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New Brain Pathways for Old Memories

Rats’ behavior didn’t change over time following fear conditioning but the underlying circuitry that was activated to retrieve the fear memory shifted. The initial circuit (top) ran from the pre-limbic prefrontal cortex (PL) to the basolateral amygdala (BLA). A week later (bottom), that was supplanted by a circuit to the central amygdala (CeA) via the paraventricular nucleus of the thalamus (PVT).Gregory Quirk, Ph.D., University of Puerto Rico School of Medicine

Fearful memories can play a role in anxiety disorders such as post-traumatic stress disorder (PTSD), which may develop after a terrifying event. People with PTSD may feel stressed or frightened even when they’re no longer in danger.

Animal studies have shown that, when long-term memories are recalled, they become fragile and changeable. New proteins must be produced to reconsolidate retrieved memories and return them to long-term storage in the brain. Recalling a memory thus opens a window of opportunity for that memory to be changed—a “reconsolidation window.” Certain drugs can block reconsolidation, but using such drugs in people can be problematic.

To better understand the brain circuitry involved in retrieving memories of fearful events, a team led by Drs. Gregory Quirk and Fabricio Do-Monte at the University of Puerto Rico School of Medicine used a genetic/light technique called optogenetics in rats. The approach allowed the scientists to activate or silence specific neural pathways. Their work was funded in part by NIH’s National Institute of Mental Health (NIMH). The study appeared online on January 19, 2015, in Nature.

The team conditioned rats to fear a tone associated with a mild shock. Although the rats’ behavior didn’t change over time following fear conditioning, the underlying brain circuitry activated to retrieve the fear memory shifted. The initial circuit ran from the pre-limbic prefrontal cortex (PL) to the basolateral amygdala. A week later, the PL was still involved in retrieving the fear memory. However, after one week the retrieval circuit activated an area in the thalamus called the paraventricular region (PVT) that connects to the central amygdala—a brain region that orchestrates fear learning and expression.

In the same issue of Nature, a group led by NIMH grantees Drs. Bo Li and Mario Penzo of Cold Spring Harbor Laboratory in New York examined the role of the PVT in memory retrieval after fear conditioning in mice. The team traced activity in the PVT to the action of a messenger chemical, called brain-derived neurotrophic factor (BDNF), that has previously been implicated in mood and anxiety disorders like PTSD.

BDNF from the PVT, working via a specific receptor, activated the memory-storing central amygdala neurons. Infusing BDNF into the central amygdala caused mice to freeze in fear, suggesting that it not only enables the formation of fear memories, but also the expression of fear responses.

“While our memories feel constant across time, the neural pathways supporting them actually change with time,” Quirk explains. “Uncovering new pathways for old memories could change scientists’ view of post-traumatic stress disorder, in which fearful events occur months or years prior to the onset of symptoms.”