Timing of chemical signal critical for normal emotional development

March 27, 2002

A signaling protein suspected of malfunctioning in anxiety and mood disorders plays a key role in the development of emotional behavior, report researchers funded by the National Institute of Mental Health. Mice lacking it in frontal brain circuits during an early critical period fail to develop normal reactions in anxiety-producing situations.

Rene Hen, Ph.D., Columbia University, and colleagues created mice that lacked the protein, which brain cells use to receive signals from the chemical messenger serotonin, by knocking-out the gene that codes for it. As adults, these "knockout" mice were slow to venture into -- or eat in -- unfamiliar environments. By selectively restoring, or "rescuing" certain populations of the receptor proteins, the researchers have now pinpointed when and where they enable the brain to cope with anxiety. Hen, Cornelius Gross, Ph.D., Xiaoxi Zhuang, Ph.D, and colleagues report on their discovery in the March 28, 2002 Nature.

Brain neurons communicate with each other by secreting messenger chemicals, such as serotonin, which cross the synaptic gulf between cells and bind to receptors on neighboring cell membranes. Medications that enhance such binding of serotonin to its receptor (serotonin selective reuptake inhibitors, or SSRIs) are widely prescribed to treat anxiety and depression, suggesting that the receptor plays an important role in regulating these emotions.

Behavior of the animals in the study mimicked human anxiety. The mice bred not to express the gene that codes for the serotonin receptor (5-HT1A) moved around less than normal animals in open spaces, balked at entering elevated mazes, and were slower to begin eating in such novel environments. Yet, the researchers didn't know which of two populations of serotonin receptors -- one in the forebrain and another deep in the brainstem -- was responsible. To find out, they crossed the receptor knockout mice with mice engineered to turn receptor expression on and off in specific brain regions. This gave birth to a line of transgenic animals in which only the forebrain receptors were rescued from the gene knockout. This "rescue" line of mice behaved normally when tested for the anxiety-like behaviors, suggesting a key role for the receptor in forebrain circuits mediating anxiety.

Next, the researchers treated adult mice - knockout, rescue, and normal - with a drug (doxycycline) that shuts off receptor expression. Even without the receptors, the adult rescue mice continued to show normal anxiety-like behavior. The researchers inferred that the receptor "functions earlier in development to establish normal adult anxiety-like behavior."

To find out when this occurs, they gave the receptor-abolishing drug to breeding pairs of rescue mice to turn off receptor expression in their pups during the embryonic and early postnatal period. As adults, these offspring behaved just as anxiously as knockout mice when tested. This, together with the timing of receptor expression in the rescue mice, suggested that the critical period for establishing normal anxiety-like behavior is between 5 and 21 days after birth.

Serotonin stimulation of the forebrain receptor during this period likely triggers "long lasting changes in brain chemistry or structure that are essential for normal emotional behavior throughout life," suggest the researchers. They note a number of studies pointing to such a role for serotonin during this critical time.

Intrigued by evidence that the serotonin receptor may be abnormal in patients with panic disorder and post-traumatic stress syndrome, other NIMH-supported researchers are embarking on brain imaging studies of its function in these anxiety disorders.

The current study was supported under a NIMH grant on the biology of serotonin to Irwin Lucki, Ph.D., University of Pennsylvania. Also participating were: Kimberly Stark, Ph.D., Sylvie Ramboz, Ph.D., Ronald Oosting, Ph.D., Luca Santarelli, M.D., Columbia University; Lynn Kirby, Ph.D., Sheryl Beck, Ph.D., Children's Hospital of Philadelphia.

The National Institute of Mental Health (NIMH) is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

NIH/National Institute of Mental Health

Related Mental Health Articles from Brightsurf:

Mental health strained by disaster
A new study found that suicide rates increase during all types of disasters -- including severe storms, floods, hurricanes and ice storms -- with the largest overall increase occurring two years after a disaster.

The mental health impact of pandemics for front line health care staff
New research shows the impact that pandemics have on the mental health of front-line health care staff.

World Mental Health Day -- CACTUS releases report of largest researcher mental health survey
On the occasion of 'World Mental Health Day' 2020, CACTUS, a global scientific communications company, has released a global survey on mental health, wellbeing and fulfilment in academia.

Mental illness, mental health care use among police officers
A survey study of Texas police officers examines how common mental illness and mental health care use are in a large urban department.

COVID-19 outbreak and mental health
The use of online platforms to guide effective consumption of information, facilitate social support and continue mental health care delivery during the COVID-19 pandemic is discussed in this Viewpoint.

COVID-19 may have consequences for mental health
The COVID-19 pandemic appears to be adversely affecting mental health among hospitalised patients, the healthcare professionals treating them and the general population.

Mental health outcomes among health care workers during COVID-19 pandemic in Italy
Symptoms of posttraumatic stress disorder, depression, anxiety and insomnia among health care workers in Italy during the COVID-19 pandemic are reported in this observational study.

Mental ill health 'substantial health concern' among police, finds international study
Mental health issues among police officers are a 'substantial health concern,' with around 1 in 4 potentially drinking at hazardous levels and around 1 in 7 meeting the criteria for post traumatic stress disorder and depression, finds a pooled data analysis of the available international evidence, published online in Occupational & Environmental Medicine.

Examining health insurance nondiscrimination policies with mental health among gender minority individuals
A large private health insurance database was used to examine the association between between health insurance nondiscrimination policies and mental health outcomes for gender minority individuals.

Mental health care for adolescents
Researchers examined changes over time in the kinds of mental health problems for which adolescents in the United States received care and where they got that care in this survey study with findings that should be interpreted within the context of several limitations including self-reported information.

Read More: Mental Health News and Mental Health Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.