Anxiety Modulation: Portion of hippocampus found to play major role

Columbia University Medical Center (CUMC) researchers have found the first evidence that selective activation of the dentate gyrus, a portion of the hippocampus, can reduce anxiety without affecting learning. 

The findings suggest that therapies that target this brain region could be used to treat certain anxiety disorders, such as panic disorder and post-traumatic stress syndrome (PTSD), with minimal cognitive side effects.

The study, conducted in mice, was published today in the online edition of the journal Neuron. The dentate gyrus is known to play a key role in learning.

Rene Hen

Some evidence suggests that the structure also contributes to anxiety. "But until now no one has been able to figure out how the hippocampus could be involved in both processes," said senior author Rene Hen, PhD, professor of neuroscience and pharmacology (in psychiatry) at CUMC.

"It turns out that different parts of the dentate gyrus have somewhat different functions, with the dorsal portion largely dedicated to learning and the ventral portion dedicated to anxiety," said lead author Mazen A. Kheirbek, PhD, a postdoctoral fellow in neuroscience at CUMC.

To examine the role of the dentate gyrus in learning and anxiety, the investigators used a state-of-the-art technique called optogenetics, in which light-sensitive proteins, or opsins, are genetically inserted into neurons in the brains of mice.

Neurons with these genes can then be selectively activated or silenced through the application of light (via a fiber-optic strand), allowing researchers to study the function of the cells in real time.

Previously, the only way to study the dentate gyrus was to silence portions of it using such long-term manipulations as drugs or lesions, techniques that yielded conflicting results.

In the current study, opsins were inserted into dentate gyrus granule cells (the principal cells of the dentate gyrus).

The researchers then activated or silenced the ventral or dorsal portions of the dentate gyrus for three minutes at a time, while the mice were subjected to two well-validated anxiety tests (the elevated plus maze and the open field test).

"Our main findings were that elevating cell activity in the dorsal dentate gyrus increased the animals' desire to explore their environment. But this also disrupted their ability to learn. Elevating activity in the ventral dentate gyrus lowered their anxiety, but had no effect on learning," said Dr. Kheirbek.

The effects were completely reversible—that is, when the stimulation was turned off, the animals returned to their previous anxiety levels.

"The therapeutic implication is that it may be possible to relieve anxiety in people with anxiety disorders by targeting the ventral dentate gyrus, perhaps with medications or deep-brain stimulation, without affecting learning," said Dr. Hen.

Dr Hen is also a director of the Division of Integrative Neuroscience, The New York State Psychiatric Institute, and a member of The Kavli Institute for Brain Science.

"Given the immediate behavioral impact of such manipulations, these strategies are likely to work faster than current treatments, such as serotonin reuptake inhibitors."

According to Dr. Hen, such an intervention would probably work best in people with panic disorder or PTSD.

"There is evidence that people with these anxiety disorders tend to have a problem with pattern separation—the ability to distinguish between similar experiences," he said.

"In other words, they overgeneralize, perceiving minor threats to be the same as major ones, leading to a heightened state of anxiety. Such patients could conceivably benefit from therapies that fine-tune hippocampal activity."

Dr. Hen and his team are currently exploring strategies aimed at modulating the activity of the ventral dentate gyrus by stimulating neurogenesis in the ventral dentate gyrus.

"Indeed the dentate gyrus is one of the few areas in the adult brain where neurons are continuously produced, a phenomenon termed adult hippocampal neurogenesis," added Dr. Hen.

More information: The title of the paper is "Differential control of learning and anxiety along the dorso-ventral axis of the dentate gyrus."  

Anti-anxiety Drug calms fears by altering brain chemistry

An advance in understanding the brain’s fear circuitry has been revealed by a research team. They say it may hold particular promise for people at risk for anxiety disorders, including those suffering post-traumatic stress disorder (PTSD). Findings are reported in the journal Molecular Psychiatry.

“What is most compelling is our ability to translate first from mice to human neurobiology and then all the way out to human behaviour,” says Ahmad Hariri, a neurobiologist at Duke University. “That kind of translation is going to define the future of psychiatry and neuroscience.”

Read the original study DOI: 10.1038/mp.2012.72

 

The common thread in their studies is a gene encoding an enzyme called fatty acid amide hydrolase, or FAAH.

The enzyme breaks down a natural endo-cannabinoid chemical in the brain that acts in essentially the same way that Cannabis, aka marijuana, does (hence the name endo-cannabinoid).

Earlier studies had suggested that blocking the FAAH enzyme could decrease fear and anxiety by increasing endo-cannabinoids, which is consistent with the decreased anxiety some experience after smoking marijuana.

In 2009, Hariri’s lab found that a common variant in the human FAAH gene leads to decreased enzyme function with affects on the brain’s circuitry for processing fear and anxiety.

In the new study, Andrew Holmes’ group at the National Institute on Alcoholism and Alcohol Abuse tested the effects of a drug that blocks FAAH activity in fear-prone mice that had also been trained to be fearful through experiences in which they were delivered foot shocks.

Tests for the ability of those mice to get over their bad experiences found that the drug allowed a faster recovery from fear thanks to higher brain endo-cannabinoid levels.

More specifically, the researchers showed that those drug effects traced to the amygdala, a small area of the brain that serves as a critical hub for fear processing and learning.

To test for the human relevance of the findings, Hariri’s group went back to the genetic variant they had studied earlier in a group of middle-aged adults.

