MicroRNAs Help Control HIV Life Cycle

Scientists at Burnham Institute for Medical Research (Burnham) have discovered that specific microRNAs (non-coding RNAs that interfere with gene expression) reduce HIV replication and infectivity in human T-cells. In particular, miR29 plays a key role in controlling the HIV life cycle. The study suggests that HIV may have co-opted this cellular defense mechanism to help the virus hide from the immune system and antiviral drugs.

Tariq Rana, Ph.D., director of the Program for RNA Biology at Burnham, and colleagues, found that the microRNA miR29 suppresses translation of the HIV-1 genome by transporting the HIV mRNA to processing-bodies (P-bodies), where they are stored or destroyed. This results in a reduction of viral replication and infectivity. The study also showed that inhibition of miR29 enhances viral replication and infectivity. The scientists further demonstrated that strains of HIV-1 with mutations in the region of the genome that interact with miR29 are not inhibited by miR29.

“We think the virus may use this mechanism to modulate its own lifecycle, and we may be able to use this to our advantage in developing new drugs for HIV,” said Dr. Rana. “Retroviral therapies greatly reduce viral load but cannot entirely eliminate it. This interaction between HIV and miR29 may contribute to that inability. Perhaps, by targeting miR29, we can force HIV into a more active state and improve our ability to eliminate it.”

Rana’s team looked at miR29 expression levels in infected and uninfected cells and found that miR29 expression was enhanced by HIV-1 infection. Blocking the activity of miR29 with interfering RNA resulted in increased replication and infectivity of the virus. The scientists tested the association of miR29 and HIV-1 by mutating both miR29 and its target region on the HIV virus. When either was altered, miR29s suppression of HIV replication and infectivity was reduced or eliminated.

In addition, the team suppressed P-bodies in the cells and noted a similar effect. This suggests that HIV may use miRNAs to become dormant and escape immune response.

Molecular Cell, Volume 34, Issue 6, 686-695, 26 June 2009
doi:10.1016/j.molcel.2009.04.032
Cellular MicroRNA and P Bodies Modulate Host-HIV-1 Interactions p696
Robin Nathans 1,Chia-ying Chu 1,2, Anna Kristina Serquina 1,Chih-Chung Lu 1,2, Hong Cao 1 and Tariq M. Rana 1,2, Corresponding Authors,

1 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
2 Program for RNA Biology, Sanford Children’s Health Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA

Summary

MicroRNAs (miRNAs), 22 nt noncoding RNAs, assemble into RNA-induced silencing complexes (RISCs) and localize to cytoplasmic substructures called P bodies. Dictated by base-pair complementarity between miRNA and a target mRNA, miRNAs specifically repress posttranscriptional expression of several mRNAs. Here we report that HIV-1 mRNA interacts with RISC proteins and that disrupting P body structures enhances viral production and infectivity. In HIV-1-infected human T lymphocytes, we identified a highly abundant miRNA, miR-29a, which specifically targets the HIV-1 3UTR region. Inhibiting miR-29a enhanced HIV-1 viral production and infectivity, whereas expressing a miR-29 mimic suppressed viral replication. We also found that specific miR-29a-HIV-1 mRNA interactions enhance viral mRNA association with RISC and P bodyproteins. Thus we provide an example of a single host miRNA regulating HIV-1 production and infectivity. These studies highlight the significance of miRNAs and P bodies in modulating host cell interactionswith HIV-1 and possibly other viruses.

Fear: Where It Happens In The Brain

Fear is a powerful emotion, and neuroscientists have for the first time located the neurons responsible for fear conditioning in the mammalian brain. Fear conditioning is a form of Pavlovian, or associative, learning and is considered to be a model system for understanding human phobias, post-traumatic stress disorder and other anxiety disorders.

Using an imaging technique that enabled them to trace the process of neural activation in the brains of rats, University of Washington researchers have pinpointed the basolateral nucleus in the region of the brain called the of amygdala as the place where fear conditioning is encoded.

Neuroscientists previously suspected that both the amygdala and another brain region, the dorsal hippocampus, were where cues get associated when fear memories are formed. But the new work indicates that the role of the hippocampus is to process and transmit information about conditioned stimuli to the amygdala, said Ilene Bernstein, corresponding author of the new study and a UW professor of psychology.

