Pregnant mothers’ exposure to the flu was associated with a nearly fourfold increased risk that their child would develop bipolar disorder in adulthood, in a study funded by the National Institutes of Health. The findings add to mounting evidence of possible shared underlying causes and illness processes with schizophrenia, which some studies have also linked to prenatal exposure to influenza.

This colorized transmission electron micrograph shows H1N1 influenza virus particles. Surface proteins on the virus particles are shown in black.
Source: NIAID

“Prospective mothers should take common sense preventive measures, such as getting flu shots prior to and in the early stages of pregnancy and avoiding contact with people who are symptomatic,” said Alan Brown, M.D., M.P.H, of Columbia University and New York State Psychiatric Institute, a grantee of the NIH’s National Institute of Mental Health (NIMH).  “In spite of public health recommendations, only a relatively small fraction of such women get immunized. The weight of evidence now suggests that benefits of the vaccine likely outweigh any possible risk to the mother or newborn.”

Brown and colleagues reported their findings online May 8, 2013 in JAMA Psychiatry.

Although there have been hints of a maternal influenza/bipolar disorder connection, the new study is the first to prospectively follow families in the same HMO, using physician-based diagnoses and structured standardized psychiatric measures. Access to unique Kaiser-Permanente, county and Child Health and Development StudyExternal Link: Please review our disclaimer. databases made it possible to include more cases with detailed maternal flu exposure information than in previous studies.

Among nearly a third of all children born in a northern California county during 1959-1966, researchers followed 92 who developed bipolar disorder, comparing rates of maternal flu diagnoses during pregnancy with 722 matched controls.

The nearly fourfold increased risk implicated influenza infection at any time during pregnancy, but there was evidence suggesting slightly higher risk if the flu occurred during the second or third trimesters. Moreover, the researchers linked flu exposure to a nearly sixfold increase in a subtype of bipolar disorder with psychotic features. 

A previous study, by Brown and colleagues, in a related northern California sample, found a threefold increased risk for schizophrenia associated with maternal influenza during the first half of pregnancy. Autism has similarly been linked to first trimester maternal viral infections and to possibly related increases in inflammatory molecules.

“Future research might investigate whether this same environmental risk factor might give rise to different disorders, depending on how the timing of the prenatal insult affects the developing fetal brain,” suggested Brown.

Bipolar disorder shares with schizophrenia a number of other suspected causes and illness features, the researchers note. For example, both share onset of symptoms in early adulthood, susceptibility genes, run in the same families, affect nearly one percent of the population, show psychotic behaviors and respond to antipsychotic medications. 

Increasing evidence of such overlap between traditional diagnostic categories has led to the NIMH Research Domain Criteria (RDoC) project, which is laying the foundation for a new mental disorders classification system based on brain circuits and dimensional mechanisms that cut across traditional diagnostic categories.

The research was also funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Reference

Gestational Influenza and bipolar Disorder in Adult Offspring. Parboosing R, Bao Y, Shen L, Schaefer CA, Brown AS. JAMA Psychiatry, May 8, 2013.

Grant Numbers

5 R01 MH073080 05
5 K02 MH065422 10
5 R01 MH069819 05
N01-HD-1-3334
N01-HD-6-3258

###

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the NICHD website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Scientists funded by the National Institutes of Health have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33.

“Too much CD33 activity appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” explained Rudolph TanziExternal Link: Please review our disclaimer., Ph.D., of Massachusetts General Hospital and Harvard University, a grantee of the NIH’s National Institute of Mental Health (NIMH) and National Institute on Aging (NIA). “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”

Tanzi and colleagues report on their findings April 25, 2013 in the journal Neuron.

“These results reveal a previously unknown, potentially powerful mechanism for protecting neurons from damaging toxicity and inflammation,” said NIMH Director Thomas R. Insel, M.D. “Given increasing evidence of overlap between brain disorders at the molecular level, understanding such workings in Alzheimer’s disease may also provide insights into other mental disorders.”

Variation in the CD33 gene turned up as one of four prime suspects in the largest genome-wide dragnet of Alzheimer’s-affected families, reported by Tanzi and colleagues in 2008. The gene was known to make a protein that regulates the immune system, but its function in the brain remained elusive. To discover how it might contribute to Alzheimer’s, the researchers brought to bear human genetics, biochemistry and human brain tissue, mouse and cell-based experiments.

