Humans share similar behavior as mice with similar anxiety related gene abnormality

Studying animals in behavioral experiments has been a cornerstone of psychological research, but whether the observations are relevant for human behavior has been unclear. Weill Cornell Medical College researchers have identified an alteration to the DNA of a gene that imparts similar anxiety-related behavior in both humans and mice, demonstrating that laboratory animals can be accurately used to study these human behaviors.
The findings may help researchers develop new clinical strategies to treat humans with anxiety disorders, such as phobias and post-traumatic stress disorder (PTSD).
Results from the study, funded by the National Institutes of Health, are published January 15 in the journal Science.
"We found that humans and mice who had the same human genetic alteration also had greater difficulty in extinguishing an anxious-like response to adverse stimuli," explains Dr. B.J. Casey, co-senior author of the study and professor of psychology in psychiatry from The Sackler Institute for Developmental Psychobiology at Weill Cornell Medical College.
The researchers observed common behavioral responses between humans and mice that possess an alteration in the brain-derived neurotrophic factor (BDNF) gene. The mice were genetically altered -- meaning that they had a human genetic variation inserted within their genome.
To make their comparison, the researchers paired a harmless stimulus with an aversive one, which elicits an anxious-like response, known as conditioned fear. Following fear learning, exposure to numerous presentations of the harmless stimulus alone, in the absence of the aversive stimulus, normally leads to subjects extinguishing this fear response. That is, a subject should eventually stop having an anxious response towards the harmless stimulus.
"But both the mice and humans found to have the alternation in the BDNF gene took significantly longer to 'get over' the innocuous stimuli and stop having a conditioned fear response," explains Dr. Fatima Soliman, lead author of the study, who is currently a Tri-Institutional MD-PhD student, and has completed her Ph.D. in the labs of Drs. B.J. Casey and Francis S. Lee.
In addition to the observational testing, the researchers also performed brain scans using functional magnetic resonance imaging (fMRI), on the human participants, to see if brain function differed between people with the abnormal BDNF gene and those with normal BDNF genes.
They found that a circuit in the brain involving the frontal cortex and amygdala -- responsible for learning about cues that signal safety and danger -- was altered in people with the abnormality, when compared with control participants who did not have the abnormality.
"Testing for this gene may one day help doctors make more informed decisions for treatment of anxiety disorders," explains Dr. Francis S. Lee, co-senior author of the study and associate professor of psychiatry and pharmacology at Weill Cornell Medical College.
Therapists use exposure therapy -- a type of behavior therapy in which the patient confronts a feared situation, object, thought, or memory -- to treat individuals who experience stress and anxiety due to certain situations. Sometimes, exposure therapy involves reliving a traumatic experience in a controlled, therapeutic environment and is based on principles of extinction learning. The goal is to reduce the distress, physical or emotional, felt in situations that trigger negative emotion. Exposure therapy is often used for the treatment of anxiety, phobias and PTSD.
"Exposure therapy may still work for patients with this gene abnormality, but a positive test for the BDNF genetic variant may let doctors know that exposure therapy may take longer, and that the use of newer drugs may be necessary to accelerate extinction learning," explains Dr. Soliman.
Co-authors of the study include Dr. Charles Glatt, Dr. Kevin Bath, Dr. Liat Levita, Rebecca Jones, Siobhan Pattwell, Dr. Deqiang Jing, Dr. Nim Tottenham, Dr. Dima Amso, Dr. Leah Somerville, Dr. Henning Voss, Dr. Douglas Ballon, Dr. Conor Liston, Theresa Teslovich and Tracey Van Kempen, all from Weill Cornell; and Dr. Gary Glover, from Stanford University, Stanford, Calif.

