2014 Nobel Prize Winners Speak at the University of Arizona

Thursday afternoon, Edvard Moser, May-Britt Moser, and John O'Keefe, the three 2014 Nobel Prize winners for Physiology or Medicine, along with Eleanor Maguire, the winner of the 2003 Ig Nobel Prize for her "London taxi driver" study on hippocampal plasticity, spoke at a public forum at the University of Arizona.

Maquire's research on London taxi drivers, before and after going through two to three years of training required to learn and memorize 25,000 streets, revealed that their hippocampus grew as they memorized London's maze of streets. This was one of the first studies that demonstrated hippocampal neuroplasticity. She was awarded a 2003 Ig Nobel Prize for this study.

According to Improbable Research, the bestowers of the Ig Nobel Prize, "The Ig Nobel Prizes honor achievements that make people LAUGH, and then THINK. The prizes are intended to celebrate the unusual, honor the imaginative — and spur people's interest in science, medicine, and technology."

The Mosers and O'Keefe won their Nobel Prize in 2014 for their discoveries of specialized cells in the brain that together act as a navigation system. The Mosers discovered neurons that function as grid cells, found in the entorhinal cortex, while O'Keefe discovered neurons that function as place cells, found in the hippocampus.

"All memories are attached in some way to where you are, and in that way, the hippocampus acts as an anchor for remembering yourself within your experience," said Carol Barnes, Regents' Professor in the Departments of Psychology, Neurology and Neuroscience, the Evelyn F. McKnight Endowed Chair for Learning and Memory in Aging.

The hippocampus, according to Wikipedia, "belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation." If a person were to suffer severe damage to the hippocampus (both hippocampi, as one exists in each brain hemisphere), it's likely they may acquire anterograde amnesia, an inability to form and/or retain new memories (episodic or autobiographical memory, which are forms of declarative memory). In Alzheimer's Disease, the hippocampus is one of the first brain regions to experience damage, resulting in the disorientation and loss of recognition so common in the disease. However, damage to the hippocampus does not inhibit the ability to learn new skills, such as riding a bicycle (procedural memory).

 

 Spatial firing patterns of 8 place cells recorded from the CA1 layer of a rat. The rat ran back and forth along an elevated track, stopping at each end to eat a small food reward. Dots indicate positions where action potentials were recorded, with color indicating which neuron emitted that action potential. [via Wikipedia]

Below, I have included the honored guests as well as the first half of the press release about the public forum (which is heavy on the U of A is awesome rhetoric).

Guests

Edvard Moser, Professor and Director, Kavli Institute of Systems Neuroscience; Co-Director, Centre of Neural Computation, Norwegian University of Science and Technology

May-Britt Moser, Professor and Director, Centre of Neural Computation; Co-Director, Kavli Institute of Systems Neuroscience, Norwegian University of Science and Technology

The Moser’s received the 2014 Nobel Prize in Medicine or Physiology (along with J. O’Keefe) for this discovery of grid cells.

John O’Keefe, Professor, Institute of Cognitive Neuroscience and Department of Anatomy, University College London. Dr. O’Keefe received the 2014 Nobel Prize in Medicine or Physiology (along with the Moser’s) for his discovery of place cells.

Eileen O’Keefe (John’s wife), Emeritus Professor, Public Health, London Metropolitan University

Eleanor Maguire, Professor of Cognitive Neuroscience, University College Dublin Dr. Maguire received the 2003 Ig Nobel Prize for Medicine for her ‘London taxi driver’ student on hippocampal plasticity.

And here is the beginning of the press release . . . 

Nobel Laureates Say UA Scientists Paved Way

By Daniel Stolte, University Relations - Communications | March 27, 2015
 

UA researcher Carol Barnes says the new Center for Innovation in Brain Science will serve as a hub of transdisciplinary research. (Photo: John de Dios/UANews)

 Four internationally renowned brain scholars visit campus and describe the UA as "one of the centers of neuroscience." The new Center for Innovation in Brain Science will foster transdisciplinary research, with the goal of better diagnostics and treatments for disorders such as Alzheimer's disease.

Nobel Prize laureate John O'Keefe, with May-Britt Moser (left) and Eleanor Maguire, says the UA's Carol Barnes "has told us as much about how the brain ages as anyone else." (Photo: John de Dios/UANews)

Take it from several Nobel laureates: Brain researchers at the University of Arizona are poised to make important contributions to finding better diagnoses and possibly treatments for brain disorders such as Alzheimer's disease.

To help commemorate three milestones in brain science research at the UA, four internationally renowned brain scholars — including three who shared the latest Nobel Prize in Physiology or Medicine — visited the UA campus this week to speak about their scientific careers and reflect on the tight connections they have shared with UA colleagues over many years.

This year marks the 25th anniversary of the UA Arizona Research Laboratories Division of Neural Systems, Memory and Aging, or NSMA; the 10th anniversary of the Evelyn F. McKnight Brain Institute at the UA; and the fifth anniversary of the UA School of Mind, Brain and Behavior.

UA President Ann Weaver Hart has named neuroscience as a research priority under the UA's strategic Never Settle plan. The BIO5 Institute and the UA Health Sciences Center have goals of supporting transdisciplinary neuroscience research in partnership with institutions across the state — from the molecular underpinnings of brain-cell health to the translation of this biological knowledge into treatments for neurological disease. The College of Science and the Office for Research and Discovery also are involved in supporting these efforts through the School of Mind, Brain and Behavior; NSMA; and the Evelyn F. McKnight Brain Institute.

