Stem Cell Research Helps to Identify Origins of Schizophrenia

New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.

The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.

Partial funding for the research came from New York Stem Cell Science (NYSTEM).

The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder. 

“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.

A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.

“How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?” asks Stachowiak. “It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.

“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”

Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.

Brain region associated with selfishness

People with damage to a specific part of the brain entrusted unexpectedly large amounts of money to complete strangers. In an investment game played in the lab, three women with damage to a small part of the brain called the basolateral amygdala handed over nearly twice as much money as healthy people.

These women didn’t expect to make a bunch of money back, an international team of researchers reports online the week of January 21 in the Proceedings of the National Academy of Sciences. Nor did they think the person they invested with was particularly trustworthy. When asked why they would invest so generously, the volunteers couldn’t provide an answer.

The results suggest that normally, the basolateral amygdala enables selfishness — putting the squeeze on generosity.

(Image credit)

Researchers turn one form of neuron into another in the brain

A new finding by Harvard stem cell biologists turns one of the basics of neurobiology on its head – demonstrating that it is possible to turn one type of already differentiated neuron into another within the brain.

The discovery by Paola Arlotta and Caroline Rouaux “tells you that maybe the brain is not as immutable as we always thought, because at least during an early window of time one can reprogram the identity of one neuronal class into another,” said Arlotta, an Associate Professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB).

The principle of direct lineage reprogramming of differentiated cells within the body was first proven by SCRB co-chair and Harvard Stem Cell Institute (HSCI) co-director Doug Melton and colleagues five years ago, when they reprogrammed exocrine pancreatic cells directly into insulin producing beta cells.

Arlotta and Rouaux now have proven that neurons too can change their mind. The work is being published on-line by the journal Nature Cell Biology.

In their experiments, Arlotta targeted callosal projection neurons, which connect the two hemispheres of the brain, and turned them into neurons similar to corticospinal motor neurons, one of two populations of neurons destroyed in Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. To achieve such reprogramming of neuronal identity, the researchers used a transcription factor called Fezf2, which long as been known for playing a central role in the development of corticospinal neurons in the embryo.

What makes the finding even more significant is that the work was done in the brains of living mice, rather than in collections of cells in laboratory dishes. The mice were young, so researchers still do not know if neuronal reprogramming will be possible in older laboratory animals – and humans. If it is possible, this has enormous implications for the treatment of neurodegenerative diseases.

"Neurodegenerative diseases typically effect a specific population of neurons, leaving many others untouched. For example, in ALS it is corticospinal motor neurons in the brain and motor neurons in the spinal cord, among the many neurons of the nervous system, that selectively die," Arlotta said. "What if one could take neurons that are spared in a given disease and turn them directly into the neurons that die off? In ALS, if you could generate even a small percentage of corticospinal motor neurons, it would likely be sufficient to recover basic functioning," she said.

The experiments that led to the new finding began five years ago, when “we wondered: in nature you never seen a neuron change identity; are we just not seeing it, or is this the reality? Can we take one type of neuron and turn it into another?” Arlotta and Rouaux asked themselves.

Over the course of the five years, the researchers analyzed “thousands and thousands of neurons, looking for many molecular markers as well as new connectivity that would indicate that reprogramming was occurring,” Arlotta said. “We could have had this two years ago, but while this was a conceptually very simple set of experiments, it was technically difficult. The work was meant to test important dogmas on the irreversible nature of neurons in vivo. We had to prove, without a shadow of a doubt, that this was happening.”

The work in Arlotta’s lab is focused on the cerebral cortex, but “it opens the door to reprogramming in other areas of the central nervous system,” she said.

Arlotta, an HSCI principal faculty member, is now working with colleague Takao Hensch, of Harvard’s Department of Molecular and Cellular Biology, to explicate the physiology of the reprogrammed neurons, and learn how they communicate within pre-existing neuronal networks.

"My hope is that this will facilitate work in a new field of neurobiology that explores the boundaries and power of neuronal reprogramming to re-engineer circuits relevant to disease," said Paola Arlotta.

(Image courtesy Tulane University)

Robot Allows ‘Remote Presence’ in Programming Brain and Spine Stimulators

With the rapidly expanding use of brain and spinal cord stimulation therapy (neuromodulation), new “remote presence” technologies may help to meet the demand for experts to perform stimulator programming, reports a study in the January issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The preliminary study by Dr. Ivar Mendez of Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada, supports the feasibility and safety of using a remote presence robot—called the “RP-7”—to increase access to specialists qualified to program the brain and spine stimulators used in neuromodulation.

