Since the early 1900s, scientists have pondered an age old question: what are memories made of? In the 1920s, Karl Lashley embarked on his famous journey to find “the engram” – the place in the brain where memories are stored. In 1949, Donald Hebb proposed his famous postulate of how memories could be formed, insisting that brain “cells that fire together, wire together” as part of a “cell assembly.” Since those early days of neuroscience, scientists have worked extensively to characterize brain mechanisms that could support memory formation.

The first support for Hebb’s idea was the demonstration of long-term potentiation (LTP), an increase in strength between connected groups of brain cells after artificial high-frequency stimulation. While this was an important demonstration that scientists would work to explain for the next several decades, they have not always agreed on whether LTP is a memory mechanism. Carol Barnes, Ph.D., Regents’ Professor of Psychology & Neurology at Arizona State University, posed the famous question – what would constitute proof? After decades of research, we finally have the answer.

The study was led by Nobel laureate Roger Y. Tsien, Ph.D., Professor of Pharmacology at the University of California at San Diego School of Medicine and Roberto Malinow, Ph.D., Professor of Neuroscience at the University of California at San Diego and National Academy of Sciences member. The study was published online in the June 2014 issue of Nature.

To investigate, the researchers trained rats to fear a tone by pairing it with a foot shock, which resulted in freezing behavior indicative of fear learning. Subsequently, the researchers replaced the tone with a pulse of blue light that could be used to stimulate specific inputs to the lateral amygdala, part of the brain’s fear learning center.

In these rats, the lateral amygdala had previously been injected with a virus containing a gene capable of producing light-sensitive channels that could respond to light stimulation, an approach known as optogenetics. In this paradigm, pairing the pulse of light (aimed at the rats’ lateral amygdalae) with a foot shock produced robust fear learning, as indicated by freezing behavior.

Interestingly, cells of the lateral amygdala showed LTP, indicating that the light-driven stimulation of the amygdala was capable of inducing in LTP in rats that learned to fear. Interestingly, this light-driven fear memory could be inactivated by light stimulation capable of inducing long-term depression (a pattern opposite of LTP) in the amygdala. In this case, freezing behavior was not observed, indicating that LTP is an essential component of inducing fear memory in the amygdala. Importantly, light stimulation that re-induced LTP in the lateral amygdala was capable of reinstating the fear memory. These observations indicate that LTP of the lateral amygdala is necessary for fear learning.

While many previous studies have demonstrated parallels between LTP, LTD, and memory, this is the first study to directly manipulate specific populations of brain cells to demonstrate the relationship between LTP and behavioral memory.

“This is the best evidence so far, period,” said Eric R. Kandel, M.D., Nobel laureate and Professor of Brain Science at Columbia University. Indeed, “no previous studies showed definitively that LTP is a basis for and required for memory,” said Robert Malenka, M.D., Ph.D., Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and National Academy of Sciences member.

Dr. Malinow is clearly happy that the experiments worked. “It’s a bit of a relief and we can celebrate a little too,” he said.

References

Barnes CA (1995). Involvement of LTP in memory: are we “searching under the street light”? Neuron, 15 (4), 751-4 PMID: 7576624

Callaway, E. (2014). Flashes of light show how memories are made Nature DOI: 10.1038/nature.2014.15330

Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, Ehrlich I, Sprengel R, Deisseroth K, Stadler MB, Müller C, Lüthi A. (2010). Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468(7321): 277-282. PMID: 21068837.

Hebb DO. (1949). The organization of behavior. John Wiley & Sons.

Josselyn SA (2010). Continuing the search for the engram: examining the mechanism of fear memories. Journal of psychiatry & neuroscience : JPN, 35 (4), 221-8 PMID: 20569648

Bliss TV, & Lomo T (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. The Journal of physiology, 232 (2), 331-56 PMID: 4727084

Lin JY, Knutsen PM, Muller A, Kleinfeld D, & Tsien RY (2013). ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nature neuroscience, 16 (10), 1499-508 PMID: 23995068

Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, & Tonegawa S (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 484 (7394), 381-5 PMID: 22441246

Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, & Malinow R (2014). Engineering a memory with LTD and LTP. Nature PMID: 24896183

Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, & Tonegawa S (2013). Creating a false memory in the hippocampus. Science (New York, N.Y.), 341 (6144), 387-91 PMID: 23888038

Shors TJ, & Matzel LD (1997). Long-term potentiation: what’s learning got to do with it? The Behavioral and brain sciences, 20 (4) PMID: 10097007

Stevens CF (1998). A million dollar question: does LTP = memory? Neuron, 20 (1), 1-2 PMID: 9459434

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