During a public forum on Thursday, the UA welcomed the four guests to share their stories of discoveries in neuroscience with UA students, members of the public and the media. The visitors were John O'Keefe and Edvard and May-Britt Moser, who shared the 2014 Nobel Prize in Physiology or Medicine, and Eleanor Maguire, who received the Ig Nobel Prize for Medicine in 2003.

O'Keefe and the Mosers received the prize for their discoveries of specialized cells in the brain that together act like a navigation system.

"All memories are attached in some way to where you are, and in that way, the hippocampus acts as an anchor for remembering yourself within your experience," said Carol Barnes, who organized the visit along with two other UA brain researchers: Lynn Nadel, a Regents' Professor of Psychology and Cognitive Science and chair of the UA faculty; and Mary Peterson, professor of psychology and chair of the School of Mind, Brain and Behavior executive committee; director of the Cognitive Science Program; and chair of the Cognitive Science Graduate Interdisciplinary Program.

Edvard Moser said that some important work leading up to the Nobel Prize was done at the UA — for example, developing the technology for recording the activity of many brain cells at the same time, and developing ideas of how memory is generated in the hippocampus.

"The UA is one of the centers of neuroscience," O'Keefe said. "As one of the world's experts on the aging brain, Carol has told us as much about how the brain ages by looking at the hippocampus as anyone else.

Read the whole report on the event.

Anyone who has experienced trauma, or works with survivors of trauma, already that one of the most common neuromechanisms for dealing overwhelming fear is to dissociate the emotional impact from the narrative memory of the event(s). Maybe you have had the experience of someone telling you about a horrible thing that happened to him, and all the while he is smiling or even laughing. As a therapist, I immediately think, "affect incongruity." This is a clear indication that the person in question has dissociated the emotions from the experience.

The reason for this, as far as we know, is that part of what the thalamus does is assemble all of the sense data (sight, sound, touch, emotions, etc.) when encoding a memory into a coherent package, but it does not function correctly under conditions of extreme stress, so the memory ends of being fragmented. Often the emotional content gets separated out so that the person can describe the event with no related affect being visible. On the other hand, a sound associated with the trauma may trigger a flashback of the emotional experience.

We are finally beginning to understand the neuroscience behind how the brain processes trauma.

Our Brain Dissociates Emotional Response from Explicit Memory in Fearful Situations

Neuroscience News
November 6, 2014

Researchers at the Cognition and Brain Plasticity Group of the Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona have been tracking the traces of implicit and explicit memories of fear in human. The study was published in the journal Neurobiology of Learning and Memory; it describes how, in a context of fear, our brain differently encodes contextual memory of a negative event (the place, what we saw, etc) and the emotional response associated.

The study measures electrodermal activity of eighty-six individuals in a fearful context generated in the laboratory and in a neutral context in which they have to learn a list of words. One week and two weeks after the experiment they were tested to see which words they remembered.

“In both contexts —explains Pau Packard, author of the study—, forgetting curve was normal. Over time, they forgot all the words, the explicit trace. Moreover, in the fearful context the electrodermal activity —the emotional implicit response— was exactly the same, much higher than in the neutral context”.

In traumatic events, it seems that, over time, there is a portion of memory that is erased or inaccesible; we forget the details but still maintaining the emotional reaction. This image is for illustrative purposes only. Credit geralt.

In traumatic events, it seems that, over time, there is a portion of memory that is erased or inaccesible; we forget the details but still maintaining the emotional reaction. The imprint is divided into two separate paths. According to Packard, “the brain dissociates the explicit memory of a negative event from the emotional response”.

This may help to understand why in pathological situations of post-traumatic stress disorders, the uncontrolled emotional response linked to the negative event is generated without knowing what causes it.

Lluís Fuentemilla, project coordinator, emphasises that “the study helps to explain how the processing of fearful memories can lead to post-traumatic stress disorder”. Furthermore, it opens the door to the investigation of new therapeutic strategies for these disorders because “the implicit memory trace in a fearful context does not loose over time and can be detected through electrodermal measures”.

About this memory research

Contact: Press Office – University of Barcelona
Source: University of Barcelona press release
Image Source: The image is credited to geralt and is in the public domain

Original Research:

Packard, P. A., Rodríguez Fornells, A., Stein, L. M., Nicolás, B., and Fuentemilla, Ll. (2014, Dec). Tracking explicit and implicit long-lasting traces of fearful memories in humans. Neurobiology of Learning and Memory; 116: 96–104. Published online September 26 2014 doi:10.1016/j.nlm.2014.09.004

* * * * *

Here is the original abstract from Neurobiology of Learning and Memory.

Tracking explicit and implicit long-lasting traces of fearful memories in humans

Pau Alexander Packarda, Antoni Rodríguez-Fornellsa, Lilian Milnitsky Stein, Berta Nicolás, Lluís Fuentemilla,

Highlights

 

• We track implicit and explicit memory traces for fearful episodes over time.

• SCR at test was higher for verbatim words encoded in a fearful context.

• Subjects were unable to report words’ emotional encoding context.

•Implicit memory traces of a fearful context was dissociated from the gist.

