Stray prenatal gene network suspected in schizophrenia

Researchers have reverse-engineered the outlines of a disrupted prenatal gene network in schizophrenia, by tracing spontaneous mutations to where and when they likely cause damage in the brain. Some people with the brain disorder may suffer from impaired birth of new neurons, or neurogenesis, in the front of their brain during prenatal development, suggests the study, which was funded by the National Institutes of Health.

“Processes critical for the brain’s development can be revealed by the mutations that disrupt them,” explained Mary-Claire King, Ph.D., University of Washington (UW), Seattle, a grantee of NIH’s National Institute of Mental Health (NIMH). “Mutations can lead to loss of integrity of a whole pathway, not just of a single gene. Our results implicate networked genes underlying a pathway responsible for orchestrating neurogenesis in the prefrontal cortex in schizophrenia.”

King, and collaborators at UW and seven other research centers participating in the NIMH genetics repository, report on their discovery Aug. 1, 2013 in the journal Cell.

“By linking genomic findings to functional measures, this approach gives us additional insight into how early development differs in the brain of someone who will eventually manifest the symptoms of psychosis,” said NIMH Director Thomas R. Insel, M.D.

Earlier studies had linked spontaneous mutations to non-familial schizophrenia and traced them broadly to genes involved in brain development, but little was known about convergent effects on pathways. King and colleagues set out to explore causes of schizophrenia by integrating genomic data with newly available online transcriptome resources that show where in the brain and when in development genes turn on. They compared spontaneous mutations in 105 people with schizophrenia with those in 84 unaffected siblings, in families without previous histories of the illness.

Unlike most other genes, expression levels of many of the 50 mutation-containing genes that form the suspected network were highest early in fetal development, tapered off by childhood, but conspicuously increased again in early adulthood – just when schizophrenia symptoms typically first develop. This adds to evidence supporting the prevailing neurodevelopmental model of schizophrenia. The implicated genes play important roles in migration of cells in the developing brain, communication between brain cells, regulation of gene expression, and related intracellular workings.

Having an older father increased the likelihood of spontaneous mutations for both affected and unaffected siblings. Yet affected siblings were modestly more likely to have mutations predicted to damage protein function. Such damaging mutations were estimated to account for 21 percent of schizophrenia cases in the study sample. The mutations tend to be individually rare; only one gene harboring damaging mutations turned up in more than one of the cases, and several patients had damaging mutations in more than one gene.

The networks formed by genes harboring these damaging mutations were found to vary in connectivity, based on the extent to which their proteins are co-expressed and interact. The network formed by genes harboring damaging mutations in schizophrenia had significantly more nodes, or points of connection, than networks modeled from unaffected siblings. By contrast, the network of genes harboring non-damaging mutations in affected siblings had no more nodes than similar networks in unaffected siblings.

When the researchers compared such network connectivity across different brain tissues and different periods of development, they discovered a notable difference between affected and unaffected siblings: Genes harboring damaging mutations that are expressed together in the fetal prefrontal cortex of people with schizophrenia formed a network with significantly greater connectivity than networks modeled from genes harboring similar mutations in their unaffected siblings at that time in development.

The study results are consistent with several lines of evidence implicating the prefrontal cortex in schizophrenia. The prefrontal cortex organizes information from other brain regions to coordinate executive functions like thinking, planning, attention span, working memory, problem-solving, and self-regulation. The findings suggest that impairments in such functions — often beginning before the onset of symptoms in early adulthood, when the prefrontal cortex fully matures – appear to be early signs of the illness.

The study demonstrates how integrating genomic data and transcriptome analysis can help to pinpoint disease mechanisms and identify potential treatment targets. For example, the mutant genes in the patients studied suggest the possible efficacy of medications targeting glutamate and calcium channel pathways, say the researchers.

"These results are striking, as they show that the genetic architecture of schizophrenia cannot be understood without an appreciation of how genes work in temporal and spatial networks during neurodevelopment," said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch.

Scientists Identify Key Brain Circuits that Control Compulsive Drinking in Rats

Gallo Center Research Could Have Direct Application For Treating Human Drinking Problems

A research team led by scientists from the Ernest Gallo Clinic and Research Center at UC San Francisco has identified circuitry in the brain that drives compulsive drinking in rats, and likely plays a similar role in humans.

