Posts tagged depression

Decreased activity of a group of genes may explain why in young children the “fear center” of the anxious brain can’t learn to distinguish real threats from the imaginary, according to a new University of Wisconsin study.

The study, published this week in the Proceedings of the National Academy of Sciences (PNAS), lays out evidence that young primates with highly anxious temperaments have decreased activity of specific genes within the amygdala, the brain’s fear center.

The authors hypothesize that this may result in over activity of the brain circuit that leads to higher risk for developing disabling anxiety and depression.

This may be particularly important since the genes involved play a major role in forming the brain connections needed for learning about fears. While all children have fears and anxieties, the authors suggest that children with low levels of activity of these genes develop anxious dispositions because they fail to learn to cope by overcoming their early childhood fears.

“Working with my close collaborator and graduate student, Drew Fox, we focused on understanding the function of genes that promote learning and plasticity in the amygdala,” says Dr. Ned H. Kalin, chair of psychiatry at the University of Wisconsin School of Medicine and Public Health, who led the research. “We found reduced activity in key genes that could impair the ability to sculpt the brain, resulting in a failure to develop the capacity to discriminate between real and imaginary fears.”

Kalin says the study helps support the need for early intervention in children identified as excessively shy and anxious. It may also point a way to better treatments aimed at decreasing the likelihood of children developing more severe psychiatric problems. Anxiety in children is quite common and can lead to anxiety and depression in adolescence and often precedes anxiety disorders, depression and substance abuse in adults.

Most small children go through a phase when they’re frightened of many things, including monsters or new social situations, Kalin says, but their maturing brains soon learn to distinguish real threats from the imaginary. But some children do not adapt, generalize their fears to numerous situations, and may later develop serious anxiety and mood disorders. These children tend to be more sensitive to stress, produce more stress hormones and have heightened nervous-system activity.

Kalin, Fox and co-authors wondered whether some differences in the developing amygdala prevent it from learning how to regulate and adapt to anxiety. Kalin’s earlier work identified a subset of young monkeys, similar to extremely shy children, with an inherited anxious disposition. Using brain imaging, the authors showed that high levels of amygdala activity predicted trait-like anxiety in anxious young primates. Like their stable and enduring anxious dispositions, these individuals also had chronically elevated levels of amygdala activity.

“We believe that this pinpoints a critical region in the brain that determines an individual’s level of trait anxiety,’’ Kalin explains.

In examining a specific part of the amygdala, the central nucleus, the researchers analyzed gene expression, which reflects both environmental and inherited influences. Within the central nucleus of the amygdala the authors found that anxious individuals tended to have decreased expression of a gene called neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Low levels of this gene that encodes for a brain cell surface receptor may be why the amygdala of an anxious monkey or child is chronically overactive and unable to overcome anxiety and fears.

“This is the first demonstration that the early risk to develop anxiety and depression may be related to the underactivity of particular genes in the developing primate amygdala,’’ Kalin says. “These findings have provided the basis for our hypothesis that can explain the early childhood risk to develop anxiety and depression. It also suggests some creative ways to help children with extreme anxiety by developing new treatments focused on increasing the activity of specific genes involved in facilitating the brain development that underlies fear learning and coping.”

(Source: newswise.com)

Millions of Americans take antidepressants such as Prozac, Effexor, and Paxil, but the explanations for how they work never satisfied René Hen, a professor of psychiatry, neuroscience and pharmacology.

So the French-born researcher began a series of experiments a decade ago that are now helping to overturn conventional wisdom about the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and providing new insights into the biological mechanisms in the brain that affect mood and cognition.

Adult-born neurons in the hippocampus have been engineered to express channelrhodopsin (red), a protein that allows the activation of these neurons and the study of their impact on pattern separation and mood. (Image credit: Mazen Kheirbek and René Hen)

SSRIs, it has long been thought, work by inhibiting brain cells from reabsorbing serotonin, a signaling agent in the brain associated with positive mood. Yet unlike with psychoactive substances, the effects of the drugs take weeks to be felt—even though the increase in serotonin circulating in the brain begins almost immediately. Something more, Hen concluded, must be happening after that to create such a profound effect in depressed patients.

In 2003, Hen demonstrated an important finding in mice: The change in mood—measured by the amount of time it took the animals to overcome anxiety and feed in new environments—appeared to be due in part to the production of new brain cells in the hippocampus, an area of the brain associated with learning and memory. And those new brain cells, Hen thinks, are the result of growth-stimulating chemicals released in the brain, in response to the increased serotonin.

Last year, Hen published another groundbreaking study, suggesting how these new brain cells might affect mood. The new brain cells are located in the dentate gyrus, an area of the hippocampus involved in pattern separation, a cognitive process that helps us to recognize that something is new and different from similar experiences and stimuli. This information is then sent to other brain regions where the new stimulus is assigned a positive or negative emotional value.

Using genetic manipulations that block or enhance the production of brain cells in the dentate gyrus, Hen demonstrated that the new brain cells led to a marked improvement not just in the cognitive abilities of mice, but also in their mood. “What we think, even though it hasn’t been proven yet, is that some depressed human patients also have a problem with pattern separation,” Hen says. “What we are hoping is, if we can boost production of new neurons in their hippocampus, maybe we can improve pattern separation in patients and decrease general symptoms.”

Hen sees numerous ways that a disruption in pattern separation might lead to negative emotions such as anxiety and depression. The hippocampus is located next to, and is strongly linked with, another brain structure, the almond-shaped amygdala, thought to be the seat of our emotions.

If wrong judgments were assigned to novel stimuli in the amygdala, that could easily trigger the brain’s fight-or-flight instinct or, at the very least, produce fear. That might help explain features of anxiety disorders—why survivors of the 9/11 terrorist attacks suffering from post-traumatic stress disorder, for instance, might be hit with a panic attack whenever they see an airplane fly over a skyscraper, Hen says.