Read more

(Image: NEUROSURGERY® Editorial Office)

How the brain copes with multi-tasking alters with age

The pattern of blood flow in the prefrontal cortex in the brains alters with age during multi-tasking, finds a new study in BioMed Central’s open access journal BMC Neuroscience. Increased blood volume, measured using oxygenated haemoglobin (Oxy-Hb) increased at the start of multitasking in all age groups. But to perform the same tasks, healthy older people had a higher and more sustained increase in Oxy-Hb than younger people.

Age related changes to the brain occur earliest in the prefrontal cortex, the area of the brain associated with memory, emotion, and higher decision making functions. It is changes to this area of the brain that are also associated with dementia, depression and other neuropsychiatric disorders. Some studies have shown that regular physical activity and cognitive training can prevent cognitive decline (use it or lose it!) but to establish what occurs in a healthy aging brain researchers from Japan and USA have compared brain activity during single and dual tasks for young (aged 21 to 25) and older (over 65) people.

Near infrared spectroscopy (NIRS) measurements of Oxy-Hb showed that blood flow to the prefrontal cortex was not affected by the physical task for either age group but was affected by the mental task. For both the young and the over 65s the start of the calculation task  coincided with an increase in blood volume which reduced to baseline once the task was completed.

The main difference between the groups was only seen when performing the physical and mental tasks at the same time - older people had a higher prefrontal cortex response which lasted longer than the younger group.

Hironori Ohsugi, from Seirei Christopher University, and one of the team who performed this research explained “From our observations during the dual task it seems that the older people turn their attention to the calculation at the expense of the physical task, while younger people are able to maintain concentration on both. Since our subjects were all healthy it seems that this requirement for increased activation of the prefrontal cortex is part of normal decrease in brain function associated with aging. Further study will show whether or not dual task training can be used to maintain a more youthful brain.”

(Image: Photos.com)

Is Athleticism Linked to Brain Size?

To find out, researchers at the University of California, Riverside performed laboratory experiments on house mice and found that mice that have been bred for dozens of generations to be more exercise-loving have larger midbrains than those that have not been selectively bred this way.

Theodore Garland’s lab measured the brain mass of these uniquely athletic house mice, bred for high voluntary wheel-running, and analyzed their high-resolution brain images. The researchers found that the volume of the midbrain — a small region of the brain that relays information for the visual, auditory, and motor systems — in the bred-for-athleticism mice was nearly 13 percent larger than the midbrain volume in the control or “regular” mice.

“To our knowledge, this is the first example in which selection for a particular mammalian behavior — high voluntary wheel running in house mice in our set of experiments — has been shown to result in a change in size of a specific brain region,” said Garland, a professor of biology and the principal investigator of the research project.

Study results appeared online Jan. 16 in The Journal of Experimental Biology

Individuals with a low risk for cocaine dependence have a differently shaped brain to those with addiction

People who take cocaine over many years without becoming addicted have a brain structure which is significantly different from those individuals who developed cocaine-dependence, researchers have discovered. New research from the University of Cambridge has found that recreational drug users who have not developed a dependence have an abnormally large frontal lobe, the section of the brain implicated in self-control. Their research was published in the journal Biological Psychiatry.

For the study, led by Dr Karen Ersche, individuals who use cocaine on a regular basis underwent a brain scan and completed a series of personality tests. The majority of the cocaine users were addicted to the drug but some were not (despite having used it for several years).

The scientists discovered that a region in the frontal lobes of the brain, known to be critically implicated in decision-making and self-control, was abnormally bigger in the recreational cocaine users. The Cambridge researchers suggest that this abnormal increase in grey matter volume, which they believe predates drug use, might reflect resilience to the effects of cocaine, and even possibly helps these recreational cocaine users to exert self-control and to make advantageous decisions which minimize the risk of them becoming addicted.

They found that this same region in the frontal lobes of the brain was significantly reduced in size in people with cocaine dependence, confirming earlier research that had found similar results. They believe that at least some of these changes are the result of drug use, which causes drug users to lose grey matter.

They also found that people who use illicit drugs like cocaine exhibit high levels of sensation-seeking personality traits, but only those developing dependence show personality traits of impulsivity and compulsivity.

Dr Ersche, of the Behavioural and Clinical Neuroscience Institute (BCNI) at the University of Cambridge, said: “These findings are important because they show that the use of cocaine does not inevitably lead to addiction in people with good self-control and no familial risk.