The study is being published on July 6, in PLoS One, a journal of the Public Library of Science.

Associative conditioning is a basic form of learning across the animal kingdom and is regularly used in studying how brain circuits can change as a result of experience. In earlier research, UW neuroscientists looked at taste aversion, another associative learning behavior, and found that neurons critical to how people and animals learn from experience are located in the amygdala.

The new work was designed to look for where information about conditioned and unconditioned stimuli converges in the brain as fear memories are formed. The researchers used four groups of rats and placed individual rodents inside of a chamber for 30 minutes. Three of the groups had never seen the chamber before.

When control rats were placed in the chamber, they explored it, became less active and some fell asleep. A delayed shock group also explored the chamber, became less active and after 26 minutes received an electric shock through the floor of the chamber. The third group was acclimated to the chamber by a series of 10 prior visits and then went through the same procedure as the delayed shock rats. The final group was shocked immediately upon being introduced inside the chamber.

The following day the rats were individually returned to the chamber and the researchers observed them for freezing behavior. Freezing, or not moving, is the most common behavioral measure of fear in rodents. The only rats that exhibited robust freezing were those that received the delayed shock in a chamber which was unfamiliar to them.

“We didn’t know if we could delay the shock for 26 minutes and get a fear reaction after just one trial. I thought it would be impossible to do this with fear conditioning,” said Bernstein. “This allowed us to ask where information converged in the brain.”

To do this, the researchers repeated the procedure, but then killed the rats. They then took slices of the brains and used Arc catfish, an imaging technique, which allowed them to follow the pattern of neural activation in the animals.

Only the delayed shock group displayed evidence of converging activation from the conditioned stimulus (the chamber) and the unconditioned stimulus (the shock). The experiment showed that animals can acquire a long-term fear when a novel context is paired with a shock 26 minutes later, but not when a familiar context is matched with a shock.

“Fear learning and taste aversion learning are both examples of associative learning in which two experiences occur together. Often they are learned very rapidly because they are critical to survival, such as avoiding dangerous places or toxic foods,” said Bernstein.

“People have phobias that often are set off by cues from something bad that happened to them, such as being scared by a snake or being in a dark alley. So they develop an anxiety disorder,” she said.

“By understanding the process of fear conditioning we might learn how to treat anxiety by making the conditioning weaker or to go away. It is also a tool for learning about these brain cells and the underlying mechanism of fear conditioning.”

PLoS ONE 4(7): e6156. doi:10.1371/journal.pone.0006156
Amygdalar Neurons during Pavlovian Fear Conditioning. PLoS ONE 4(7): e6156.
Sabiha K. Barot1,2, Ain Chung2, Jeansok J. Kim1,2, Ilene L. Bernstein1,2*

1 Program in Neurobiology & Behavior, University of Washington, Seattle, Washington, United States of America, 2 Department of Psychology, University of Washington, Seattle, Washington, United States of America
Abstract
Background
Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS) and unconditioned stimulus (US) during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain.
Methodology/Principal Findings
Here, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH) to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus.
Conclusions/Significance
Based on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.

The Problem With Self-help Books: The Negative Side To Positive Self-statements

In times of doubt and uncertainty, many Americans turn to self-help books in search of encouragement, guidance and self-affirmation. The positive self-statements suggested in these books, such as “I am a lovable person” or “I will succeed,” are designed to lift a person’s low self-esteem and push them into positive action.

According to a recent study in Psychological Science, however, these statements can actually have the opposite effect.

Psychologists Joanne V. Wood and John W. Lee from the University of Waterloo, and W.Q. Elaine Perunovic from the University of New Brunswick, found that individuals with low self-esteem actually felt worse about themselves after repeating positive self-statements.

The researchers asked participants with low self-esteem and high self-esteem to repeat the self-help book phrase “I am a lovable person.” The psychologists then measured the participants’ moods and their momentary feelings about themselves. As it turned out, the individuals with low self-esteem felt worse after repeating the positive self-statement compared to another low self-esteem group who did not repeat the self-statement. The individuals with high self-esteem felt better after repeating the positive self-statement–but only slightly.