They found over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer’s disease, the most common form of the illness. The more CD33 protein on the cell surface of microglia, the more beta-amyloid protein and plaques – damaging debris – had accumulated in their brains. Moreover, the researchers discovered that brains of people who inherited a version of the CD33 gene that protected them from Alzheimer’s conspicuously showed reduced amounts of CD33 on the surface of microglia and less beta-amyloid.

Brain levels of beta-amyloid and plaques were also markedly reduced in mice engineered to under-express or lack CD33. Microglia cells in these animals were more efficient at clearing out the debris, which the researchers traced to levels of CD33 on the cell surface.

Evidence also suggested that CD33 works in league with another Alzheimer’s risk gene in microglia to regulate inflammation in the brain.

The study results – and those of a recent rat study that replicated many features of the human illness – add support to the prevailing theory that accumulation of beta-amyloid plaques are hallmarks of Alzheimer’s pathology. They come at a time of ferment in the field, spurred by other recent contradictory evidenceExternal Link: Please review our disclaimer. suggesting that these presumed culprits might instead play a protective role.

Since increased CD33 activity in microglia impaired beta-amyloid clearance in late onset Alzheimer’s, Tanzi and colleagues are now searching for agents that can cross the blood-brain barrier and block it.

NIH-funded scientists have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33. Too much CD33 activity may promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques. Future medications that impede CD33 activity might help prevent or treat the disorder. Dr. Thomas Lehner, director of NIMH’s Office of Genomics Research Coordination, explains the significance of the new findings.
Credits:
Microglia photo -- Sam Listwak, Ph.D., Miles Herkenham, Ph.D., NIMH Section on Functional Neuroanatomy
CD33 photo -- Rudolph Tanzi, Ph.DExternal Link: Please review our disclaimer., Massachusetts General Hospital and Harvard University
Video animation – National Institute on Aging, National Human Genome Research Institute

Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyoid beta. Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE. Neuron, April 25, 2013.

5 R37 MH060009 13

5 P01 AG015379 15

5 R01 AG008487 15

5 P50 AG005134 29

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. It provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer’s Disease Education and Referral (ADEAR) Center at http://www.nia.nih.gov/Alzheimers. For expanded information on Alzheimer’s care and resources, please visit the federal government’s portal website http://www.alzheimers.govExternal Link: Please review our disclaimer.. Information on health and on aging generally can be found at http://www.nia.nih.gov. To sign up for e-mail alerts about new findings or publications, please visit either NIA website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Slicing optional. Scientists can now study the brain’s finer workings, while preserving its 3-D structure and integrity of its circuitry and other biological machinery.

A breakthrough method, called CLARITY, developed by National Institutes of Health-funded researchers, opens the intact postmortem brain to chemical, genetic and optical analyses that previously could only be performed using thin slices of tissue. By replacing fat that normally holds the brain’s working components in place with a clear gel, they made its normally opaque and impenetrable tissue see-through and permeable. This made it possible to image an intact mouse brain in high resolution down to the level of cells and molecules. The technique was even used successfully to study a human brain.

“CLARITY has the potential to unmask fine details of brains from people with brain disorders without losing larger-scale circuit perspective,” said NIH Director Francis S. Collins, M.D., Ph.D., whose NIH Director’s Transformative Research Award Program helped to fund the research, along with a grant from the National Institute of Mental Health (NIMH).

“CLARITY will help support integrative understanding of large-scale, intact biological systems, explained Karl Deisseroth, M.D., Ph.D.External Link: Please review our disclaimer., of Stanford University in California. “It provides access to subcellular proteins and molecules, while preserving the continuity of intact neuronal structures such as long-range circuit projections, local circuit wiring and cellular spatial relationships.”

Deisseroth, Kwanghun Chung, Ph.D.External Link: Please review our disclaimer., and other Stanford colleagues report on their findings April 10, 2013 in the journal Nature.

“This feat of chemical engineering promises to transform the way we study the brain’s anatomy and how disease changes it,” said NIMH Director Thomas R. Insel, M.D. “No longer will the in-depth study of our most important three-dimensional organ be constrained by two-dimensional methods.”