The scientists found they could reduce compulsive drinking in rats by inhibiting key neural pathways that run between the prefrontal cortex, which is involved with higher functions such as critical thinking and risk assessment, and the nucleus accumbens, a critical area for reward and motivation.

The authors noted that there are already several FDA-approved medications that target activity in these pathways, thus potentially opening an accelerated track to new treatments for compulsive drinking.

The study describing their finding was published online on June 30 in Nature Neuroscience.

The study was conducted on rats that regularly drank 20 percent alcohol. The rats drank both unmixed alcohol and alcohol mixed with extremely bitter quinine, said senior investigator F. Woodward Hopf, PhD, an assistant adjunct professor of neurology at UCSF.

Hopf explained that this alcohol-quinine solution, which he described as “like a vodka tonic without the sugar,” is often used as a rodent model of compulsive drinking, or “drinking in the face of negative consequences.” In rats, he said, the negative consequence is the bitter taste, while in humans who drink compulsively, “the negative consequences are profound: people continue to drink despite the potential loss of jobs, marriages, freedom, even their lives.”

The drinking rats showed a notable increase in the NMDA receptor (NMDAR), which lead author Taban Seif, PhD, a Gallo Center researcher, called “a molecule that excites the brain.” When the rats were injected with an NMDAR blocker, their consumption of quinine-laced alcohol dropped significantly, while regular alcohol use was unaffected. “In other words, only the compulsive drinking was affected,” said Seif.

Focus on Two Regions of the Prefrontal Cortex

The team then focused its research on connections from two specific regions of the rats’ prefrontal cortex where they had discovered the presence of unusual types of NMDARs: the medial prefrontal cortex, which mediates conflict during decision-making, and the insula, which is critical for self-awareness and feelings.

“In a non-addict, these brain areas tell you when something is potentially harmful and bad, and to run away as fast as possible,” said Hopf. “But if you’re a compulsive drinker, it seems instead that they give you a comforting pat on the back, in effect telling you it’s OK to have another drink, nothing to worry about.”

Using a technique called optogenetics, the scientists inserted halorhodopsin, a light-sensitive protein, into these areas. They then used fiber-optic cables implanted in the rats’ brains to send pulses of laser light that activated the halorhodopsin, which in turn inhibited the regions’ connections to the nucleus accumbens. The researchers found that rats inhibited in this way drank significantly less quinine-laced alcohol, while their intake of regular alcohol solution remained unaffected.

“The fact that we reduced the rats’ compulsive drinking using two different methods – an NMDAR blocker and direct inhibition of connections – tells us that we have probably identified the right areas,” said Hopf.

Potential Treatments for Humans

The next logical step for the research team, said Hopf, would be to work with clinical researchers on an NMDAR blocker trial in human subjects.

“What is interesting is that we have a new drug which could perhaps treat compulsive aspects of drinking,” said Hopf, “but only if you are in conflict about your drinking – if you care. Any therapy with NMDAR blockers would need a strong behavioral and cognitive component to make sure the patient stayed mentally engaged.”

Seif and Hopf also plan further experimental studies focusing on how the insula drives behavior and connects to other areas of the brain.

The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course

The prefrontal cortex (PFC) is involved in working memory and self-regulatory and goal-directed behaviors and displays remarkable structural and functional plasticity over the life course. Neural circuitry, molecular profiles, and neurochemistry can be changed by experiences, which influence behavior as well as neuroendocrine and autonomic function. Such effects have a particular impact during infancy and in adolescence. Behavioral stress affects both the structure and function of PFC, though such effects are not necessarily permanent, as young animals show remarkable neuronal resilience if the stress is discontinued. During aging, neurons within the PFC become less resilient to stress. There are also sex differences in the PFC response to stressors. While such stress and sex hormone-related alterations occur in regions mediating the highest levels of cognitive function and self-regulatory control, the fact that they are not necessarily permanent has implications for future behavior-based therapies that harness neural plasticity for recovery.

Teens’ Self-Consciousness Linked With Specific Brain, Physiological Responses

Teenagers are famously self-conscious, acutely aware and concerned about what their peers think of them. A new study reveals that this self-consciousness is linked with specific physiological and brain responses that seem to emerge in adolescence.

“Our study identifies adolescence as a unique period of the lifespan in which self-conscious emotion, physiological reactivity, and activity in specific brain areas converge and peak in response to being evaluated by others,” says psychological scientist and lead researcher Leah Somerville of Harvard University.