In a follow-up study, the psychologists allowed the participants to list negative self-thoughts along with positive self-thoughts. They found that, paradoxically, low self-esteem participants’ moods fared better when they were allowed to have negative thoughts than when they were asked to focus exclusively on affirmative thoughts.

The psychologists suggested that, like overly positive praise, unreasonably positive self-statements, such as “I accept myself completely,” can provoke contradictory thoughts in individuals with low self-esteem. Such negative thoughts can overwhelm the positive thoughts. And, if people are instructed to focus exclusively on positive thoughts, they may find negative thoughts to be especially discouraging.

As the authors concluded, “Repeating positive self-statements may benefit certain people [such as individuals with high self-esteem] but backfire for the very people who need them the most.”

Psychological Science, 2009; DOI: 10.1111/j.1467-9280.2009.02370.x
Positive Self-Statements: Power for Some, Peril for Others.
Joanne V. Wood, W.Q. Elaine Perunovic, and John W. Lee

ABSTRACT—Positive self-statements are widely believed to boost mood and self-esteem, yet their effectiveness has not been demonstrated. We examined the contrary prediction that positive self-statements can be ineffective or even harmful. A survey study confirmed that people often use positive self-statements and believe them to be effective. Two experiments showed that among participants with low self-esteem, those who repeated a positive self-statement (”I’m a lovable person”) or who focused on how that statement was true felt worse than those who did not repeat the statement or who focused on how it was both true and not true. Among participants with high self-esteem, those who repeated the statement or focused on how it was true felt better than those who did not, but to a limited degree. Repeating positive self-statements may benefit certain people, but backfire for the very people who “need” them the most.

über liebe

Nähe, die nicht erdrückt, Distanz, die nicht entfremdet, Freiheit, die nicht verletzt.

Gene Transfer Technology For HIV Vaccine

A research team may have broken the stubborn impasse that has frustrated the invention of an effective HIV vaccine, by using an approach that bypasses the usual path followed by vaccine developers. By using gene transfer technology that produces molecules that block infection, the scientists protected monkeys from infection by a virus closely related to HIV—the simian immunodeficiency virus, or SIV—that causes AIDS in rhesus monkeys.

“We used a leapfrog strategy, bypassing the natural immune system response that was the target of all previous HIV and SIV vaccine candidates,” said study leader Philip R. Johnson, M.D., chief scientific officer at The Children’s Hospital of Philadelphia. Johnson developed the novel approach over a ten-year period, collaborating with K. Reed Clark, Ph.D., a molecular virologist at Nationwide Children’s Hospital in Columbus, Ohio.

Johnson cautioned that many hurdles remain before the technique used in this animal study might be translated into an HIV vaccine for humans. If the technique leads to an effective HIV vaccine, such a vaccine may be years away from realization.

Most attempts at developing an HIV vaccine have used substances aimed at stimulating the body’s immune system to produce antibodies or killer cells that would eliminate the virus before or after it infected cells in the body. However, clinical trials have been disappointing. HIV vaccines have not elicited protective immune responses, just as the body fails on its own to produce an effective response against HIV during natural HIV infection.

The approach taken in the current study was divided into two phases. In the first phase, the research team created antibody-like proteins (called immunoadhesins) that were specifically designed to bind to SIV and block it from infecting cells. Once proven to work against SIV in the laboratory, DNA representing SIV-specific immunoadhesins was engineered into a carrier virus designed to deliver the DNA to monkeys. The researchers chose adeno-associated virus (AAV) as the carrier virus because it is a very effective way to insert DNA into the cells of a monkey or human.

In the second part of the study, the team injected AAV carriers into the muscles of monkeys, where the imported DNA produced immunoadhesins that entered the blood circulation. One month after administration of the AAV carriers, the immunized monkeys were injected with live, AIDS-causing SIV. The majority of the immunized monkeys were completely protected from SIV infection, and all were protected from AIDS. In contrast, a group of unimmunized monkeys were all infected by SIV, and two-thirds died of AIDS complications. High concentrations of the SIV-specific immunoadhesins remained in the blood for over a year.

Further studies need to be conducted if this technique is to become an actual preventive measure against HIV infection in people, Johnson said. “To ultimately succeed, more and better molecules that work against HIV, including human monoclonal antibodies, will be needed,” he and his co-authors conclude. Finally, added Johnson, their approach may also have potential use in preventing other infectious diseases, such as malaria.