---

Abstract

Recent accounts of Posttraumatic Stress Disorder (PTSD) suggest that the encoding of an episode within a fearful context generates different implicit and explicit memory representations. Whilst implicit memory traces include the associated emotional states, explicit traces include a recoding into an abstract or gist-based structural context of the episode. Theoretically, the long-term preservation of implicit memory traces may facilitate the often untreatable memory intrusions in PTSD. Here, we tracked in two experiments how implicit and explicit memory traces for fearful episodes dissociate and evolve over time. Subjects (N = 86) were presented with semantically-related word-lists in a contextual fear paradigm and tested for explicit memories either immediately (i.e., 30 min) or after a delay (i.e., 1 or 2 weeks) with a verbal recognition task. Skin Conductance Response (SCR) was used to assess implicit memory responses.

Subjects showed high memory accuracy for words when tested immediately after encoding. At test, SCR was higher during the presentation of verbatim but not gist-based words encoded in a fearful context, and remained unchanged after 2 weeks, despite subjects being unaware of words’ encoding context. We found no clear evidence of accurate explicit memory traces for the fearful or neutral contexts of words presented during encoding, either 30 min or 2 weeks afterwards. These findings indicate that the implicit, but not the explicit, memory trace of a fearful context of an episode can be detected at long-term through SCR and is dissociated from the gist-based memory. They may have implications towards the understanding of how the processing of fearful memories could lead to PTSD.

Inflammation, the Immune System, and the Brain - New Models of Disease

In recent years, science is finally beginning to grasp the obvious fact that the human body is a system, so that when something goes wrong in one part of the organism, it has effects in other parts of the organism as well. The most obvious example of this is the new focus on the microbiome (the enteric nervous system and the flora that inhabit it) and its relation to physical and mental health.

The microbiome is also where the heart of the immune system resides. When the "gut" is not healthy, the immune system is not healthy, which leads to higher levels of inflammation.

One of the key issues researchers are focusing on is inflammation - a normal and healthy response to a wound or exposure to a pathogen, but not so healthy when levels of inflammation remain elevated for long periods of time (which can happen when we are under chronic stress conditions).

Inflammation has been linked to Alzheimer's Disease, diabetes, depression, damaged memory retrieval, schizophrenia, and many other physical and psychological issues.

Here are some recent articles on the intersection of the immune system and mental health and the role of inflammation, and specifically neuroinflammation, on the brain and the mind. These are arranged from easiest to read to the more technical research at the bottom of the post.

Mind and body: Scientists identify immune system link to mental illness

Date: August 13, 2014
Source: University of Cambridge

Summary:
Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research that suggests a role for the immune system in mental illness. The study indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.
___

A team of scientists led by the University of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children -- also known as Children of the 90s -- taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. The team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the 'high' group were nearly two times more likely to have experienced depression or psychosis than those in the 'low' group.

* * * * *

Inflammation in Pregnancy Strongly Linked to Schizophrenia

Caroline Cassels | Science Codex

September 04, 2014

Elevated levels of C-reactive protein in pregnant women are strongly linked to an increased risk for schizophrenia in offspring, new research shows.

A nested case-control study showed that increasing maternal levels of C-reactive protein, a well-established and reliable marker of inflammation, were associated with a nearly 60% increased risk for schizophrenia in children. The finding remained significant after adjusting for a wide range of potential confounders, including parental history of mental illness.

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implication for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders," the authors, led by Sarah Cannetta, PhD, Columbia University and New York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.

* * * * *

Inflammation in Pregnancy Strongly Linked to Schizophrenia

Caroline Cassels | Medscape

September 04, 2014

Elevated levels of C-reactive protein in pregnant women are strongly linked to an increased risk for schizophrenia in offspring, new research shows.

A nested case-control study showed that increasing maternal levels of C-reactive protein, a well-established and reliable marker of inflammation, were associated with a nearly 60% increased risk for schizophrenia in children. The finding remained significant after adjusting for a wide range of potential confounders, including parental history of mental illness.

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implication for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders," the authors, led by Sarah Cannetta, PhD, Columbia University and New York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.

* * * * *

The common inflammatory etiology of depression and cognitive impairment: a therapeutic target

David J Allison and David S Ditor

Journal of Neuroinflammation (2014, Sep 2); 11:151 
doi:10.1186/s12974-014-0151-1 

Abstract

Chronic inflammation has been shown to contribute to the development of a wide variety of disorders by means of a number of proposed mechanisms. Depression and cognitive impairment are two such disorders which may share a closely linked inflammatory etiology. The ability of inflammatory mediators to alter the activity of enzymes, from key metabolic pathways, may help explain the connection between these disorders. The chronic up-regulation of the kynurenine pathway results in an imbalance in critical neuroactive compounds involving the reduction of tryptophan and elevation of tryptophan metabolites. Such imbalances have established implications in both depression and cognitive impairment. This may implicate the immune system as a potential therapeutic target in the treatment of these disorders. The most common treatment modalities currently utilized, involve drug interventions which act on downstream targets. Such treatments help to reestablish protein balances, but fail to treat the inflammatory basis of the disorder. The use of anti-inflammatory interventions, such as regular exercise, may therefore, contribute to the effectiveness of current drug interventions in the treatment of both depression and cognitive impairment.

* * * * *

Calcineurin and glial signaling: neuroinflammation and beyond

Jennifer L Furman and Christopher M Norris

Journal of Neuroinflammation (2014, Sep 10); 11:158 
doi:10.1186/s12974-014-0158-7
 
Abstract

Similar to peripheral immune/inflammatory cells, neuroglial cells appear to rely on calcineurin (CN) signaling pathways to regulate cytokine production and cellular activation. Several studies suggest that harmful immune/inflammatory responses may be the most impactful consequence of aberrant CN activity in glial cells. However, newly identified roles for CN in glutamate uptake, gap junction regulation, Ca²⁺ dyshomeostasis, and amyloid production suggest that CN’s influence in glia may extend well beyond neuroinflammation. The following review will discuss the various actions of CN in glial cells, with particular emphasis on astrocytes, and consider the implications for neurologic dysfunction arising with aging, injury, and/or neurodegenerative disease.

