Reading the brain’s map: coordinated brain activation supports spatial learning and decision-making

NIH-supported study finds that spatial “replay” in neurons may help rats learn how to navigate toward goals.

Specialized brain activation “replays” the possible routes that rats can take as they navigate a space, helping them keep track of the paths they’ve already taken and choose among the routes that they can take next, according to a National Institutes of Health-funded study published in the journal Neuron.

“These findings reveal an internal ‘replay’ process in the brain that allows animals to learn from past experiences to form memories of paths leading toward goals, and subsequently to recall these paths for planning future decisions,” said Shantanu Jadhav, Ph.D., assistant professor at Brandeis University, Waltham, Massachusetts, and senior author of the study. “These results help us better understand how coordinated activation at the level of neurons can contribute to the complex processes involved in learning and decision-making.” 

The hippocampus, a structure located in the middle of the brain, is critical to learning and memory and contains specialized “place” cells that relay information about location and orientation in space. These place cells show specific patterns of activity during navigation that can be “replayed” later in forward or reverse order, almost as if the brain were fast-forwarding or rewinding through routes the rats have taken.

In previous research, Jadhav and colleagues had discovered these replay events, marked by bursts of neural activity called sharp-wave ripples, lead to coordinated activity in the hippocampus and the prefrontal cortex, an area of the brain just behind the forehead that is involved in decision-making.

But how these forward and reverse replay events influence actual learning and decision-making over time remained unclear. To find out, Jadhav and co-first authors Justin D. Shin and Wenbo Tang continuously recorded the rats’ brain activity as the rats learned how to navigate a special W-shaped maze over the course of one day. This allowed the investigators to see how neural representations changed as the rats were learning.

The researchers trained the rats over eight sessions to follow paths according to two rules – a simple rule and a complex rule – giving the rats a reward whenever they reached the correct destination. The simple rule required remembering the start and end locations of the maze paths. The complex rule depended on working memory, requiring that the rats remember the previous path in order to choose the next destination.

The scientists focused their analyses on moments of transition when the rats had paused in between completing one path and choosing the next one. As the researchers expected, replay events in the hippocampus showed reactivation of past paths in a reverse order, as if on rewind, and showed reactivation of the possible future paths in a forward order, as if on fast forward.

The forward and reverse replay patterns were so robust that the researchers could use the recordings to predict where the rats had paused in the W-shaped maze. Continuous recordings of brain activity throughout the entire task revealed shifts in activation patterns as the rats learned the simple rule. At different stages of learning, the researchers could use reverse replay and forward replay patterns to predict the path the animals had just taken and where they were about to go next, respectively. These shifts indicated that reverse replay was important for learning from the previous path, especially in the early stages of learning, while forward replay was important for planning for the next route, especially in the later stages of learning.

Activation patterns related to learning the complex working-memory rule were more consistent over time: Reverse replay events reactivated all possible past choices and forward replay events reactivated all possible future options throughout the learning process.

However, when the researchers looked at coordination between replay events in the hippocampus and the prefrontal cortex, they found that the coordinated reactivation in the two brain areas was correlated with the rats’ actual choices – that is, reactivation was stronger for replay of paths that the rats took than for the paths they didn’t take.

Together, the findings suggest that coordinated replay across the hippocampus and prefrontal cortex serves an important function in spatial learning and memory-guided decision-making. Specifically, the results suggest that reverse replay is likely to support the ability to reflect on and evaluate paths that have led to goals in the past, whereas forward replay seems to support the ability to think ahead and plan choices that will lead to goals in the future.

“The involvement of ‘replay’ in memory processes has been observed across many species, including humans, and this study establishes that replay serves as a key neural substrate underlying an internal dialogue across multiple brain regions to support our ability to learn, plan, choose, and deduce,” Jadhav concluded.

Grants: MH112661

This news release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.
For more on mental health and psychology resource articles 10 Ways to Reduce Holiday Stress

Excess body fat increases the risk of depression

A new study from Aarhus University and Aarhus University Hospital, Denmark, shows that ten kilograms of extra body fat increases the risk of depression by seventeen percent.

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Carrying ten kilograms of excess body fat increases the risk of depression by seventeen per cent. The more fat, the greater the probability of developing depression. This is the main conclusion of a new study carried out by researchers from Aarhus University and Aarhus University Hospital, Denmark.