Grants from the National Institute of Allergic and Infectious Diseases of the National Institutes of Health supported this study. Johnson’s collaborators, in addition to Clark, were Jianchao Zhang, of Nationwide Children’s Hospital, Columbus, Ohio; Eloisa Yuste and Ronald C. Desrosiers of the New England Primate Research Center and Harvard Medical School; and Bruce C. Schnepp, Mary J. Connell, and Sean M. Greene, of Children’s Hospital and the University of Pennsylvania School of Medicine. Johnson also is on the University of Pennsylvania faculty.

Nature Medicine, May 17, 2009 Published online: 17 May 2009 DOI: 10.1038/nm.1967
Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys.
Philip R Johnson, Bruce C Schnepp, Jianchao Zhang, Mary J Connell, Sean M Greene, Eloisa Yuste, Ronald C Desrosiers & K Reed Clark.

The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.

Human Brain Makes Its Own ‘Marijuana’

U.S. and Brazilian scientists have discovered that the brain manufactures proteins that act like marijuana at specific receptors in the brain itself. This discovery may lead to new marijuana-like drugs for managing pain, stimulating appetite, and preventing marijuana abuse.

Scientists made their discovery by first extracting several small proteins, called peptides, from the brains of mice and determining their amino acid sequence. The extracted proteins were then compared with another peptide previously known to bind to, but not activate, the receptor (THC) affected by marijuana. Out of the extracted proteins, several not only bound to the brain’s THC receptors, but activated them as well.

The FASEB Journal Published online before print April 20, 2009 as doi: 10.1096/fj.09-132142.

Novel endogenous peptide agonists of cannabinoid receptors
Ivone Gomes, Julia S. Grushko, Urszula Golebiewska, Sascha Hoogendoorn, Achla Gupta, Andrea S. Heimann, Emer S. Ferro, Suzanne Scarlata, Lloyd D. Fricker, and Lakshmi A. Devi

E-mail contact: lakshmi.devi@mssm.edu

Hemopressin (Hp), a 9-residue {alpha}-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp{alpha}) or two (VD-Hp{alpha}) additional amino acids, as well as a {beta}-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hp{beta}). Characterization of the {alpha}-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB1 cannabinoid receptor antagonist, both RVD-Hp{alpha} and VD-Hp{alpha} function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca2+ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB1 agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB1 receptor is involved in the integration of signals from both lipid- and peptide-derived signaling molecules.—Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors.

Who I Am Depends on How I Feel

Scientists have long been interested in the interplay of emotions and identity, and some have recently focused on cultural identity. One’s heritage would seem to be especially stable and impervious to change, simply because it’s been passed down generation after generation and is deeply ingrained in the collective psyche. But how deeply, exactly?

Psychologists Claire Ashton-James of the University of British Columbia, William W. Maddux from INSEAD, Adam Galinsky of Northwestern University, and Tanya Chartrand from Duke University decided to explore this intriguing question in the laboratory, to see if even something as potent as culture might be tied to normal mood swings. European cultures are known to value independence and individuality, whereas Asian cultures prize community and harmony. This fundamental East-West cultural difference is well established, and so offered the researchers an ideal test.

The volunteers consisted of students hailing from a number of different countries and the researchers unconsciously raised or lowered their moods via two different methods. In one study, the volunteers listened to some upbeat Mozart on the stereo to lift their moods, or some Rachmaninov to bring them down. In another study, the volunteers held pens in their mouths: Some held the pen with their teeth, which basically forces the face into a smile, which improves mood. Others held the pen with their lips, forcing a frown. Then the volunteers completed a variety of tests, each designed to measure the strength of their values. In one test, the volunteers were offered a choice of five pens, four blue and one red. In keeping with cultural values, Asians typically pick from the more common blue pens in this test — to be part of the group — while Westerners usually take the one red pen. In another test, the volunteers thought about the questions “Who am I?” and listed 20 answers. The lists were analyzed to see if they reflected predominantly individualistic or predominantly group values.