* * * * *

Up-regulation of miRNA-146a in progressive, age-related inflammatory neurodegenerative disorders of the human CNS

Peter N. Alexandrov, Prerna Dua and Walter J. Lukiw

Frontiers in Neurology: Neurogenomics; (2014, Sep 29)
doi: 10.3389/fneur.2014.00181

Overview

The human brain- and retinal-resident microRNA-146a (miRNA-146a) is an inducible, NF-kB-regulated small non-coding RNA (sncRNA) whose increased expression is associated with pro-inflammatory neurodegeneration in Alzheimer’s disease (AD), age-related macular degeneration (AMD), and prion disease (PrD). In AD, AMD, and PrD miRNA-146a modulates the innate-immune response, inflammation, and the microglial activation state. This short paper will review and comment on the role of miRNA-146a signaling and how it underlies common molecular-pathogenetic mechanisms in each of these progressive, age-related neurological disorders for which there are currently no effective treatment or cure.

I have no doubt that this will eventually be used to target traumatic memories, but I am also quite sure that is not a good thing. We form memories for a reason - the goal should be to reduce the emotional impact of the memories, not erase them.

Manipulating memory with light: Scientists erase specific memories in mice

Date: October 9, 2014
Source: University of California - Davis  

Summary:
Neuroscientists have used light to erase a specific memory in mice, showing how the hippocampus and cortex work together to retrieve memories.

During memory retrieval, cells in the hippocampus connect to cells in the brain cortex.
Credit: Photo illustration by Kazumasa Tanaka and Brian Wiltgen/UC Davis

Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.

Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.

Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories -- memories about specific places and events -- involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.

"The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event," Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.

But this model has been difficult to test directly, until the arrival of optogenetics.

Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.

They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a "fear response."

Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.

"The cortex can't do it alone, it needs input from the hippocampus," Wiltgen said. "This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true."

They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.

Co-authors are Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa and Jalina Graham, all at the Center for Neuroscience. The work was funded by grants from the Whitehall Foundation, McKnight Foundation, Nakajima Foundation and the National Science Foundation.

Story Source:
The above story is based on materials provided by University of California - Davis. Note: Materials may be edited for content and length.

Journal Reference:
Kazumasa Z. Tanaka, Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa, Jalina Graham, Brian J. Wiltgen. (2014). Cortical Representations Are Reinstated by the Hippocampus during Memory Retrieval. Neuron;  DOI: 10.1016/j.neuron.2014.09.037

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Cortical Representations Are Reinstated by the Hippocampus during Memory Retrieval

Kazumasa Z. Tanaka, Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa, Jalina Graham, Brian J. Wiltgen

DOI: http://dx.doi.org/10.1016/j.neuron.2014.09.037

Highlights

• Neurons active during context fear learning can be selectively tagged with H2B-GFP
• When tagged CA1 neurons are silenced, memory retrieval is impaired
• CA1 silencing disrupts the activity of tagged neurons in cortex and amygdala
• CA1 reinstates representations in cortex and amygdala during memory retrieval

Summary

The hippocampus is assumed to retrieve memory by reinstating patterns of cortical activity that were observed during learning. To test this idea, we monitored the activity of individual cortical neurons while simultaneously inactivating the hippocampus. Neurons that were active during context fear conditioning were tagged with the long-lasting fluorescent protein H2B-GFP and the light-activated proton pump ArchT. These proteins allowed us to identify encoding neurons several days after learning and silence them with laser stimulation. When tagged CA1 cells were silenced, we found that memory retrieval was impaired and representations in the cortex (entorhinal, retrosplenial, perirhinal) and the amygdala could not be reactivated. Importantly, hippocampal inactivation did not alter the total amount of activity in most brain regions. Instead, it selectively prevented neurons that were active during learning from being reactivated during retrieval. These data provide functional evidence that the hippocampus reactivates specific memory representations during retrieval.

This is a cool study, and it helps me understand why it's often very easy for me to learn new things. I am curious about so many things.

First up a summary of the research from Sci-News.com, then the abstract for the original article from Neuron (the full article is paywalled).

New Study Provides Insight into How Piquing Curiosity Changes Our Brains

Oct 3, 2014 by Sci-News.com

The more curious we are about a topic, the easier it is to learn information about that topic. A new study carried out by California University scientists provides insights into what happens in our brains when curiosity is piqued.

Curiosity helps learning and memory, scientists say. Anonymous painter, 15th century – Cahiers de Science et Vie no. 114.

Participants in the study first rated their curiosity about the answers to a series of trivia questions. Later, they had their brains scanned via functional magnetic resonance imaging while they learned the answers to these questions.

The participants were presented with a selected trivia question and while they waited for the answer to pop up on the screen, they were shown a picture of a neutral, unrelated face.

Afterwards, they performed a surprise recognition memory test for the presented faces, followed by a memory test for the answers to the trivia questions.

As expected, when people were highly curious to find out the answer to a question, they were better at learning that information.

More surprising, however, was that once their curiosity was aroused, they showed better learning of entirely unrelated information that they encountered but were not necessarily curious about.

The participants were also better able to retain the information learned during a curious state across a 24-hour delay.