The findings, published in Psychological Science, a journal of the Association for Psychological Science, suggest that teens’ sensitivity to social evaluation might be explained by shifts in physiological and brain function during adolescence, in addition to the numerous sociocultural changes that take place during the teen years.

Somerville and colleagues wanted to investigate whether just being looked at — a minimal social-evaluation situation — might register with greater importance, arousal, and intensity for adolescents than for either children or adults. The researchers hypothesized that late-developing regions of the brain, such as the medial prefrontal cortex (MPFC), could play a unique role in the way teens monitor these types of social evaluative contexts.

The researchers had 69 participants, ranging in age from 8 to almost 23 years old, come to the lab and complete measures that gauged emotional, physiological, and neural responses to social evaluation.

They told the participants that they would be testing a new video camera embedded in the head coil of a functional MRI scanner. The participants watched a screen indicating whether the camera was “off,” “warming up,” or “on”, and were told that a same-sex peer of about the same age would be watching the video feed and would be able to see them when the camera was on. In reality, there was no camera in the MRI machine.

The consistency and strength of the resulting data took the researchers by surprise:

“We were concerned about whether simply being looked at was a strong enough ‘social evaluation’ to evoke emotional, physiological and neural responses,” says Somerville. “Our findings suggest that being watched, and to some extent anticipating being watched, were sufficient to elicit self-conscious emotional responses at each level of measurement.”

Specifically, participants’ self-reported embarrassment, physiological arousal, and MPFC activation showed reactivity to social evaluation that seemed to converge and peak during adolescence.

Adolescent participants also showed increased functional connectivity between the MPFC and striatum, an area of the brain that mediates motivated behaviors and actions. Somerville and colleagues speculate that the MPFC-striatum pathway may be a route by which social evaluative contexts influence behavior. The link may provide an initial clue as to why teens often engage in riskier behaviors when they’re with their peers.

Breaking habits before they start

Our daily routines can become so ingrained that we perform them automatically, such as taking the same route to work every day. Some behaviors, such as smoking or biting your fingernails, become so habitual that we can’t stop even if we want to.

Although breaking habits can be hard, MIT neuroscientists have now shown that they can prevent them from taking root in the first place, in rats learning to run a maze to earn a reward. The researchers first demonstrated that activity in two distinct brain regions is necessary in order for habits to crystallize. Then, they were able to block habits from forming by interfering with activity in one of the brain regions — the infralimbic (IL) cortex, which is located in the prefrontal cortex.

The MIT researchers, led by Institute Professor Ann Graybiel, used a technique called optogenetics to block activity in the IL cortex. This allowed them to control cells of the IL cortex using light. When the cells were turned off during every maze training run, the rats still learned to run the maze correctly, but when the reward was made to taste bad, they stopped, showing that a habit had not formed. If it had, they would keep going back by habit.

“It’s usually so difficult to break a habit,” Graybiel says. “It’s also difficult to have a habit not form when you get a reward for what you’re doing. But with this manipulation, it’s absolutely easy. You just turn the light on, and bingo.”

Graybiel, a member of MIT’s McGovern Institute for Brain Research, is the senior author of a paper describing the findings in the June 27 issue of the journal Neuron. Kyle Smith, a former MIT postdoc who is now an assistant professor at Dartmouth College, is the paper’s lead author.

Patterns of habitual behavior

Previous studies of how habits are formed and controlled have implicated the IL cortex as well as the striatum, a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward. It is believed that the motor patterns needed to execute a habitual behavior are stored in the striatum and its circuits.

Recent studies from Graybiel’s lab have shown that disrupting activity in the IL cortex can block the expression of habits that have already been learned and stored in the striatum. Last year, Smith and Graybiel found that the IL cortex appears to decide which of two previously learned habits will be expressed.

“We have evidence that these two areas are important for habits, but they’re not connected at all, and no one has much of an idea of what the cells are doing as a habit is formed, as the habit is lost, and as a new habit takes over,” Smith says.

To investigate that, Smith recorded activity in cells of the IL cortex as rats learned to run a maze. He found activity patterns very similar to those that appear in the striatum during habit formation. Several years ago, Graybiel found that a distinctive “task-bracketing” pattern develops when habits are formed. This means that the cells are very active when the animal begins its run through the maze, are quiet during the run, and then fire up again when the task is finished.