The results, published in Psychological Science, a journal of the Association for Psychological Science, were consistent for all of the tests: Feeling good did indeed encourage the volunteers — both European and Asian — to explore values that are inconsistent with their cultural norms. And elevated mood even shaped behavior, allowing volunteers to act “out of character.” These findings suggest that people in an upbeat mood are more exploratory and daring in attitude — and therefore more apt to break from cultural stereotype. That is, Asians act more independently than usual, and Europeans are more cooperative. Feeling bad did the opposite: It reinforced traditional cultural stereotypes and constrained both Western and Eastern thinking about the world.

The researchers note these results suggest that emotions may serve an important social purpose. They surmise that positive feelings may send a signal that it’s safe to broaden one’s view of the world — and to explore novel notions of one’s self. The researchers go on to indicate that negative feelings may do the opposite: They may send a signal that it’s time to circle the wagons and stick with the “tried and true.” They conclude that the findings also suggest that the “self” may not be as robust and static as we like to believe and that the self may be dynamic, constructed again and again from one’s situation, heritage and mood.

Psychological Science Volume 20 Issue 3, Pages 340 – 346 Published Online: 23 Feb 2009
Who I Am Depends on How I Feel: The Role of Affect in the Expression of Culture
Claire E. Ashton-James 1 , William W. Maddux 2 , Adam D. Galinsky 3 , and Tanya L. Chartrand 4
1 University of British Columbia, 2 INSEAD, 3 Northwestern University, and 4 Duke University
Address correspondence to Claire E. Ashton-James, University of British Columbia, School of Psychology, 2136 West Mall, Vancouver, British Columbia, Canada V6T 1Z4, e-mail: cajames@psych.ubc.ca.

ABSTRACT—We present a novel role of affect in the expression of culture. Four experiments tested whether individuals’ affective states moderate the expression of culturally normative cognitions and behaviors. We consistently found that value expressions, self-construals, and behaviors were less consistent with cultural norms when individuals were experiencing positive rather than negative affect. Positive affect allowed individuals to explore novel thoughts and behaviors that departed from cultural constraints, whereas negative affect bound people to cultural norms. As a result, when Westerners experienced positive rather than negative affect, they valued self-expression less, showed a greater preference for objects that reflected conformity, viewed the self in more interdependent terms, and sat closer to other people. East Asians showed the reverse pattern for each of these measures, valuing and expressing individuality and independence more when experiencing positive than when experiencing negative affect. The results suggest that affect serves an important functional purpose of attuning individuals more or less closely to their cultural heritage.

Binge Eating: The Perfectionistm Model

In everyday life, someone who takes a perfectionist’s approach to activities might be admired or even rewarded with a pat on the back.

These attitudes are tied to a commonly held, but mistaken, belief that perfectionism will ultimately produce achievement and social success. But a psychologist warns that perfectionism is not a healthy, or even effective, approach to life’s challenges.

“Perfectionism is a double-edged personality trait,” says Simon Sherry, assistant professor of psychology.

A newly-published study shows why individuals with a high degree of perfectionism are often setting themselves up for a host of physical, emotional and mental problems– particularly related to binge eating. Although less well recognized than anorexia or bulimia, binge eating is a serious disorder. Binge eating occurs when a person feels out of control and rapidly consumes a large amount of food in a short period of time. Binge eating elevates the risk of developing depression, obesity, diabetes and other problems.

Dr. Sherry, of Dalhousie University in Halifax Nova Scotia, has published “The Perfectionism Model of Binge Eating” in the Journal of Personality and Social Psychology, along with co-author Peter Hall of the University of Waterloo. By closely following the daily activities of a large group of undergraduates, the researchers believe that they’re the first to identify why perfectionism results in binge eating.

They have also honed in on the type of perfectionist who is most at risk–someone who believes that others are evaluating their performance critically (as opposed to someone who is self-critical). This kind of perfectionist concludes that a parent, a friend or a boss is being harshly judgmental of their performance and pressuring them to be perfect.

“It seems that as perfectionists go about their day-to-day lives, they generate a lot of friction,” says Dr. Sherry. “Because of their inflexibility and unrealistic expectations they also create problems in their relationships.”

Let’s imagine how a perfectionist might begin their day.

Today’s Goals

* Run faster than yesterday’s personal best.
* Drink coffee instead of having breakfast.
* Earn the highest grade in the class on that mid-term.
* Meet for group project at 3 p.m. sharp to fix presentation.
* Find the most original gift for friend’s birthday.