“Our findings potentially have far-reaching implications for the public because they reveal insights into how a form of intrinsic motivation – curiosity – affects memory,” said Dr Matthias Gruber, who is the first author of the paper published in the journal Neuron.

“These findings suggest ways to enhance learning in the classroom and other settings.”

He added: “curiosity may put the brain in a state that allows it to learn and retain any kind of information, like a vortex that sucks in what you are motivated to learn, and also everything around it.”

The scientists also discovered that when curiosity is stimulated, there is increased activity in the brain circuit related to reward.

“We showed that intrinsic motivation actually recruits some of the same brain areas that are heavily involved in tangible, extrinsic motivation. This reward circuit relies on dopamine, a chemical that relays messages between neurons.”

In addition, they found that when learning was motivated by curiosity, there was increased activity in the hippocampus, a brain region that is important for forming new memories, as well as increased interactions between the hippocampus and the dopamine reward circuit.

Prof Charan Ranganath, who is the senior author on the study, explained: “so curiosity recruits the reward system, and interactions between the reward system and the hippocampus seem to put the brain in a state in which you are more likely to learn and retain information, even if that information is not of particular interest or importance.”

_____

Matthias J. Gruber et al. (2014, Oct 2). States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit. Neuron; doi: 10.1016/j.neuron.2014.08.060

* * * * *

States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit

Matthias J. Gruber, Bernard D. Gelman, Charan Ranganath

Highlights

• People are better at learning information that they are curious about
• Memory for incidental material presented during curious states was also enhanced
• Curiosity associated with anticipatory activity in nucleus accumbens and midbrain
• Memory benefits for incidental material depend on midbrain-hippocampus involvement

Summary

People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences.

The Amazing Brain (To the Best of Our Knowledge)

Here is this week's To the Best of Our Knowledge from PRI (Public Radio International and NPR). The topic this week is the amazing brain.

The Amazing Brain

09.07.2014 | TTBOOK

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• Download

It's hard to wrap your head around the future of the human brain. Augmented intelligence, memory playback, downloadable skills - it's all coming. We explore the future of the mind, and hear how a brain injury can transform your life.



Guest(s):

• Jason Padgett
• Michio Kaku
• Noa Guy
• Albert Nerenberg
• Steve Almond

Producer(s):

• Steve Paulson

Stories: 

Struck By Genius - Jason Padgett

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Jason Padgett was a hard-partying guy until a traumatic brain injury turned him into a math genius. Now, he sees complex geometric designs everywhere he looks.

***

Future of the Mind - Michio Kaku

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What if you could take a pill or download netware to supercharge your brain? Physicist Michio Kaku says augmented intelligence and memory playback systems are the future of brain science.

***

Disharmony - Noa Guy

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Noa Guy was a promising Israeli composer whose musical career was derailed by a car accident. In this episode from Israel Story, Shai Satran tells the story of how she learned to make music again.

Click here to hear more pieces from Israel Story.

***

Dangerous Idea: Simulating drugs through hypnosis

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Filmmaker and hypnotist Albert Nerenberg explains how we can simulate the effects of drugs through hypnosis.

***

On Our Minds: Against Football

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Steve Almond has loved football his whole life. But after investigating the violence and social ills that shape football, he explains why he no longer watches his favorite sport.

Related Books:

Struck By Genius (Jason Padgett, Maureen Ann Seaberg)


The Future of the Mind: The Scientific Quest to Understand, Enhance, and Empower the Mind (Michio Kaku)


Against Football (Steve Almond)

Tom Stafford - How to Speak the Language of Thought

From BBC Future, Tom Stafford looks at the state of the research in our efforts to understand how the brain functions. At this point, we have little more than a few snippets of information, or pieces of the code, that reveal only very specific activity. For example:

While the rat runs the maze we record where it is, and simultaneously how the cells in the hippocampus are firing. The cell firing patterns are thrown into a mathematical algorithm which finds the pattern that best matches each bit of the maze. The language of the cells is no less complex, but now we have a Rosetta Stone against which we can decode it. We then test the algorithm by feeding it freshly recorded patterns, to see if it correctly predicts where the rat was at the point that pattern was recorded.

It's not much, but each new piece of the code moves us a step closer to forming a better gestalt of what is really happening in our brains.

How to speak the language of thought

Tom Stafford | BBC Future
18 August 2014


(Thinkstock)

We are now beginning to crack the brain’s code, which allows us to answer such bizarre questions as “what is the speed of thought?”

When he was asked, as a joke, to explain how the mind works in five words, cognitive scientist Steven Pinker didn't hesitate. "Brain cells fire in patterns", he replied. It's a good effort, but all it really does is replace one enigma with another mystery.

It’s long been known that brain cells communicate by firing electrical signals to each other, and we now have myriad technologies for recording their patterns of activity – from electrodes in the brain or on the scalp, to functional magnetic resonance scanners that can detect changes in blood oxygenation. But, having gathered these data, the meaning of these patterns is still an enduring mystery. They seem to dance to a tune we can't hear, led by rules we don't know.

Neuroscientists speak of the neural code, and have made some progress in cracking that code. They are figuring out some basic rules, such as when cells in specific parts of the brain are likely to light up depending on the task at hand. Progress has been slow, but in the last decade various research teams around the world have been pursuing a far more ambitious project. We may never be able to see the complete code book, they realised, but by trying to write our own entries, we can begin to pick apart the ways that different patterns correspond to different actions.