This kind of pattern “chunks” habits into a large unit that the brain can simply turn on when the habitual behavior is triggered, without having to think about each individual action that goes into the habitual behavior.

The researchers found that this pattern took longer to appear in the IL cortex than in the striatum, and it was also less permanent. Unlike the pattern in the striatum, which remains stored even when a habit is broken, the IL cortex pattern appears and disappears as habits are formed and broken. This was the clue that the IL cortex, not the striatum, was tracking the development of the habit.

Multiple layers of control

The researchers’ ability to optogenetically block the formation of new habits suggests that the IL cortex not only exerts real-time control over habits and compulsions, but is also needed for habits to form in the first place.

“The previous idea was that the habits were stored in the sensorimotor system and this cortical area was just selecting the habit to be expressed. Now we think it’s a more fundamental contribution to habits, that the IL cortex is more actively making this happen,” Smith says.

This arrangement offers multiple layers of control over habitual behavior, which could be advantageous in reining in automatic behavior, Graybiel says. It is also possible that the IL cortex is contributing specific pieces of the habitual behavior, in addition to exerting control over whether it occurs, according to the researchers. They are now trying to determine whether the IL cortex and the striatum are communicating with and influencing each other, or simply acting in parallel.

“A role for the IL cortex in the regulation of habit is not a new idea, but the details of the interaction between it and the striatum that emerge from this analysis are novel and interesting,” says Christopher Pittenger, an assistant professor of psychiatry and psychology at Yale University School of Medicine, who was not part of the research team. “Thinking in the long term, it raises the question of whether targeted manipulations of the IL cortex might be useful for the breaking habits — and exciting possibility with potential clinical ramifications.”

The study suggests a new way to look for abnormal activity that might cause disorders of repetitive behavior, Smith says. Now that the researchers have identified the neural signature of a normal habit, they can look for signs of habitual behavior that is learned too quickly or becomes too rigid. Finding such a signature could allow scientists to develop new ways to treat disorders of repetitive behavior by using deep brain stimulation, which uses electronic impulses delivered by a pacemaker to suppress abnormal brain activity.

Neuroscience Research Project Examines Neural Synchronization Patterns During Addiction

A cross-disciplinary collaboration of researchers in the School of Science at Indiana University-Purdue University Indianapolis (IUPUI) explores the neural synchrony between circuits in the brain and their behavior under simulated drug addiction. The two-year study could have broad implications for treating addiction and understanding brain function in conditions such as Parkinson’s disease.

Advanced mathematical models coupled with extensive laboratory testing revealed recurrent stimulant injections in rodents resulted in neural circuits that could easily synchronize but were more likely to become unstable. In other words, the introduction and restriction of drugs over time caused neurons to lose their ability to engage supervisory control over brain function and behavior. Researchers noticed these short periods of desynchronization were much more prevalent and caused changes in neurobiology and behavior.

“A better understanding of the dynamics of neural synchrony could have very important implications for understanding the addicted brain and may provide a physiological target to understand persistent neural changes that contribute to the probability of relapse,” said Christopher Lapish, Ph.D., assistant professor of psychology at IUPUI.

Lapish, with expertise in neurophysiology and addiction, and Leonid Rubchinsky, Ph.D., associate professor of mathematical sciences, collaborated on the project with support from the IUPUI Institute for Mathematical Modeling and Computational Science. Rubchinsky is an applied mathematician and neuroscientist who has extensively studied the neurophysiology of Parkinson’s disease.

Sungwoo Ahn, Ph.D., a post-doctoral fellow in mathematical sciences, also co-authored the study, recently published in the Cerebral Cortex scientific journal.

The research was patterned after the various stages of drug addiction: the first introduction of amphetamines, periods of abstinence that model withdrawal and then relapse.

The neural synchrony patterns of models injected with a stimulant were compared to those injected with a saline solution. Short periods of desychronization were prevalent in both groups, but the drug-affected group displayed a marked connection between synchrony and brain function. Synchrony has long been considered to play an important role in how the brain processes data, so any disruption of this pattern could hold significant research value, according to the published study.

“Through these long and progressive experimental examinations, we were able to explore the different areas of the brain and how they are connected to each other,” Rubchinsky said. “In addition to understanding, monitoring, diagnosing and treating addiction, this type of study is helpful in better understanding how the normal brain works.”

