The Molecules of Fear

Scientists close in on the process that records -- and erases -- memories of terror

By Jason Castro | December 14, 2010  

The voicemail rant. The overheard insult. The lonely moral slip when your chips were down.

Despite their sting, these unkind memories eventually slacken their grip. We manage, move on, shrug it off, and go about the business of filling our heads with thoughts of a better tomorrow.

But for war veterans and victims of violent crime, the persistence of traumatic memories can mean a life of disability. Even when emotional demons are quieted with therapy or drugs, they are prone to return. A whispered reminder in an unfamiliar setting is sometimes all it takes.

Frustrated with these grim facts, scientists have been looking for biologically based therapies that may some day help troubled minds forget debilitating fears. The most recent of these studies, by Drs. Roger Clem and Richard Huganir at Johns Hopkins, gives a spectacularly detailed view of how fear is learned, and points out fear’s Achilles Heel. The very molecular machinery that implants fear in the brain may also hold the key to its undoing.

We already understand a good deal about how specific fears come to be thanks to classical neuroscience experiments, many done by Joseph LeDoux and his colleagues at New York University. Fear lives in a small almond-shaped pair of brain structures, called the amgydalae, that control your body’s panic buttons. Each amygdala receives two basic kinds of inputs: streaming images from our senses, as well as incoming alerts conveying threats, danger, or pain. When one of these alert signals – say the pain of a shock or cut – is detected together with a sensory image (such as a particular face or the sound of a gunshot), neurons in the amygdala take notice.

More specifically, amygdala neurons undergo specific chemical and structural changes that form an imprint, or memory, of the sensory image that accompanies a particular threat. In neuroscience lingo, the sensory input is “potentiated.” In plain language: the previously unremarkable mugger’s face now evokes terror.

But how do we unlearn a traumatic memory that’s become dysfunctional? On these questions, we’re more in the dark. The good news is that after they’re formed, fear memories are attentively curated by a host of brain enzymes and proteins that can muffle, modify, and even possibly remove fear. The bad news is that we don’t know which curator handles fear removal.

This is what Clem and Huganir set out to discover. Their first step was to implant fear memories in mice by training them to associate a tone with an electrical shock. After pairing tones and shocks for a few trials, the mice came to respond fearfully – by freezing in place – to the tones alone. As shown before, these behavioral changes were accompanied by long-lasting increases in the strength of sensory input to the amygdala.

So far, this was unsurprising. But Clem and Huganir were just getting started. After finding fear-related changes in amygdala circuits, the scientists went in for a closer and longer look. Their observations paid off with a puzzle. Although the strengthened inputs remained stable and steady for days after fear was learned, amygdala neurons underwent a major molecular overhaul during that time. Glutamate receptors – the main chemical sensors that detect messages sent from neuron to neuron – were being continuously added and removed from the neurons’ surfaces.

This adding and removal of glutamate receptors is not in itself unusual. In fact, it’s one of the main ways that neurons change their connection strength. Pack more receptors into a small area, and a neuron can more sensitively sniff out its inputs; reduced to chemistry, this is what a memory is. What Clem and Huganir found, though, was that amygdala cells swapped one kind of glutamate receptor for another with nearly identical function. It was an exchange that seemed to go nowhere.

Why have a molecular-level song and dance that doesn’t lead to a functional change? The authors made an intriguing speculation, supported by pharmacology experiments in brain slices. Even though the newly inserted receptors do essentially the same job as the ones they replace, perhaps they are much easier to remove. This would imply that shortly after fear memories are formed, they could be easily undone since they’re assembled out of temporary, readily removable parts. In effect, the receptor remodeling that occurs shortly after fear induction may be a way of instilling a fearful memory on a trial basis.

This core insight was gleaned from related work showing that human fear memories could be eliminated if they were manipulated within a one-day window of being formed. In those experiments, Daniela Schiller, working together with Joseph LeDoux and Elizabeth Phelps, monitored volunteers’ panic responses as they ‘unlearned’ an association from the previous day between a colored square and a mild electrical shock. The unlearning was accomplished through simple behavioral extinction – basically, showing the square repeatedly without a shock – but it required a trick. The square-shock memory could only be expunged if a reminder (the colored square alone) was shown 10 minutes before the extinction trials began. If this reminder was omitted, or presented hours before extinction, fear tended to persist, and could be easily reawakened.

Schiller’s experiments, together with several others (reviewed here), lent credence to a prominent theory of fear memory stressing its malleability. Under this view, each time a memory is accessed, it transiently loses its cohesiveness, providing an opportunity for modification. If the memory is accessed in a setting that reaffirms the learned fear, it is strengthened and filed away in a more permanent form. If that same memory is summoned in a safe setting though, it is weakened.

The more recent results by Clem and Huganir fit remarkably well with this picture, with their receptor-swapping observation providing the missing mechanism for fear’s impressive (if short-lived and quirky) malleability. Indeed, they showed that the readily removable receptors are only present for a few days after inducing fear, and peak at around one day. This is the cellular analog of the one-day window of opportunity for fear removal in humans described above.

To flesh out their mechanism further, and draw deeper parallels with the memory erasure results in humans, Clem and Huganir also performed fear extinction experiments in their mice. Just like in humans, snuffing out fear memories in mice required a reminder stimulus (in this case, the tone alone) one day after initial learning, and minutes before extinction trials. Notably, this extinction failed in mice that were injected with a compound preventing the accumulation of the more transient receptor population. Driving the point home, the authors also showed that fear removal failed in genetically modified mice with faulty receptor shuttling.

Taken together with other studies, these results sharpen our view of what goes on in a brain that successfully discards its fears. Our fears may come to be unwieldy and persistent, but they start their lives in a physically vulnerable state. By intervening at this critical time, when fears are plastic and willing to change, we can tip the balance in favor of brain mechanisms that naturally undo fear, rather than entrench it.

One intriguing application of Clem and Huganir’s work may be the eventual development of pharmacological aids that help re-open or extend fear’s malleable period, and offer a chance to quiet a damaging memory formed long ago. Indeed, the chemical cascades that precede the increased receptor turnover in the amygdala were quite well characterized in their paper, and suggested several possibilities for intervention.

It’s worth stressing though, that erasing pathological fear in a medical context – when the right techniques arrive – will probably bear no resemblance to Hollywood depictions of mind erasure as practiced by the wicked or the deranged. In fact, it’s becoming increasingly clear that our best therapeutic strategy will be to piggyback on the brain’s natural ‘uninstall’ routines for fear, which are very thorough and specific.

Jason Castro is a postdoctoral fellow in the Center for Neuroscience at the University of Pittsburgh. He studies synaptic processing and plasticity in the auditory system.

http://www.scientificamerican.com/article.cfm?id=the-molecules-of-fear&page=3