"Our study also indicated that the location of the fat on the body makes no difference to the risk of depression. This suggests that it is the psychological consequences of being overweight or obese which lead to the increased risk of depression, and not the direct biological effect of the fat. If the opposite was true we would have seen that fat located centrally on the body increased the risk the most, as it has the most damaging effect in biological terms," says the study's last author Dr. Søren Dinesen Østergaard. 

He is professor at the Department of Clinical Medicine at Aarhus University and affiliated with the Department of Affective Disorders at Aarhus University Hospital. 

Prior studies in the field have predominantly used Body Mass Index (BMI) to measure obesity. BMI is calculated solely on the basis of body weight and height and is therefore a fairly crude measure, that does not, for example, take build and muscle mass into account.

"BMI is an inaccurate way of measuring overweight and obesity. Many elite athletes with a large muscle mass and a low body fat mass will have a BMI above 25, which is classified as overweight according to the common definition. This obviously doesn't make much sense. Therefore, one of the strengths of our study is that we've been able to zoom in and look at the specific relationship between the amount of body fat and the risk of depression," explains Dr. Østergaard.

In the study, which has been published in the journal Translational Psychiatry, the researchers have analysed data from two large genetic data sets: the UK Biobank, which contains data on the correlation between genetic variants and physical measurements (including body fat mass distributed around parts of the body); and the Psychiatric Genomics Consortium, which contains information on the correlation between genetic variants and depression.

Dr. Østergaard also highlights his research group's choice of the 'Mendelian randomization' method as the main reason why the study was successful. He also emphasises that the findings are particularly significant in light of the fact that almost 40 per cent of the world's adult population is overweight. 

"In addition to the known physical consequences of obesity such as diabetes and cardiovascular disease, there is also a significant and now well-documented psychological component, which needs to be dealt with as well. This is yet another argument for resolving the obesity epidemic," he says, before emphasising that it is important to have a balanced approach to the issue: 

"As it appears to be the psychological consequences of obesity, such as a negative body image and low self-esteem that is the main driving force behind the increased risk of depression, society's efforts to combat obesity must not stigmatise, as this will probably increase the risk of depression even further. It is important to bear this in mind so we can avoid doing more harm than good in the effort to curb the obesity epidemic," says Dr. Østergaard. 

FACTS ABOUT MENDELIAN RANDOMIZATION:

Mendelian randomization (named after the Austrian monk Gregor Mendel, who was the father of modern genetics) is a method which in recent years has helped researchers to overcome a major challenge associated with observational studies - namely that of making causal inference. In observational studies researchers often find correlations between two conditions - e.g. between obesity and depression - where it is difficult, or rather impossible, to determine whether there is indeed a causal effect going from obesity to depression - or vice versa. Mendelian randomization may solve this challenge.

Mendelian randomization can be described as nature's version of the randomised controlled trials that are carried out when testing whether a new drug has the desired (causal) effect in the treatment of a disease. In the clinical trials of drugs, lots are drawn to determine whether individual participants will receive the active drug or a placebo, without them knowing which treatment they have been assigned to. Instead, Mendelian randomization takes advantage of the fact that a completely natural randomization takes place during the formation of the sex cells (egg cells and sperm cells), which represent the origin of all human beings. When sex cells are formed, the parents' genetic variants - including those that give rise to increased body fat- are randomly distributed. Therefore, some individuals will have received many of these variants and others less. In the study in question, the researchers have utilised this natural and random source of variation to determine whether people who have received many genetic variants for increased body fat have an increased risk of suffering depression.

THE RESEARCH RESULT - MORE INFORMATION

Genetic epidemiological study utilising data from the UK Biobank (with information on the association between genetic variants and fat mass based on a study of 330,000 people) and the Psychiatric Genomics Consortium (with information on the association between genetic variants and depression based on a study of 135,000 people with depression and 345,000 control subjects).

The research group comprises Maria S. Speed, Oskar H. Jefsen, Anders D. Børglum, Doug Speed and Søren D. Østergaard - all from Aarhus University.

Crisis and suicide prevention services struggle with demand after celebrity suicides NIH study identifies importance of support for critical suicide prevention services.

Thoughts about this article? "The United States may lack the resources needed to meet increases in demand for suicide prevention services that occur after celebrity suicides, according to a recent study of crisis mental health services. The study, conducted by a team of researchers, which included scientists from the National Institute of Mental Health (NIMH), part of the National Institutes of Health, highlights the need for suicide prevention hotlines to procure additional funds, allocate existing funds more efficiently, and develop contingency plans to accommodate increases in call volumes, particularly for the first two days after a celebrity suicide. The findings appear in the journal Psychiatric Services. “Suicide prevention is a significant public health concern and a top priority for NIMH,” said Joshua A. Gordon, M.D., Ph.D., director of NIMH. “This study highlights the importance of the National Suicide Prevention Lifeline and other crisis mental health services, and the need to build surge capacity of these services that could help save lives.” 