They showed study participants a series of pictures depicting threatening faces while they monitored the activity of their amygdalas using functional magnetic resonance imaging (fMRI) scans. They then looked for how the genetic variant affected this activity.

While the activity of the amygdala in all participants decreased over repeated exposures to the pictures. But people who carried the version of the FAAH gene associated with lower enzyme function and higher endo-cannabinoid levels showed a greater decrease in activity.

Hariri says that suggests that those individuals may be better able to control and regulate their fear response.

Further confirmation came from an analysis led by Duke’s Avshalom Caspi and Terrie Moffitt of 1,000 individuals in the Dunedin Study, who have been under careful observation since their birth in the 1970s in New Zealand.

Consistent with the mouse and brain imaging studies, those New Zealanders carrying the lower-expressing version of the FAAH gene were found to be more likely to keep their cool under stress.

“This study in mice reveals how a drug that boosts one of the brain’s naturally occurring endo-cannaboids enables fear extinction, a process that forms the basis of exposure therapy for PTSD,” Holmes says.

“It also shows how human gene variation in the same chemical pathways modulates the amygdala’s processing of threats and predicts how well people cope with stress.”

Studies are now needed to further explore both the connections between FAAH variation and PTSD risk as well as the potential of FAAH inhibition as a novel therapy for fear-related disorders, the researchers say.

More news from Duke University: http://today.duke.edu/

Our brains get confused when we're anxious

Competing neurons in this part of the brain help us make decisions, such as choosing words. (Credit: Image courtesy of Marie Banich)

A new University of Colorado at Boulder study sheds light on the brain mechanisms that allow us to make choices and ultimately could be helpful in improving treatments for the millions of people who suffer from the effects of anxiety disorders.

In the study, CU-Boulder psychology Professor Yuko Munakata and her research colleagues found that "neural inhibition," a process that occurs when one nerve cell suppresses activity in another, is a critical aspect in our ability to make choices.

"The breakthrough here is that this helps us clarify the question of what is happening in the brain when we make choices, like when we choose our words," Munakata said.

"Understanding more about how we make choices, how the brain is doing this and what the mechanisms are, could allow scientists to develop new treatments for things such as anxiety disorders."

Researchers have long struggled to determine why people with anxiety can be paralyzed when it comes to decision-making involving many potential options.

Munakata believes the reason is that people with anxiety have decreased neural inhibition in their brain, which leads to difficulty making choices.

"A lot of the pieces have been there," she said. "What's new in this work is bringing all of this together to say here's how we can fit all of these pieces of information together in a coherent framework explaining why it's especially hard for people with anxiety to make decisions and why it links to neural inhibitors."

A paper on the findings appeared in the Aug. 30 Proceedings of the National Academy of Sciences.

CU-Boulder professors Tim Curran, Marie Banich and Randall O'Reilly, graduate students Hannah Snyder and Erika Nyhus and undergraduate honors thesis student Natalie Hutchison co-authored the paper.

In the study, they tested the idea that neural inhibition in the brain plays a big role in decision-making by creating a computer model of the brain called a neural network simulation.

"We found that if we increased the amount of inhibition in this simulated brain then our system got much better at making hard choices," said Hannah Snyder, a psychology graduate student who worked with Munakata on the study.

"If we decreased inhibition in the brain, then the simulation had much more trouble making choices."

Through their model they looked at the brain mechanisms involved when we choose words. They then tested the model's predictions on people by asking them to think of the first verb that comes to mind when they are presented with a noun.

Eliminating range anxiety in Electric Cars

The ultimate cure for the “range anxiety” that afflicts electric car drivers worried they’ll run out of juice mid-trip could come when road-embedded wireless charging strips power up cars as they motor down the highway.

HaloIPT, a London-based developer of cable-free charging systems, took a small step in that direction yesterday, as it signed an agreement with another UK company, Chargemaster plc, to manufacture HaloIPT’s wireless transmitting pads.

On the surface, the deal is not huge- Chargemaster will make “dozens” of charging pads, according to a joint press release. But the “strategic partnership” is significant because it calls for Chargemaster to help develop and deploy a wireless charging infrastructure and billing system in Britain.

Chargemaster is already the largest provider of cabled charging bays in the UK, where it has installed posts in parking lots, supermarkets and other public spaces. It has done the same across Europe, where it has about 500 charging posts. It should be a key ally for HaloIPT, a company owned by international engineering firm Arup, by the University of Auckland in New Zealand, and by Australian venture capital firm Trans-Tasman Commercialization.

Fear: What is it Good For? Fuzzy Logic!

FEAR changes how we see things, enhancing our ability to identify blurry shapes but impairing our perception of fine details. This may help us to escape threats.

Looking at a fearful face, which activates the brain in a similar way to feeling fear, enhances sensitivity to visual contrast, but whether it improves vision across the board wasn't clear. So Bruno Bocanegra and René Zeelenberg at Erasmus University in Rotterdam, the Netherlands, showed people pictures of faces with either fearful or neutral expressions, followed by a "blob" covered in stripes of varying thicknesses.

Those shown a fearful face were better at identifying whether thick stripes were vertical or slightly tilted and worse at identifying the orientation of thin stripes than those shown neutral faces (Psychological Science, DOI: 10.1111/j.1467-9280.2009.02354.x).

This response may have evolved because coarse-grained features, which enable you to evaluate movement and distance, better aid survival in scary situations than fine details. "You don't care whether the object has wrinkles, you care whether its movement is threatening," Bocanegra says.