Anti Inflammation therapy for Retinal Disease

The discovery of an inflammatory mediator key to the blinding effects of diabetic retinopathy is pointing toward a potential new treatment, Medical College of Georgia researchers said.
Interleukin-6, known to contribute to the debilitating joint inflammation of rheumatoid arthritis, also helps ignite inflammation of the retina, a first step in a disease that is the leading cause of blindness is working-age adults, MCG researchers reported online in Investigative Ophthalmology & Visual Science.
The finding has the scientists looking at whether an interleukin-6 antibody, which is showing success in treating rheumatoid arthritis, can halt inflammation in mice with diabetic retinopathy. "We expect that this neutralizing antibody can be used to treat diabetic retinopathy in the future," said Dr. Wenbo Zhang, assistant research scientist in MCG's Vascular Biology Center. Drs. Zhang and Modesto Rojas, senior postdoctoral fellow, are co-first authors on the paper.
Angiotensin II, a powerful constrictor of blood vessels, is typically associated with the kidneys where it plays a vital role in regulating blood pressure. The scientists suspect angiotensin II helps promotes wound healing and regulation of pressure within small blood vessels in the eye.
However in diabetes, angiotensin II levels increase in the eye -- probably in response to high glucose levels -- and help promote inflammation, spurring remodeling of blood vessels and tissue destruction, Dr. Rojas said. "Vascular inflammation is one of the first steps to inducing the changes in the retina."
MCG scientists have shown interleukin-6 is a needed accomplice whose previously undetectable levels in the eye also increase, said Dr. Ruth Caldwell, cell biologist a the Vascular Biology Center and the Charlie Norwood Veterans Affairs Medical Center and the study's corresponding author.
With the help of interleukin-6, angiotensin II induces white blood cells to stick to the endothelial cells lining blood vessels of the retina, which slows blood flow. The white blood cells also start producing inflammatory and vascular growth factors that cause blood vessel walls to leak and thicken, further constricting blood flow. Retinal cells start dying from the reduced blood and oxygen supplies that result. In response, the body prompts growth of new blood vessels, presumably to help but instead causing more vision impairment.
If the trigger, high glucose, was temporary, these natural responses might help clear damaged cells and protect the eye. "Inflammation is a compensatory mechanism that gets activated as a survival mechanism," Dr. Rojas said. "If it continues, the effect is bad."
"We have known for along time if patients keep their blood sugar under perfect control, they don't have these problems, but that's hard," Dr. Caldwell adds. "That is why it's such a difficult disease."
To examine interleukin-6's role in the destruction, the researchers injected angiotensin II into the vitreous portion of the eyes of mice missing the gene for the inflammatory factor as well as normal mice. The extra angiotensin did little to the retinal vessels of mice lacking interleukin-6 but vessels in the normal mouse retina mimicked the inflammatory reaction found in diabetic retinopathy. When they reintroduced interleukin-6 to the genetically altered mice, the damage mimicked that of the normal mice. "So when we knock out interleukin-6, we can block the effects of angiotensin II," Dr. Caldwell said.
The scientists want to see whether the interleukin-6 antibody can be used to prevent damage by giving it shortly after the onset of diabetes in rodents and as a treatment by using it later in the disease process.
The research was funded by the National Institutes of Health, the Department of Veterans Affairs and postdoctoral fellowship awards from the Juvenile Diabetes Research Foundation International and the American Heart Association.
Email or share this story:

Chlamydial Infections can't be prevented by just screening girls alone

Chlamydial Inclusion Bodies

Frequent testing and treatment of infection does not reduce the prevalence of chlamydia in urban teenage girls, according to a long-term study by Indiana University School of Medicine researchers published in the January 1, 2010 issue of the Journal of Infectious Diseases.
Despite the fact they were screened every three months and treated when infected, the proportion of infected girls did not change over the course of the study. On entering the study, 10.9 percent of the young women were infected. After 18 months of participation, 10.6 percent were infected; 10.4 percent were infected at the four-year mark.
Eighty-four percent of repeated infections were reinfections. In spite of being so highly motivated that they kept diaries of their sexual encounters and interacted at least quarterly with the study staff, some of the young women had unprotected sex with either an untreated partner or a new partner and subsequent infection occurred. The researchers determined that 13 percent of repeated infections were due to failure of antibiotics to cure an earlier infection; considering all infections, antibiotic treatment was 92.1 percent effective.
"The rate of infection we found in the 365 Indianapolis girls we followed is similar to the rates reported by other researchers for girls in Denver and Baltimore, so it is likely that our important new findings on reinfection can be generalized to urban teenage girls in other cities," said Byron E. Batteiger, M.D., professor of medicine at the IU School of Medicine, an infectious disease specialist who is the first author of the study.
The researchers obtained a biological sample from as many sex partners of the study participants as possible to determine if the boys were chlamydia infected. "We were able to test 22.6 percent of all the partners that the girls named in the study. We determined that 26.2 percent of the participating boys were infected -- a very high level of infection in this pool of young men to whom young women in the study were exposed," noted Dr. Batteiger.
Current national recommendations call for routine chlamydia screening of women based on age and history of sexual activity. There is no similar recommendation for screening young men.
"The high rate of reinfection we found in our study strongly suggests there may be some real limits on what we can do to control chlamydia without doing a better job of controlling chlamydia in young men," said J. Dennis Fortenberry M.D. M.S., professor of pediatrics at the IU School of Medicine, an adolescent medicine physician who is the senior author of the study.
"We also need to make sure that sexually active teens are aware of fact that unlike some other diseases, having chlamydia and being successfully treated for it does not give the individual immunity from reoccurrence," said Dr. Fortenberry, who urges physicians to repeatedly screen adolescents for the disease.
Chlamydia is the most common bacterial sexually transmitted infection and is associated with an increased risk of pelvic inflammatory disease, ectopic pregnancy, tubal infertility, and increased susceptibility to human immunodeficiency virus infection. Chlamydia is more common in sexually active teens than in any other age group.
In addition to Dr. Batteiger and Dr. Fortenberry, co-authors of the study are IU School of Medicine faculty members Wanzhu Tu, Ph.D.; Susan Ofner, M.S.; Barbara Van Der Pol, Ph.D.; Diane R. Stothard, Ph.D.; Donald P. Orr, M.D.; and Barry P. Katz, Ph.D. In addition to their IU affiliations, Dr. Tu is a Regenstrief Institute investigator, Dr. Orr and Dr. Katz are Regenstrief Institute affiliated scientists and Dr. Van Der Pol is with the Marion County Department of Health. Dr. Stothard, formerly with the IU School of Medicine, is presently affiliated with Eli Lilly and Company. The study was funded by the National Institutes of Health.
The IU School of Medicine is located on the Indiana University-Purdue University Indianapolis campus.