What happens when the day ends up looking more like this instead?

Today’s Failures

* Running time misses personal best altogether.
* Earned 89 on the midterm, so six others are ahead of me now.
* Manage to limit lunch to a salad.
* Group is late for meeting, so presentation is still boring.
* Friend is disappointed with birthday gift.

Chances are the next sequence of events will involve self-harm.

Today’s Secret

* Late in the day, lose control and binge eat.
* Feel a horrible ‘pit in the stomach.’
* Hide the evidence to keep the secret.
* Criticize and loathe myself.
* Dwell on being alone and isolated.

Binge eating becomes an effort to escape from being overwhelmed with feelings of loneliness, failure and sadness. To temporarily escape from a discouraging reality, it’s necessary to do away with higher order thought. The experience of eating–smelling, chewing, tasting–is immediate and visceral.

“Think about it–when was the last time that you were rapidly eating a pizza and pondering a major life decision at exactly the same time?” asks Dr. Sherry.

While binge eating banishes troubles and difficulties in the short term, it also generates powerful negative emotions of guilt and shame that are longer lasting.

“We want to improve the lives of perfectionists with patterns of disordered eating,” he says.

The intent is that this research will translate directly into better care, through improved assessment and treatment opportunities. Society does demand achievement, but perfectionism is often maladaptive–a conscientious and adaptable person who can modify goals and expectations is better able to excel.

Perfectionists are often not self aware and are reluctant to seek help, posing a conundrum: They don’t want to admit they’re imperfect.

“I’m hopeful that students will read about this and realize that there are effective interventions for binge eating, including some help for perfectionism–change is possible.”

Journal of Personality and Social Psychology. Vol 96(3), Mar 2009, 690-709.
The perfectionism model of binge eating: Tests of an integrative model.
By Sherry, Simon B.; Hall, Peter A.

This study proposes, tests, and supports the perfectionism model of binge eating (PMOBE), a model aimed at explaining why perfectionism is related to binge eating. According to this model, socially prescribed perfectionism (SPP) confers risk for binge eating by generating exposure to 4 triggers of binge episodes: interpersonal discrepancies, low interpersonal esteem, depressive affect, and dietary restraint. In testing the PMOBE, a daily diary was completed by 566 women for 7 days. Predictions derived from the PMOBE were supported, with tests of mediation suggesting that the indirect effect of SPP on binge eating through triggers of binge episodes was significant. Reciprocal relations were also observed, with certain triggers of binge episodes predicting binge eating (and vice versa). Results supported the incremental validity of the PMOBE over and above self-oriented perfectionism and neuroticism and the generalizability of this model across Asian and European Canadian participants. The PMOBE offers a novel view of individuals with high levels of SPP as active agents who raise their risk of binge eating by generating conditions in their daily lives that are conducive to binge episodes. (PsycINFO Database Record (c) 2009 APA, all rights reserved)

Key for Learning And Learning-related Behavior – Dopamine

Researchers at UT Southwestern Medical Center have shed light on how the neurotransmitter dopamine helps brain cells process important information.

Researchers found in a study of mouse cells that this neurotransmitter, one of the molecules used by nerve cells to communicate with one another, causes certain brain cells to become more flexible and changes brain-cell circuitry to process important information differently than mundane information.

“This can help one remember a new, important episode as distinct from any other episode, such as remembering where you parked your car today versus yesterday,” said Dr. Robert Greene, professor of psychiatry at UT Southwestern.

“If we can one day manipulate the way that salient information is processed, we might be able to not only improve learning, but also improve the learning needed to extinguish severe fear responsiveness, such as when a soldier can’t forget emotional war memories associated with post-traumatic stress disorder,” he said.

Dr. Greene said the research also could have implications for addictions and schizophrenia, because those conditions are associated with alterations in dopamine in the brain.

Researchers have known that dopamine is released in the brain in association with experiencing “important” events and remembering salient acts, such as learning to avoid a hot stove or that a good grade is rewarded. The current research focused on how dopamine operates on the cells associated with this type of memory formation.