A deficit in pattern separation might also help explain why depressed patients often are unable to experience pleasure, exhibit a lack of interest in novel experiences, and feel profound malaise. Perhaps they are simply unable to register an experience as novel or pleasurable because they are unable to recognize it as sufficiently different from prior experiences.

Hen is quick to point out that new brain cell production in the hippocampus is just one effect of a cascade of neurochemical changes unleashed by SSRIs. Other researchers have demonstrated, among other things, that the drugs also have a strong impact on the prefrontal cortex, the area of the brain associated with executive functions such as decision-making and restraint.

Even so, Hen hopes his findings will have significant implications for some depressed patients—and perhaps even reveal why certain antidepressants work for some people and not others. Over the next several years, he plans to explore his hypotheses further by evaluating the pattern-separation abilities of depressed patients before and after they are treated with SSRIs.

“There is still a long way to go, but we are at least starting to provide a theoretical framework,” Hen says. “With complex disorders such as anxiety and depression, you are dealing with many parts of the brain. We think we have identified the biological basis for one of the symptoms present in a subgroup of patients, and maybe by targeting it, we will be able to help them.”

(Source: news.columbia.edu)

Hear the word “party” and memories of your 8th birthday sleepover or the big bash you attended last New Year’s may come rushing to mind. But it’s exactly these kinds of memories, embedded in a specific place and time, that people with depression have difficulty recalling.

Research has shown that people who suffer from, or are at risk of, depression have difficulty tapping into specific memories from their own past, an impairment that affects their ability to solve problems and leads them to focus on feelings of distress.

In a study forthcoming in Clinical Psychological Science, a new journal of the Association for Psychological Science, psychological scientists Hamid Neshat-Doost of the University of Isfahan, Iran, Laura Jobson of the University of East Anglia, Tim Dalgleish of the Cognition and Brain Sciences Unit, Medical Research Council, Cambridge and colleagues investigated whether a particular training program, Memory Specificity Training, might improve people’s memory for past events and ameliorate their symptoms of depression.

In Iran, the researchers recruited 23 adolescent Afghani refugees who had lost their fathers in the war in Afghanistan and who showed symptoms of depression. Twelve of the adolescents were randomly assigned to participate in the memory training program and 11 were randomly assigned to a control group that received no training.

All of the adolescents completed a memory test in which they saw 18 positive, neutral, and negative words in Persian and were asked to recall a specific memory related to each word. Their responses were categorized as either a specific or a non-specific type of memory. They also completed questionnaires design to measure symptoms of depression and anxiety symptoms.

For five weeks, the adolescents assigned to the training attended a weekly 80-minute group session, in which they learned about different types of memory and memory recall, and practiced recalling specific memories after being given positive, neutral, and negative keywords.

At the end of the five weeks, both the training group and the control group were given the same memory test that they were given at the beginning of the study. And they took the memory test again as part of a follow-up visit two months later.

The adolescents who participated in the training were able to provide more specific memories after the training than those who did not receive intervention. They also showed fewer symptoms of depression than the control group at the two month follow-up. The researchers found that the relationship between participant group (training or control) and their symptoms of depression at follow-up could be accounted for by changes in specific memory recall over time.

These findings are promising because they suggest that a standalone training program that focuses on specific memory recall can actually improve depression symptoms.

Based on the results of this study, Jobson, Dalgleish, and colleagues conclude that, for individuals suffering from depression, “including a brief training component that targets memory recall as an adjunct to cognitive behavioral therapy or prior therapy may have beneficial effects on memory recall and mood.”

Depression takes a substantial toll on brain health. Brain imaging and post-mortem studies provide evidence that the wealth of connections in the brain are reduced in individuals with depression, with the result of impaired functional connections between key brain centers involved in mood regulation. Glial cells are one of the cell types that appear to be particularly reduced when analyzing post-mortem brain tissue from people who had depression. Glial cells support the growth and function of nerve cells and their connections.

Over the past several years, it has become increasingly recognized that antidepressants produce positive effects on brain structure that complement their effects on symptoms of depression. These structural effects of antidepressants appear to depend, in large part, on their ability to raise the levels of growth factors in the brain.

In a new study, Elsayed and colleagues from the Yale University School of Medicine report their findings on a relatively novel growth factor named fibroblast growth factor-2 or FGF2. They found that FGF2 can increase the number of glial cells and block the decrease caused by chronic stress exposure by promoting the generation of new glial cells.

Senior author Dr. Ronald Duman said, “Our study uncovers a new pathway that can be targeted for treating depression. Our research shows that we can increase the production and maintenance of glial cells that are important for supporting neurons, providing an enriched environment for proper neuronal function.”

To study whether FGF2 can treat depression, the researchers used rodent models where animals are subjected to various natural stressors, which can trigger behaviors that are similar to those expressed by depressed humans, such as despair and loss of pleasure. FGF2 infusions restored the deficit in glial cell number caused by chronic stress. An underlying molecular mechanism was also identified when the data showed that antidepressants increase glial generation and function via increasing FGF2 signaling.

"Although more research is warranted to explore the contribution of glial cells to the antidepressant effects of FGF2, the results of this study present a fundamental new mechanism that merits attention in the quest to find more efficacious and faster-acting antidepressant drugs," concluded Duman.

"The deeper that science digs into the biology underlying antidepressant action, the more complex it becomes. Yet understanding this complexity increases the power of the science, suggesting reasons for the limitations of antidepressant treatment and pointing to novel approaches to the treatment of depression," commented Dr. John Krystal, Editor of Biological Psychiatry and Chairman of the Department of Psychiatry at the Yale University School of Medicine.

Source: Bio-Medicine