This collaboration moves scientists closer to understanding brain function and disruptions, Rubchinsky said, by incorporating mathematical models that recreate events and reactions in the brain over time. Lapish agreed, saying computational science ultimately will drive the growth and success of future neuroscience research.

“Neuroscience is an inherently data-rich science and, by combining experimentalists with theorists, there is a tremendous potential for discovery,” Lapish. “The interactive effects of this collaboration are certainly greater than the sum of its parts. We’re able to create a fully dynamic picture of this process that would not be possible without combining these two areas of expertise.”

Moving forward, the team will continue to seek funding to advance their research methods and better understand the role of synchrony in brain function. By doing so, scientists could map the progress and deterioration of neural circuits in various scenarios.

Changing gut bacteria through diet affects brain function

UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.

The study, conducted by scientists with UCLA’s Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and the Ahmanson–Lovelace Brain Mapping Center at UCLA, appears in the current online edition of the peer-reviewed journal Gastroenterology.

The discovery that changing the bacterial environment, or microbiota, in the gut can affect the brain carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function, the researchers said.

"Many of us have a container of yogurt in our refrigerator that we may eat for enjoyment, for calcium or because we think it might help our health in other ways," said Dr. Kirsten Tillisch, an associate professor of medicine at UCLA’s David Geffen School of Medicine and lead author of the study. "Our findings indicate that some of the contents of yogurt may actually change the way our brain responds to the environment. When we consider the implications of this work, the old sayings ‘you are what you eat’ and ‘gut feelings’ take on new meaning."

Researchers have known that the brain sends signals to the gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.

"Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut," Tillisch said. "Our study shows that the gut–brain connection is a two-way street."

The small study involved 36 women between the ages of 18 and 55. Researchers divided the women into three groups: one group ate a specific yogurt containing a mix of several probiotics — bacteria thought to have a positive effect on the intestines — twice a day for four weeks; another group consumed a dairy product that looked and tasted like the yogurt but contained no probiotics; and a third group ate no product at all.

Functional magnetic resonance imaging (fMRI) scans conducted both before and after the four-week study period looked at the women’s brains in a state of rest and in response to an emotion-recognition task in which they viewed a series of pictures of people with angry or frightened faces and matched them to other faces showing the same emotions. This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors.

The researchers found that, compared with the women who didn’t consume the probiotic yogurt, those who did showed a decrease in activity in both the insula — which processes and integrates internal body sensations, like those form the gut — and the somatosensory cortex during the emotional reactivity task.

Further, in response to the task, these women had a decrease in the engagement of a widespread network in the brain that includes emotion-, cognition- and sensory-related areas. The women in the other two groups showed a stable or increased activity in this network.

During the resting brain scan, the women consuming probiotics showed greater connectivity between a key brainstem region known as the periaqueductal grey and cognition-associated areas of the prefrontal cortex. The women who ate no product at all, on the other hand, showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions, while the group consuming the non-probiotic dairy product showed results in between.

The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion, Tillisch said.

The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders, said Dr. Emeran Mayer, a professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA and the study’s senior author.

"There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates," Mayer said. "Now we know that this has an effect not only on the metabolism but also affects brain function."

The UCLA researchers are seeking to pinpoint particular chemicals produced by gut bacteria that may be triggering the signals to the brain. They also plan to study whether people with gastrointestinal symptoms such as bloating, abdominal pain and altered bowel movements have improvements in their digestive symptoms which correlate with changes in brain response.

Meanwhile, Mayer notes that other researchers are studying the potential benefits of certain probiotics in yogurts on mood symptoms such as anxiety. He said that other nutritional strategies may also be found to be beneficial.

By demonstrating the brain effects of probiotics, the study also raises the question of whether repeated courses of antibiotics can affect the brain, as some have speculated. Antibiotics are used extensively in neonatal intensive care units and in childhood respiratory tract infections, and such suppression of the normal microbiota may have long-term consequences on brain development.

Finally, as the complexity of the gut flora and its effect on the brain is better understood, researchers may find ways to manipulate the intestinal contents to treat chronic pain conditions or other brain related diseases, including, potentially, Parkinson’s disease, Alzheimer’s disease and autism.

Answers will be easier to come by in the near future as the declining cost of profiling a person’s microbiota renders such tests more routine, Mayer said.