Dr. Greene, director of the National Clozapine Coordinating Center at the Dallas Veterans Affairs Medical Center, and his research team isolated slices of the hippocampus region of the animals’ brains and then electrically stimulated the cells. To simulate what happens in the brain in response to a memory-worthy event, they then exposed the cells to a selective dopamine-like neurotransmitter agent and repeated the stimulation. By comparing the effects of the stimulation with and without the dopamine agent, they could identify changes in NMDA receptor responses. NMDA receptors are proteins that mediate synaptic plasticity when activated.

“The NMDA responses changed to increase the cells’ plasticity, and we think that this facilitates learning and memory,” Dr. Greene said.

In addition, the changes in NMDA responses to dopamine agents changed the functional circuitry of the cells. These changes made the cells more responsive to electrical impulses coming from an indirect route through three processing “stations” before they reached the output region of the hippocampus. Without the presence of dopamine, Dr. Greene said, the cells tend to respond instead to impulses traveling by a route that is more direct and requires less processing. Information sent by this direct route may reflect what is already known and is less likely to change the animal’s behavior.

“While the current study involved isolated mouse brain tissue containing the memory circuits, the human brain likely works the same way,” Dr. Greene said. “You don’t want to have interference from yesterday. You need to know where you parked your car today, and dopamine may help to ensure that information from today will be remembered as distinct from yesterday.”

The researchers next will study how dopamine modulation affects learning and memory-related behavior and will investigate further exactly how dopamine acts on cells and their circuits.

Adapted from materials provided by UT Southwestern Medical Center.

J. Neurosci., Mar 2009; 29: 3109 – 3119 ; doi:10.1523/JNEUROSCI.4746-08.2009
D1/D5 Modulation of Synaptic NMDA Receptor Currents
Juan A. Varela, Silke J. Hirsch, David Chapman, Leah S. Leverich, and Robert W. Greene

Correspondence should be addressed to Robert W. Greene, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: robertw.greene@utsouthwestern.edu

Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D1/D5 receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D1/D5 modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D1/D5 receptor activation elicits a bidirectional long-term plasticity of NMDA receptor-mediated synaptic currents with the polarity of plasticity determined by NMDA receptor, NR2A/B subunit composition. This plasticity results in a decrease in the NR2A/NR2B ratio of subunit composition. Synaptic responses mediated by NMDA receptors that include NR2B subunits are potentiated by D1/D5 receptor activation, whereas responses mediated by NMDA receptors that include NR2A subunits are depressed. Furthermore, these bidirectional, subunit-specific effects are mediated by distinctive intracellular signaling mechanisms. Because there is a predominance of NMDA receptors composed of NR2A subunits observed in entorhinal–CA1 inputs and a predominance of NMDA receptors composed of NR2B subunits in CA3–CA1 synapses, potentiation of synaptic NMDA currents predominates in the proximal CA3–CA1 synapses, whereas depression of synaptic NMDA currents predominates in the distal entorhinal–CA1 synapses. Finally, all of these effects are reproduced by the release of endogenous monoamines through activation of D1/D5 receptors. Thus, endogenous D1/D5 activation can (1) decrease the NR2A/NR2B ratio of NMDA receptor subunit composition at glutamatergic synapses, a rejuvenation to a composition similar to developmentally immature synapses, and, (2) in CA1, bias NMDA receptor responsiveness toward the more highly processed trisynaptic CA3–CA1 circuit and away from the direct entorhinal–CA1 input.

Is There A Seat Of Wisdom In The Brain?

Researchers at the University of California, San Diego School of Medicine have compiled the first-ever review of the neurobiology of wisdom – once the sole province of religion and philosophy.

The study by Dilip V. Jeste, MD, and Thomas W. Meeks, MD, of UC San Diego’s Department of Psychiatry and the Stein Institute for Research on Aging, is published in the Archives of General Psychiatry.

“Defining wisdom is rather subjective, though there are many similarities in definition across time and cultures,” said Jeste, who is the Estelle and Edgar Levi Chair in Aging, professor of psychiatry and neuroscience and chief of geriatric psychiatry at UC San Diego. “However, our research suggests that there may be a basis in neurobiology for wisdom’s most universal traits.”

Wisdom has been defined over centuries and civilizations to encompass numerous psychological traits. Components of wisdom are commonly agreed to include such attributes as empathy, compassion or altruism, emotional stability, self-understanding, and pro-social attitudes, including a tolerance for others’ values.

