suppresses the monosynaptic circuit. This signal originates in a type of
excitatory neurons discovered in Tonegawa's lab, dubbed "island
cells" because they form circular clusters within layer 2. Those cells
stimulate inhibitory neurons in CA1 that suppress the set of excitatory CA1
neurons that are activated by the monosynaptic circuit.
This circuit creates a
counterbalance that limits the window of opportunity for two events to become
linked. "This pathway might provide a mechanism for preventing constant
learning of unimportant temporal associations," says Michael Hasselmo, a
professor of psychology at Boston University who was not part of the research
team.
The findings are
"an important demonstration of the functional role of different
populations of neurons in entorhinal cortex that provide input to the hippocampus,"
Hasselmo adds.
Deciphering circuits
The researchers used
optogenetics, a technology that allows specific populations of neurons to be
turned on or off with light, to demonstrate the interplay of these two
circuits.
In normal mice, the
maximum time gap between events that can be linked is about 20 seconds, but the
researchers could lengthen that period by either boosting activity of layer 3
cells or suppressing layer 2 island cells. Conversely, they could shorten the
window of opportunity by inhibiting layer 3 cells or stimulating input from
layer 2 island cells, which both result in turning down CA1 activity.
The researchers
hypothesize that prolonged CA1 activity keeps the memory of the tone alive long
enough so that it is still present when the shock takes place, allowing the two
memories to be linked. They are now investigating whether CA1 neurons remain
active throughout the entire gap between events.
The research was
funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute,
and the JPB Foundation.