Albert Lee and Matthew Wilson, at the Massachusetts Institute of Technology (MIT) first helped to set out the principles in 2002. It progresses like this. First, we record from the brain of a rat – one of our closer relatives, in the grand tree of life – as it runs a maze. Studying the whole brain would be too ambitious, so we can focus our recording on an area known as the hippocampus, known to be important for navigation and memory. If you've heard of this area before it is probably because of a famous result which showed that London taxi drivers developed larger hippocampi the longer they had spent navigating the streets of England's sprawling capital.


The longer London taxi drivers navigate the city's streets, the bigger certain parts of their brain tasked with memory and navigation grow (Thinkstock)
While the rat runs the maze we record where it is, and simultaneously how the cells in the hippocampus are firing. The cell firing patterns are thrown into a mathematical algorithm which finds the pattern that best matches each bit of the maze. The language of the cells is no less complex, but now we have a Rosetta Stone against which we can decode it. We then test the algorithm by feeding it freshly recorded patterns, to see if it correctly predicts where the rat was at the point that pattern was recorded.

It doesn’t allow us to completely crack the code, because we still don't know all the rules, and it can’t help us read the patterns which aren't from this bit of the brain or which aren't about maze running, but it is still a powerful tool. For instance, using this technique, the team was able to show that the specific sequence of cell firing repeated in the brain of the rat when it slept after running the maze (and, as a crucial comparison, not in the sleep it had enjoyed before it had run the maze).

Fascinatingly, the sequence repeated faster during sleep – around 20 times faster. This meant that the rat could run the maze in their sleeping minds in a fraction of the time it took them in real life. This could be related to the mnemonic function of sleep; by replaying the memory, it might have helped the rat to consolidate its learning. And the fact that the replay was accelerated might give us a glimpse of the activity that lies behind sudden insights, or experiences where our life “flashes before our eyes”; when not restrained, our thoughts really can retrace familiar paths in “fast forward”. Subsequent work has shown that these maze patterns can run backwards as well as forwards - suggesting that the rats can imagine a goal, like the end of the maze, and work their way back from that to the point where they are.

A rat can mentally replay a route around a maze 20 times faster when sleeping than it can when it’s awake (Thinkstock)

One application of techniques like these, which are equal parts highly specialised measurement systems and fiercely complicated algorithms, has been to decode the brain activity in patients who are locked in or in a vegetative state. These patients can’t move any of their muscles, and yet they may still be mentally aware and able to hear people talking to them in the same room. First, the doctors ask the patients to imagine activities which are known to active specific brain regions – such as the hippocampus. The data is then decoded so that you know which brain activity corresponds to certain ideas. During future brain scans, the patients can then re-imagine the same activities to answer basic questions. For instance, they might be told to imagine playing tennis to answer yes and walking around their house to answer no – the first form of communication since their injury.

There are other applications, both theoretical science, to probe the inner workings of our minds, and practical domains such as brain-computer interfaces. If, in the future, a paraplegic wants to control a robot arm, or even another person, via a brain interface, then it will rely on the same techniques to decode information and translate it into action. Now the principles have been shown to work, the potential is staggering.

If you have an everyday psychological phenomenon you'd like to see written about in these columns please get in touch @tomstafford or ideas@idiolect.org.uk

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Researchers Investigate Novel Approaches to Reducing Negative Memories

Two new studies hit the news this on Wednesday, both of which involve changing the emotional impact of memories.

The first was a joint project between MIT and Howard Hughes Medical Institute researchers. We'll start with the press release from MIT, a study that uses optogenetics (light stimulation) to alter emotional connections with memories:

Neuroscientists reverse memories' emotional associations: Brain circuit that links feelings to memories manipulated

Date: August 27, 2014
Source: Massachusetts Institute of Technology

Summary:
Most memories have some kind of emotion associated with them: Recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings. A new study from neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions.

This image depicts the injection sites and the expression of the viral constructs in the two areas of the brain studied: the Dentate Gyrus of the hippocampus (middle) and the Basolateral Amygdala (bottom corners). Credit: Image courtesy of the researchers

Most memories have some kind of emotion associated with them: Recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings.

A new study from MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics -- a technique that uses light to control neuron activity.

The findings, described in the Aug. 27 issue of Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say.

"In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones," says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT's Picower Institute for Learning and Memory, and senior author of the paper.

The paper's lead authors are Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT's Department of Biology.

Shifting memories

Memories are made of many elements, which are stored in different parts of the brain. A memory's context, including information about the location where the event took place, is stored in cells of the hippocampus, while emotions linked to that memory are found in the amygdala.

Previous research has shown that many aspects of memory, including emotional associations, are malleable. Psychotherapists have taken advantage of this to help patients suffering from depression and post-traumatic stress disorder, but the neural circuitry underlying such malleability is not known.

In this study, the researchers set out to explore that malleability with an experimental technique they recently devised that allows them to tag neurons that encode a specific memory, or engram. To achieve this, they label hippocampal cells that are turned on during memory formation with a light-sensitive protein called channelrhodopsin. From that point on, any time those cells are activated with light, the mice recall the memory encoded by that group of cells.

Last year, Tonegawa's lab used this technique to implant, or "incept," false memories in mice by reactivating engrams while the mice were undergoing a different experience. In the new study, the researchers wanted to investigate how the context of a memory becomes linked to a particular emotion. First, they used their engram-labeling protocol to tag neurons associated with either a rewarding experience (for male mice, socializing with a female mouse) or an unpleasant experience (a mild electrical shock). In this first set of experiments, the researchers labeled memory cells in a part of the hippocampus called the dentate gyrus.

