False memories

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Creating False Memories in the Hippocampus

Katie Strong December 9, 2013

Liotta Group Meeting

“Memory is not all that we are, but almost. We are the entire set of memories that we acquire. Every one of our memories changes who we are.” – Alcino Silva, Ph.D.

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“Finding the Engram”

An engram is a physical representation or location in the brain of a memory

1920 – 1950 Karl Lashley spent 30 years trying to find the elusive engram and in his seminal paper, “In Search for the Engram,” he concluded that memories are distributed – not localized.

1984 Richard Thompson showed that after conditioning rabbits to fear a tone with an airpuff to the eye, removal of just a few hundred neurons from the interpositus nucleus (a section of the cerebellum) led to fear extinction.

Josselyn, S.A. Continuing the search for the engram: examining the mechanism of fear memories. J Psychiatry Neurosci 2010, 35, 221. Lanshley, K. In Search of the Engram. Symp Soc Exp Biol 1950, 4, 452.McCormick, D.A.; Thompson, R.F. Cerebellum: essential involvement in the classically conditioned eyelid response. Science 1984, 20, 296.

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Xu, L. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012, 484, 381.Ramirez, S.; Liu, X.; Lin, P.; Suh, J.; Pignatelli, M.; Redondo, R.L.; Ryan, T.J.; Tonegawa, S. Creating a False Memory in the Hippocampus. Science, 2013, 341, 387.

2012Susuma Tonegawa labeled and artificially activated specific hippocampal dentate gyrus cells, which lead to a behavioral response associated with the fear memory of foot shocking.

2013Researchers from the Tonegawa lab next set out to determine if labeling and “artificially activating a previously formed contextual memory engram while delivering foot shocks can result in the creation of a false fear memory.”

“Finding the Engram”

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Labeling dentate gyrus (DG) cells using the Tet-Off System

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H H

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Figure adapted from the Tet-Off® and Tet-On® Gene Expression Systems User Manual, ClonTech Laboratories, 2012

Tet-Off Systems: tTA binds to TRE in the absence of DOX, and this leads to increased expression of the gene of interest.

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Xu, L. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012, 484, 381.

Researchers used transgenic c-fos-tTA mice and the gene of interest contained ChR2, a photosensitive protein that could be activated with light. • Off Dox, tTA would bind to TRE and promote the expression of ChR2 protein• On Dox, the binding of tTA to TRE would be inhibited.

Off Dox On Dox

X

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Xu, L. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012, 484, 381.

Researchers used transgenic c-fos-tTA mice and the gene of interest contained ChR2, a photosensitive protein that could be activated with light. • Off Dox, tTA would bind to TRE and promote the expression of ChR2 protein• On Dox, the binding of tTA to TRE would be inhibited.

Off Dox On Dox

X

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Basic Elemental Scheme

Ramirez, S.; Liu, X.; Lin, P.; Suh, J.; Pignatelli, M.; Redondo, R.L.; Ryan, T.J.; Tonegawa, S. Creating a False Memory in the Hippocampus. Science, 2013, 341, 387.

Off Dox: Cells are selectively labeled with ChR2-mCherry, a photosensitive protein. ChR2-mCherry is then reactivated by light during the On Dox

stage.

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Creation of a False Contextual Fear Memory


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Distortion of Real and False Memories

False memory interferes with genuine memory

Memory recall can be induced for a false memory


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Conditioned Place Avoidance (CPA) Paradigm


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Conditioned Place Avoidance (CPA) Paradigm

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True and False Memory Formations Activate Same Amygdala Cell Populations

B’ A’ C


The level of c-fos expression in the basolateral amygdala (BLA) and the central amygdala (CeA), two regions involved in fear learning and memory, were measured during the false and natural recall.

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Creating a False Memory in CA1 cells

Researchers redid the experiments with CA1 cells, instead of DG cells, and found no formation of a false memory.

Xu, L. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012, 484, 381.Ramirez, S.; Liu, X.; Lin, P.; Suh, J.; Pignatelli, M.; Redondo, R.L.; Ryan, T.J.; Tonegawa, S. Creating a False Memory in the Hippocampus. Science 2013, 341, 387.

Only after activating a small, specific population of cells did a false memory occur involving a foot shock – a memory very simplistic compared to our

complex memories and experiences.

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Similar Mechanism behind False and True Memories

“Whether it’s a false or genuine memory, the brain’s neural mechanism underlying the recall of the memory is the same” - Susumu Tonegawa, Ph.D.

Trafton, A. Neuroscientists plant false memories in the brain. MIT News (accessed November 2013).

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Similar Mechanism behind False and True Memories

“Whether it’s a false or genuine memory, the brain’s neural mechanism underlying the recall of the memory is the same” - Susumu Tonegawa, Ph.D.

How reliable is our memory?

Trafton, A. Neuroscientists plant false memories in the brain. MIT News (accessed November 2013). DNA Exonerations Nationwide. The Innocence Project (accessed November 2013). Lacy, J.W.; Stark, C.E. The neuroscience of memory: implications for the courtroom. Nature Reviews Neuroscience 2013, 14, 649.