Suicide is the second leading cause of death for people in the U.S. between the ages of 10 and 34, and the suicide rate continues to rise. Suicide rates generally follow predictable patterns, with increases in the spring and a second, smaller increase in early summer. But certain events, like highly-publicized celebrity suicides, can serve as “shocks” that cause a sudden spike in suicide deaths. To test the ability of crisis mental health services to meet a sudden increase in demand for help, this study looked at increases in suicide rates within 30 days of Robin Williams’ suicide on Aug. 11, 2014. It also looked at changes in help - and information-seeking related to suicide, and changes in the percent of calls the National Suicide Prevention Lifeline (NSPL) was able to answer after Williams’ death. Daily calls to the National Suicide Prevention Lifeline (including Veterans Crisis Line) initiated and answered, August 3 to September 7, 2014. Daily calls to the National Suicide Prevention Lifeline (including Veterans Crisis Line) initiated and answered, August 3 to September 7, 2014. American Psychiatric Association. The researchers used data from the Centers for Disease Control and Prevention National Center for Health Statistics’ Compressed Mortality File (link is external) to compare the number of suicide deaths and the method of suicide in the 30 days before and after Aug. 11, 2014, and for the same time period in 2012 and 2013. In 2012-2014, there was an average of 113-117 suicide deaths per day; after Williams’ suicide, the average rate increased to 142 suicide deaths per day, something not observed in 2012 or 2013. Approximately two-thirds of the people who died by suicide immediately after the actor’s death used the same method of suicide as Williams. The study also examined the number of calls placed to NSPL immediately before and after Williams ended his life to measure whether media coverage of his death prompted more people to reach out for help. The day after he died, the number of calls increased by up to 300 percent - from between 4,000 to 6,000 calls per day to 12,972. However, without capacity to respond to this increased demand for crisis services, the fraction of answered calls decreased from an average of 73 percent to 57 percent, which highlights a gap in the ability of the NSPL to respond to surges in calls for help. To measure information-seeking behavior, the study looked at visits to the Suicide Prevention Resource Center (SRPC) (link is external) and Suicide Awareness Voices of Education (SAVE) (link is external) websites. In the week before Williams died, the SPRC website averaged 2,315 visits per day. The day after his death, there were 5,981 visits to the site. The SAVE website averaged 4,239 visits per day in the week before he died, and 24,819 visits on August 12. Average daily visits to both sites remained consistently higher for the rest of the month of August. The study suggests that both efficient allocation of existing funds and procuring new funding will be critical to continue meeting the demand for crisis mental health services, including surge capacity.> “Crisis mental health services, such as suicide prevention hotlines and websites, provide effective counseling and vital resources for people in suicide distress. We need to ensure these services have sufficient resources to serve the public 24/7, especially in times of increased demand,” said Jane Pearson, Ph.D., chair of the Suicide Research Consortium in NIMH’s Division of Services and Intervention Research. “Shocking events, like Mr. Williams’ suicide, disrupt normal patterns in suicide rates, and cause an increase in both calls for help and imitative suicides,” said lead researcher Rajeev Ramchand, Ph.D (link is external)., of the Cohen Veterans Network. “This highlights the need for additional and consistent support for crisis mental health services, including hospital emergency departments, law enforcement, poison control centers, and health departments, as well as the mental health resources that serve as referral sources.” " Reference Ramchand, R., Cohen, E., Draper, J., Schoenbaum, M., Reidenberg, D., Colpe, L., Reed, J., & Pearson, J. (in press). Increases in demand for crisis and other suicide prevention services after a celebrity suicide. Psychiatric Services in Advance. https://ps.psychiatryonline.org/doi/10.1176/appi.ps.201900007 (link is external). For more information on this and other mental health continuing education, please visit, Psychologist Continuing Education

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Early childhood depression alters brain development

What do you think about this article by WASHINGTON UNIVERSITY SCHOOL OF MEDICINE?

