Newly identified brain circuit hints at how fear memories are made

Working with rats, researchers reveal the shifting neural circuitry behind the recall of unpleasant experiences

SHIFTING CIRCUITS  In rats, a fear memory is initially recalled through brain cell connections between the prefrontal cortex (PL) and the basolateral amygdala (BLA). A week later, the circuit to recall the same memory shifts, relying on neurons in the paraventricular nucleus of the thalamus (PVT) that connect to the central amygdala (CeA).

Gregory Quirk/Univ. of Puerto Rico School of Medicine

Scientists have identified a previously unknown set of brain connections that play an important role in how fear memories are stored and recalled. The discovery may lead to a better understanding of post-traumatic stress disorder and other anxiety problems.

Two teams of researchers independently found the newly identified brain-cell circuit when studying rodents’ ability to recall a fear memory. The circuit that initially recalled the memory differed from the circuit that retrieved the memory days later, the researchers report in two papers online January 19 in Nature. It is the first time scientists have shown that a memory can be on temporary hold in one area of the brain and later released to a completely separate spot.

“This may be the tip of the iceberg in understanding these types of brain events, suggesting that our concept of memory storage in broad terms may require revision,” says neuroscientist Aryeh Routtenberg of Northwestern University in Evanston, Ill. 

Storing and recalling a memory requires nerve cells, called neurons, to talk to each other. Neurons send messages using molecules and electrical signals, linking different brain regions in a setup similar to an electrical circuit.

The idea that memories shift within regions of the brain is not new. Observations of the famous amnesiac Henry Molaison, known as H.M., and other patients suggested that where memories were stored in the brain changed with time (SN Online: 1/28/14). In the new research, scientists pinned down precisely when and where a specific memory moved, discovering the previously unidentified circuit in the process.

One team, led by neuroscientist Gregory Quirk of the University of Puerto Rico School of Medicine in San Juan, trained rats to fear a tone that came with a mild shock. Tracking which neurons later turned on in response to the tone revealed which brain circuits the rats used to recall the frightening memory of the shock. 

Initially the rats’ brains recalled the memory by turning on neurons in the brain’s frontal lobe, which controls actions and complex thoughts. A set of the frontal lobe neurons activated another set of neurons located in a subsection of the amygdala, the brain’s fear-processing center. That circuit, however, was not involved in retrieving the memory the next day. Instead, the memory was recalled through a different circuit, one that links the frontal lobe to a region that plays a role in sensing and sleep. This region, located near the brain stem and called the paraventricular nucleus of the thalamus, or PVT, turned out to have a strong connection to a distinct group of neurons in the amygdala. 

Scientists then used optogenetics, a technique for controlling cells with light, to switch off the PVT neurons linked to the amygdala. If the PVT neurons were switched off six hours after storing the fear memory, the rats could still recall their fear of the shock. But if those neurons were turned off seven days after storing the memory, the rats could not recall their fear. The results show that neurons in the PVT-amygdala circuit help to solidify and maintain fear memories, Quirk says.

A second team, led by neuroscientist Bo Li of Cold Spring Harbor Laboratory in New York, confirmed the discovery of the new fear memory circuit in mice. Li and colleagues focus on fear memories because his lab had previously shown that learning and remembering fear was rooted in the neurons of the central amygdala. Finding that neurons in the PVT region became active and communicated with the central amygdala as mice learned or recalled fear suggested that the region could be important in understanding anxiety disorders.

As a result, Li and his colleagues wanted to see if a particular brain chemical influenced fear memories in the mice. Previous research has shown that abnormalities with the chemical brain-derived neurotrophic factor, or BDNF, plays a role in post-traumatic stress and other anxiety disorders. Tracking the brain chemical in mice showed that it allows neurons in the PVT region to exert control over those in the amygdala, ultimately triggering a response to fear.

 Linking how the brain chemical and the newly identified fear circuit work together to establish and retrieve fear memories could provide a new target for treatment of post-traumatic stress disorder and other anxiety disorders, Li says.

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