“But questions remain: is wisdom universal, or culturally based?” said Jeste. “Is it uniquely human, related to age? Is it dependent on experience or can wisdom be taught?”

Empirical research on wisdom is a relatively new phenomenon. Meeks and Jeste noted that in the 1970s, there were only 20 peer-reviewed articles on wisdom, but since 2000, there have been more than 250 such publications. However, the researchers found no previous studies using the keyword “wisdom” in combination with the terms neurobiology, neuroimaging or neurotransmitters.

In order to determine if specific brain circuits and pathways might be responsible for wisdom, the researchers examined existing articles, publications and other documents for six attributes most commonly included in the definition of wisdom, and for the brain circuitry associated with those attributes.

Meeks and Jeste focused primarily on functional neuroimaging studies, studies which measure changes in blood flow or metabolic alterations in the brain, as well as on neurotransmitter functions and genetics. They found, for example, that pondering a situation calling for altruism activates the medial pre-frontal cortex, while moral decision-making is a combination of rational (the dorsolateral prefrontal cortex, which plays a role in sustaining attention and working memory), emotional/social (medial pre-frontal cortex), and conflict detection (the anterior cingulate cortex, sometimes also associated with a so-called “sixth sense”) functions.

Interestingly, several common brain regions appear to be involved in different components of wisdom. The UC San Diego researchers suggest that the neurobiology of wisdom may involve an optimal balance between more primitive brain regions (the limbic system) and the newest ones (pre-frontal cortex.) Knowledge of the underlying mechanisms in the brain could potentially lead to developing interventions for enhancing wisdom.

“Understanding the neurobiology of wisdom may have considerable clinical significance, for example, in studying how certain disorders or traumatic brain injuries can affect traits related to wisdom,” said Jeste, stressing that this study is only a first step in a long process.

Arch Gen Psychiatry. 2009;66(4):355-365. DOI: 10.1001/archgenpsychiatry.2009.8
Neurobiology of Wisdom. A Literature Overview.
Thomas W. Meeks, MD; Dilip V. Jeste, MD

Context Wisdom is a unique psychological trait noted since antiquity, long discussed in humanities disciplines, recently operationalized by psychology and sociology researchers, but largely unexamined in psychiatry or biology.

Objective To discuss recent neurobiological studies related to subcomponents of wisdom identified from several published definitions/descriptions of wisdom by clinical investigators in the field, ie, prosocial attitudes/behaviors, social decision making/pragmatic knowledge of life, emotional homeostasis, reflection/self-understanding, value relativism/tolerance, and acknowledgment of and dealing effectively with uncertainty.

Data Sources Literature focusing primarily on neuroimaging/brain localization and secondarily on neurotransmitters, including their genetic determinants.

Study Selection Studies involving functional neuroimaging or neurotransmitter functioning, examining human (rather than animal) subjects, and identified via a PubMed search using keywords from any of the 6 proposed subcomponents of wisdom were included.

Data Extraction Studies were reviewed by both of us, and data considered to be potentially relevant to the neurobiology of wisdom were extracted.

Data Synthesis Functional neuroimaging permits exploration of neural correlates of complex psychological attributes such as those proposed to comprise wisdom. The prefrontal cortex figures prominently in several wisdom subcomponents (eg, emotional regulation, decision making, value relativism), primarily via top-down regulation of limbic and striatal regions. The lateral prefrontal cortex facilitates calculated, reason-based decision making, whereas the medial prefrontal cortex is implicated in emotional valence and prosocial attitudes/behaviors. Reward neurocircuitry (ventral striatum, nucleus accumbens) also appears important for promoting prosocial attitudes/behaviors. Monoaminergic activity (especially dopaminergic and serotonergic), influenced by several genetic polymorphisms, is critical to certain subcomponents of wisdom such as emotional regulation (including impulse control), decision making, and prosocial behaviors.

Conclusions We have proposed a speculative model of the neurobiology of wisdom involving frontostriatal and frontolimbic circuits and monoaminergic pathways. Wisdom may involve optimal balance between functions of phylogenetically more primitive brain regions (limbic system) and newer ones (prefrontal cortex). Limitations of the putative model are stressed. It is hoped that this review will stimulate further research in characterization, assessment, neurobiology, and interventions related to wisdom.