"The brains of children who suffer clinical depression as preschoolers develop abnormally, compared with the brains of preschoolers unaffected by the disorder, according to new research at Washington University School of Medicine in St. Louis. Their gray matter -- tissue that connects brain cells and carries signals between those cells and is involved in seeing, hearing, memory, decision-making and emotion -- is lower in volume and thinner in the cortex, a part of the brain important in the processing of emotions. The new study is published Dec. 16 in JAMA Psychiatry. "What is noteworthy about these findings is that we are able to see how a life experience -- such as an episode of depression -- can change the brain's anatomy," said first author Joan L. Luby, MD, whose research established that children as young as 3 can experience depression. "Traditionally, we have thought about the brain as an organ that develops in a predetermined way, but our research is showing that actual experience -- including negative moods, exposure to poverty, and a lack of parental support and nurturing -- have a material impact on brain growth and development." The findings may help explain why children and others who are depressed have difficulty regulating their moods and emotions. The research builds on earlier work by Luby's group that detailed other differences in the brains of depressed children. Luby, the Samuel and Mae S. Ludwig Professor of Child Psychiatry, and her team studied 193 children, 90 of whom had been diagnosed with depression as preschoolers. They performed clinical evaluations on the children several times as they aged. The researchers also conducted MRI scans at three points in time as each child got older. The first scans were performed when the kids were ages 6 to 8, and the final scans were taken when they were ages 12 to 15. A total of 116 children in the study received all three brain scans. "If we had only scanned them at one age or stage, we wouldn't know whether these effects simply were present from birth or reflected an actual change in brain development," said co-investigator Deanna M. Barch, PhD, head of Washington University's Department of Psychological and Brain Sciences in Arts & Sciences. "By scanning them multiple times, we were able to see that the changes reflect an actual difference in brain maturation that emerges over the course of development." The gray matter is made up mainly of neurons, along with axons that extend from brain cells to carry signals. The gray matter processes information, and as children get older, they develop more of it. Beginning around puberty, the amount of gray matter begins to decline as communication between neurons gets more efficient and redundant processes are eliminated. "Gray matter development follows an inverted U-shaped curve," Luby said. "As children develop normally, they get more and more gray matter until puberty, but then a process called pruning begins, and unnecessary cells die off. But our study showed a much steeper drop-off, possibly due to pruning, in the kids who had been depressed than in healthy children." Further, the steepness of the drop-off in the volume and thickness of the brain tissue correlated with the severity of depression: The more depressed a child was, the more severe the loss in volume and thickness. The researchers determined that having depression was a key factor in gray matter development. In scans of children whose parents had suffered from depression -- meaning the kids would be at higher risk -- gray matter appeared normal unless the kids had suffered from depression, too. Interestingly, the differences in gray matter volume and thickness typically were more pronounced than differences in other parts of the brain linked to emotions. Luby explained that because gray matter is involved in emotion processing, it is possible some of the structures involved in emotion, such as the brain's amygdala, may function normally, but when the amygdala sends signals to the cortex -- where gray matter is thinner -- the cortex may be unable to regulate those signals properly. Luby and Barch are planning to conduct brain scans on even younger children to learn whether depression may cause pruning in the brain's gray matter to begin earlier than normal, changing the course of brain development as a child grows. "A next important step will involve determining whether early intervention might shift the trajectory of brain development for these kids so that they revert to more typical and healthy development," said Barch, also the Gregory B. Couch Professor of Psychiatry. Luby said that is the main challenge facing those who treat kids with depression. "The experience of early childhood depression is not only uncomfortable for the child during those early years," she said. "It also appears to have long-lasting effects on brain development and to make that child vulnerable to future problems. If we can intervene, however, the benefits might be just as long-lasting." ### Funding from the National Institute of Mental Health and the National Institutes of Health Blueprint of the National Institutes of Health (NIH), grant numbers R01 MH66031, R01 MH084840, R01 MH090786, R01 MH098454-S, U54 MH091657, 2R01 MH064769-06A1, PA-07-070 NIMH R01 5K01MH090515-04 and T32 MH100019. Luby JL, Belden AC, Jackson JL, Lessov-Schlaggar CN, Harms MP, Tillman R, Botteron K, Whalen D, Barch DM. Early childhood depression and alterations in the trajectory of gray matter maturation in middle childhood and early adolescence?. JAMA Psychiatry, published online Dec. 16, 2015. http://jamapsychiatry.com doi:10.1001/jamapsychiatry.2015.2356 Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare." For more information on depression and other mental health related topics,please visit Aspira Continuing Education Online Courses

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