“Our findings indicate that preventative strategies might be more effective if they were tailored more closely to those individuals at risk according to their personality profile and brain structure.”

The researchers will next explore the basis of the recreational users’ apparent resilience to drug dependence. Dr Ersche added: “Their high level of education, less troubled family background or the beginning of drug-taking only after puberty may all play a role.”

New research finds slower growth of preterm infants linked to altered brain development

Preterm infants who grow more slowly as they approached what would have been their due dates also have slower development in an area of the brain called the cerebral cortex, report Canadian researchers in a new study published in Science Translational Medicine.

The cerebral cortex is a two to four millimetre layer of cells that envelopes the top part of the brain and is involved in cognitive, behavioural, and motor processes.

Researchers analyzed MRI brain scans of 95 preterm infants born eight to 16 weeks too early at BC Women’s Hospital & Health Centre between 2006 and 2009. Infants were scanned soon after birth and a second time close to what would have been their due date, the ninth month of pregnancy. These MRI scans allowed researchers to measure the pattern of water movement inside the brain, which normally changes between scans as the brain matures. The researchers also assessed the babies’ weight, length, and head size. They found that preterm infants with slower growth had delayed development in the cerebral cortex compared to those infants who grew more quickly between scans.

“These results are an exciting first step because understanding the importance of growth in relation to the brain in these small babies may eventually lead to new discoveries that will help us optimize their brain development,” says Dr. Steven Miller, the study’s co‐lead. Dr. Miller is head of neurology at The Hospital for Sick Children (SickKids), the Bloorview Children’s Hospital Chair in Paediatric Neuroscience, professor in the department of Paediatrics at the University of Toronto, affiliate professor in the department of Pediatrics at the University of British Columbia (UBC), and affiliate investigator at the Child & Family Research Institute (CFRI) at BC Children’s Hospital. He led the study with Dr. Ruth Grunau, a professor in the UBC Department of Pediatrics and CFRI senior scientist.

“More research needs to be done to understand what is the optimal growth rate for the brain development of these babies,” says Jillian Vinall, the study’s first author and a UBC PhD student cosupervised by Dr. Grunau and Dr. Miller.

We’re especially grateful to the families for their generous and ongoing participation in this study,” says Dr. Miller. The researchers are following the babies through childhood to understand how preterm brain development is associated with their neurodevelopment outcomes.

Scanning the Brain: Scientists Examine the Impact of fMRI Over the Past 20 Years

Understanding the human brain is one of the greatest scientific quests of all time, but the available methods have been very limited until recently. The development of functional magnetic resonance imaging (fMRI) — a tool used to gauge real-time brain activity by measuring changes in blood flow — opened up an exciting new landscape for exploration.

Now, twenty years after the first fMRI study was published, a group of distinguished psychological scientists reflect on the contributions fMRI has made to our understanding of human thought. Their reflections are published as part of a special section of the January 2013 issue of Perspectives on Psychological Science, a journal of the Association for Psychological Science.

In the last two decades, many researchers have used fMRI to try to answer various questions about the brain and mind. But some are not convinced of its usefulness.

“Despite the many new methods and results derived from fMRI research, some have argued that fMRI has done very little to advance knowledge about cognition and, in particular, has done little to advance theories about cognitive processes,” write Mara Mather, Nancy Kanwisher, and John Cacioppo, editors of the special section.

The aim of the special section is to tackle the question of how fMRI results have (or have not) changed the way we think about human psychology and the brain, resulting in a collection of 12 provocative articles.

Some of the authors argue that fMRI has fundamentally changed that way that researchers think about the aging mind. According to researchers Tor Wager and Lauren Atlas, fMRI may also provide a more direct way of measuring pain.

Others discuss the contributions fMRI has made to the longstanding debate about whether cognitive operations are modular or distributed across domains. And some emphasize the reciprocal relationship between fMRI and cognitive theories, highlighting how each informs the others.

As appealing as fMRI images might be, researchers Martha Farah and Cayce Hook find little support for the claim that fMRI data has a “seductive allure” that makes it more persuasive than other types of data.

In their concluding commentary, Mather, Cacioppo, and Kanwisher argue that fMRI does provide unique insights to our understanding of cognition. But, as powerful as it is, the researchers acknowledge that there are some questions fMRI will never answer.

“The best approach to answering questions about cognition,” say Mather, Cacioppo, and Kanwisher, “is a synergistic combination of behavioral and neuroimaging methods, richly complemented by the wide array of other methods in cognitive neuroscience.”

(Image courtesy of Glasgow University)