Two days later, the mice were placed into a large rectangular arena. For three minutes, the researchers recorded which half of the arena the mice naturally preferred. Then, for mice that had received the fear conditioning, the researchers stimulated the labeled cells in the dentate gyrus with light whenever the mice went into the preferred side. The mice soon began avoiding that area, showing that the reactivation of the fear memory had been successful.

The reward memory could also be reactivated: For mice that were reward-conditioned, the researchers stimulated them with light whenever they went into the less-preferred side, and they soon began to spend more time there, recalling the pleasant memory.

A couple of days later, the researchers tried to reverse the mice's emotional responses. For male mice that had originally received the fear conditioning, they activated the memory cells involved in the fear memory with light for 12 minutes while the mice spent time with female mice. For mice that had initially received the reward conditioning, memory cells were activated while they received mild electric shocks.

Next, the researchers again put the mice in the large two-zone arena. This time, the mice that had originally been conditioned with fear and had avoided the side of the chamber where their hippocampal cells were activated by the laser now began to spend more time in that side when their hippocampal cells were activated, showing that a pleasant association had replaced the fearful one. This reversal also took place in mice that went from reward to fear conditioning.

Altered connections

The researchers then performed the same set of experiments but labeled memory cells in the basolateral amygdala, a region involved in processing emotions. This time, they could not induce a switch by reactivating those cells -- the mice continued to behave as they had been conditioned when the memory cells were first labeled.

This suggests that emotional associations, also called valences, are encoded somewhere in the neural circuitry that connects the dentate gyrus to the amygdala, the researchers say. A fearful experience strengthens the connections between the hippocampal engram and fear-encoding cells in the amygdala, but that connection can be weakened later on as new connections are formed between the hippocampus and amygdala cells that encode positive associations.

"That plasticity of the connection between the hippocampus and the amygdala plays a crucial role in the switching of the valence of the memory," Tonegawa says.

These results indicate that while dentate gyrus cells are neutral with respect to emotion, individual amygdala cells are precommitted to encode fear or reward memory. The researchers are now trying to discover molecular signatures of these two types of amygdala cells. They are also investigating whether reactivating pleasant memories has any effect on depression, in hopes of identifying new targets for drugs to treat depression and post-traumatic stress disorder.

David Anderson, a professor of biology at the California Institute of Technology, says the study makes an important contribution to neuroscientists' fundamental understanding of the brain and also has potential implications for treating mental illness.

"This is a tour de force of modern molecular-biology-based methods for analyzing processes, such as learning and memory, at the neural-circuitry level. It's one of the most sophisticated studies of this type that I've seen," he says.

The research was funded by the RIKEN Brain Science Institute, Howard Hughes Medical Institute, and the JPB Foundation.

Story Source:
The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton. Note: Materials may be edited for content and length.

Journal Reference:
Redondo RL, Kim J, Arons AL, Ramirez S, Liu X, Tonegawa S. (2014, Aug 27). Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature; DOI: 10.1038/nature13725

* * * * *

Here is the abstract for the Nature article, which is pay-walled, of course.

Bidirectional switch of the valence associated with a hippocampal contextual memory engram

Roger L. Redondo, Joshua Kim, Autumn L. Arons, Steve Ramirez, Xu Liu & Susumu Tonegawa

Nature (2014) doi:10.1038/nature13725 Published online 27 August 2014

The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique3, 4. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.

References:

1. Pavlov, I. P. Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex (Oxford Univ. Press, 1927)
2. Wolpe, J. Psychotherapy by Reciprocal Inhibition (Stanford Univ. Press, 1958)
3. Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012)
4. Ramirez, S. et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013)

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The second study comes from researchers at Harvard University who are using Xenon gas to remove the emotional context from traumatic memories. This is a murine study, but the results suggest further research will be coming.

Xenon gas is already being used for general anesthetic with fewer side effects and actually providing some cardioprotection and neuorprotection. From Wikipedia:

Xenon is a high-affinity glycine-site NMDA receptor antagonist.[129] However, xenon distinguishes itself from other clinically used NMDA receptor antagonists in its lack of neurotoxicity and its ability to inhibit the neurotoxicity of ketamine and nitrous oxide.[130][131] Unlike ketamine and nitrous oxide, xenon does not stimulate a dopamine efflux from the nucleus accumbens.[132]

First up the press release from Harvard (the Harvard Gazette) and then the abstract and introduction from PLOS ONE, the open access publication platform for science.

Erasing traumatic memories

Xenon exposure may be potential new treatment for people with PTSD

August 27, 2014 | Editor's Pick


By Scott O’Brien, McLean Hospital Communications
Researchers at Harvard-affiliated McLean Hospital are reporting that xenon gas, used in humans for anesthesia and diagnostic imaging, has the potential to become a treatment for post-traumatic stress disorder (PTSD) and other memory-related disorders.

“In our study, we found that xenon gas has the capability of reducing memories of traumatic events,” said Edward G. Meloni, assistant psychologist at McLean and an assistant professor of psychiatry at Harvard Medical School (HMS). “It’s an exciting breakthrough.”