• 311 people in the United States have been exonerated based on DNA evidence since 1989, and in 72% of those cases eyewitness misidentification testimony was the leading reason for a wrongful conviction.

• At many points in the justice system eyewitness testimony can become distorted, but these eyewitnesses can also become more confident.

• In a mock trial, jurors “recalled” 15% of information that was not stated, but that could fit a typical crime scene.

• Mock jurors also “recalled” 25.8% of information that was not stated by an eyewitness, but was implied by the prosecutor in a leading question.

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State v. Henderson: An Update to Eyewitness Identification and Jury Instructions

Cpgo Wrong, New Jersey Supreme Court Uses Psychological Research to Update Admissibility Standards for Out-of-Court Identifications, 125, Harv. L. Rev. 1514 (2012).

Rodney Harper and James Womble were celebrating by drinking and smoking when Harper was shot and Womble was held by the shooter’s armed accomplice. Womble later identified Larry Henderson as the accomplice 13 days after the murder and Henderson was convicted of first-degree murder.

• During the photo lineup, primary investigators interrupted and encouraged Womble to make a decision.

• After conviction, Henderson was grated a Wade hearing to determine the admissibility of the identification. The court then applied the Manson/Madison test, but found that “nothing in the case was improper, and certainly nothing that was so suggestive as to result in the likelihood of misidentification.” The Manson/Madison test considers

• witness' opportunity to view the person at the time of the crime• witness' degree of attention• accuracy of the witness' prior description• level of certainty at the time of the confrontation• time between the crime and confrontation

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Reinhart, C. Summary of New Jersey Case on Eyewitness Identification. <http://www.cga.ct.gov/2011/rpt/2011-R-0334.htm> Office of Legislative Research. (accessed December 2013).

On appeal, the Appellate Division of the Superior Court of New Jersey decided that the identification procedure was “impermissibly suggestive.” The court ruled that the legal standard for eyewitness testimony must change because it • does not offer an adequate measure of reliability• does not sufficiently deter inappropriate police conduct• relies too heavily on the jury's ability to evaluate identification evidence.

Now, the initial burden of proof for suggestive evidence lies with the defendant, and this evidence is usually tied to a systems variable: • Blind administration • Pre-identification instructions • Feedback • Lineup construction

The state then offers proof that the identification is reliable accounting for systems and estimator variables: • Stress and weapon focus • Witness and perpetrator characteristics • Race-bias

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Reinhart, C. Summary of New Jersey Case on Eyewitness Identification. <http://www.cga.ct.gov/2011/rpt/2011-R-0334.htm> Office of Legislative Research. (accessed December 2013). Lacy, J.W.; Stark, C.E. The neuroscience of memory: implications for the courtroom. Nature Reviews Neuroscience 2013, 14, 649.

The court can then suppress eyewitness identification if sufficient evidence for suggestiveness is presented. When evidence is submitted though, tailored jury instructions must be provided.

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Should neurocognitive enhancement such as deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS) be used to enhance the memory of eyewitnesses since memories are easily manipulated?

Neurotechnologies to Improve Eyewitness Memory

Vedder, A.; Klaming, L. Human Enhancement for the Common Good-Using Neurotechnologies to Improve Eyewitness Memory. AJOB Neuroscience 2010, 1, 22. Ridding, M.C.; Rothwell, J.C. Is there a future for therapeutic use of transcranial magnetic stimulation? Nature Rev Neurosci 2007, 8, 559.

• Should the safety of the eyewitness come before justice in a court case?

• Should the privacy of the eyewitness be respected?• Would all types of cases warrant eyewitness

neurocognitive enhancement or would a selection process take place?

• If neurocognitive enhancement is not mandatory, is all testimony equal?

• Should refusing neurocognitive enhancement be considered obstructing with justice, a punishable offense?

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Summary

• Recent neuroscience work that suggests specific memories are contained in a discrete number of cells also supplements the original idea from Karl Lashley that a distributed network exists.

• Researchers created a false memory in mice by optogenetically manipulating a engram-bearing neuron population in the hippocampus, suggesting that the mechanism for false and real memories is very similar.

• Many people believe that memories are similar to a video recorder, but our unreliable memories have the potential for unfortunate consequences in courts of law.

• The New Jersey Supreme Court has recently taken great strides to overcome the impact of false memories by modifying the standards for eyewitness evidence and jury instructions.

• Initial research has shown the potential for neurotechnologies in the law, but enhancing memories of eyewitnesses raises many ethical concerns.

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Degree of DG Cell Population Overlap during Exposure to Context A and C

OR

Cells activated by context A would be labeled with CHR2-mCherry (red) Cells activated by either context A’ or C would express c-Fos (green)

After second exposure to A (A’)

After exposure to novel context C (C)


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Degree of CA1 cell population overlap

CA1 cell population overlap after two consecutive exposures to context A was greater than with DG cells. Engrams rely less on population code and more on a

temporal code.

Ramirez, S.; Liu, X.; Lin, P.; Suh, J.; Pignatelli, M.; Redondo, R.L.; Ryan, T.J.; Tonegawa, S. Creating a False Memory in the Hippocampus. Science 2013, 341, 387.

After second exposure to A (A’) with DG cells labeled

After second exposure to A (A’) with CA1 cells labeled

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