In the study, published in the current issue of PLOS ONE, Meloni and HMS Associate Professor of Psychiatry Marc J. Kaufman, director of the Translational Imaging Laboratory at McLean, examined whether a low concentration of xenon gas could interfere with a process called reconsolidation — a state in which reactivated memories become susceptible to modification. “We know from previous research that each time an emotional memory is recalled, the brain actually re-stores it as if it were a new memory. With this knowledge, we decided to see whether we could alter the process by introducing xenon gas immediately after a fear memory was reactivated,” explained Meloni.

Statistics show an increase in PTSD diagnoses among the military. Harvard researchers are investigating a potential breakthrough that would treat symptoms associated with PTSD. Credit: Congressional Research Service PTSD data/McLean Hospital

The investigators used an animal model of PTSD called fear conditioning to train rats to be afraid of environmental cues that were paired with brief foot shocks. Reactivating the fearful memory was done by exposing the rats to those same cues and measuring their freezing response as a readout of fear. “We found that a single exposure to the gas, which is known to block NMDA receptors involved in memory formation in the brain, dramatically and persistently reduced fear responses for up to two weeks. It was as though the animals no longer remembered to be afraid of those cues,” said Meloni.

Meloni points out that the inherent properties of a gas such as xenon make it especially attractive for targeting dynamic processes like memory reconsolidation. “Unlike other drugs or medications that may also block NMDA receptors involved in memory, xenon gets in and out of the brain very quickly. This suggests that xenon could be given at the exact time the memory is reactivated, and for a limited amount of time, which may be key features for any potential therapy used in humans.”

“The fact that we were able to inhibit remembering of a traumatic memory with xenon is very promising because it is currently used in humans for other purposes, and thus it could be repurposed to treat PTSD,” added Kaufman.

For these investigators, several questions remain to be addressed with further testing. “From here we want to explore whether lower xenon doses or shorter exposure times would also block memory reconsolidation and the expression of fear. We’d also like to know if xenon is as effective at reducing traumatic memories from past events, so-called remote memories, versus the newly formed ones we tested in our study.”

Meloni and Kaufman indicate that future studies are planned to test whether the effects of xenon in rats that they saw in their study translate to humans. Given that intrusive re-experiencing of traumatic memories — including flashbacks, nightmares, and distress and physiological reactions induced by with trauma reminders — is a hallmark symptom for many who suffer from PTSD, a treatment that alleviates the impact of those painful memories could provide welcome relief.

The study may be viewed on the PLOS ONE website.

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Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

Edward G. Meloni, Timothy E. Gillis, Jasmine Manoukian, Marc J. Kaufman

Abstract

Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.

Full Citation: 
Meloni EG, Gillis TE, Manoukian J, Kaufman MJ. (2014. Aug 27). Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD). PLoS ONE 9(8): e106189. doi:10.1371/journal.pone.0106189

Introduction

Mitigation of persistent, intrusive, traumatic memories experienced by people with post-traumatic stress disorder (PTSD) remains a key therapeutic challenge [1]. Behavioral treatments such as extinction training – administered alone or in combination with cognitive-enhancing drugs (e.g. d-cycloserine) – attempt to inhibit underlying traumatic memories by facilitating a new set of learning contingencies, but often achieve limited success [2]. Another learning and memory phenomenon known as reconsolidation, a process by which reactivated (retrieved) memories temporarily enter a labile state (the reconsolidation window), has been studied to determine whether drug or behavioral interventions can prevent a traumatic memory trace from being re-incorporated back into the neural engram, inhibiting the memory [3]–[6]. Several chemical agents have been found to inhibit fear memory reconsolidation in animals [7] but unfortunately do not translate well to humans, limiting their clinical use. They either are toxic (e.g. protein synthesis inhibitors), induce unwanted side effects, are slow acting such that brain drug concentrations peak outside of the reconsolidation window, or are slowly eliminated such that they interfere with later onset memory processes including extinction [8]. A recent human study documented that a single electroconvulsive therapy (ECT) treatment administered to unipolar depressed subjects immediately after emotional memory reactivation disrupted reconsolidation, confirming that reconsolidation occurs in humans and that it can be inhibited by a brief treatment [9]. While ECT is indicated for therapeutic use in people with treatment-resistant major depression, it may not be a viable treatment for other clinical populations. Thus, there is a significant unmet need for a minimally invasive, safe and well-tolerated treatment that can be used clinically to inhibit fear memory reconsolidation in people with PTSD.

The noble gas xenon (Xe) inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors [10] known to play a role in memory reconsolidation [11]. Xe reduces NMDA-mediated synaptic currents and neuronal plasticity in the basolateral amygdala and CA1 region of the hippocampus [12], [13]; these brain areas are involved in Pavlovian fear conditioning, an animal model of PTSD used to elucidate learning and memory processes, including reconsolidation [14]–[16]. Xe already is used in humans at high concentration (>50%) as an anesthetic and at subsedative concentration (28%) as a diagnostic imaging agent; in both applications, Xe has excellent safety/side effect profiles and is well tolerated [17]–[19]. Further, NMDA receptor glycine antagonists like Xe [10] do not appear to have significant abuse liability and do not induce psychosis [20], [21], consistent with clinical experience [18], [19]. Thus, Xe has a number of favorable properties that might be beneficial for treating fear memory disorders. As fear memory reconsolidation is an “evolutionarily conserved memory-update mechanism” [5], we evaluated in rats whether administering a subsedative concentration of Xe (maximum concentration 25%, 1 h) via inhalation following conditioned fear memory reactivation could reduce subsequent expression of fear-like behavior. Here, we report that Xe impaired reconsolidation of fear memory demonstrated as a reduction in conditioned freezing, a behavioral readout used to measure fear in animals.