Until now, researchers seeking to understand the brain’s fine structure and connections have been faced with tradeoffs. To gain access to deeply buried structures and achieve high enough resolution to study cells, molecules and genes, they had to cut brain tissue into extremely thin sections (each a fraction of a millimeter thick), deforming it. Loss of an intact brain also makes it difficult to relate such micro-level findings to more macro-level information about wiring and circuitry, which cuts across slices.

In tackling this challenge, the researchers saw opportunity in the fact that the fats, or lipids, that physically support the brain’s working components, such as neurons and their connections, also block chemical probes and the passage of light. So replacing the lipids with something clear and permeable – that would also hold everything else in place – might make it possible to perform the same tests in an intact brain that previously could only be done with brain tissue slices.

Deisseroth’s team infused into brain a high-tech cocktail, including a plastic-like material and formaldehyde. When heated, it formed a transparent, porous gel that biochemically integrated with, and physically supported, the brain’s working tissue – while excluding the lipids, which were safely removed via an electrochemical process. The result was a brain transformed for optimal accessibility.

They called the new method Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel – CLARITY, for short.

Using CLARITY, the researchers imaged the entire brain of a mouse that had been genetically engineered to express a fluorescent protein. A conventional microscope revealed glowing details, such as proteins embedded in cell membranes and individual nerve fibers, while an electron microscope resolved even ultra-fine structures, such as synapses, the connections between neurons.

In a series of experiments using CLARITY in mouse brain, the researchers demonstrated that, for the first time, standard immune- and genetics-based tests can be performed repeatedly in the same intact brain. Tracer molecules, such as antibodies, can be readily delivered for staining tissue – or removed – leaving brain tissue undisturbed.

The researchers found that CLARITY outperformed conventional methods across a range of previously problematic technical challenges.

When they used CLARITY to analyze a post-mortem human brain of a person who had autism, even though it had been hardening in formaldehyde for six years, they were able to trace individual nerve fibers, neuronal cell bodies and their extensions.

Videos

Reference

Structural and molecular interrogation of intact biological systems. Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Nature. 2013 Apr 10. doi: 10.1038/nature12107. [Epub ahead of print] PMID:23575631

Grant numbers: 1 R01 MH099647 01

See Director’s Blog: New Views into the Brain

###

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The NIH Common Fund encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. These new programs are funded through the Common Fund, and managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Slicing optional. Scientists can now study the brain’s finer workings, while preserving its 3-D structure and integrity of its circuitry and other biological machinery.

A breakthrough method, called CLARITY, developed by National Institutes of Health-funded researchers, opens the intact postmortem brain to chemical, genetic and optical analyses that previously could only be performed using thin slices of tissue. By replacing fat that normally holds the brain’s working components in place with a clear gel, they made its normally opaque and impenetrable tissue see-through and permeable. This made it possible to image an intact mouse brain in high resolution down to the level of cells and molecules. The technique was even used successfully to study a human brain.

“CLARITY has the potential to unmask fine details of brains from people with brain disorders without losing larger-scale circuit perspective,” said NIH Director Francis S. Collins, M.D., Ph.D., whose NIH Director’s Transformative Research Award Program helped to fund the research, along with a grant from the National Institute of Mental Health (NIMH).

“CLARITY will help support integrative understanding of large-scale, intact biological systems, explained Karl Deisseroth, M.D., Ph.D.External Link: Please review our disclaimer., of Stanford University in California. “It provides access to subcellular proteins and molecules, while preserving the continuity of intact neuronal structures such as long-range circuit projections, local circuit wiring and cellular spatial relationships.”

Deisseroth, Kwanghun Chung, Ph.D.External Link: Please review our disclaimer., and other Stanford colleagues report on their findings April 10, 2013 in the journal Nature.

“This feat of chemical engineering promises to transform the way we study the brain’s anatomy and how disease changes it,” said NIMH Director Thomas R. Insel, M.D. “No longer will the in-depth study of our most important three-dimensional organ be constrained by two-dimensional methods.”

Until now, researchers seeking to understand the brain’s fine structure and connections have been faced with tradeoffs. To gain access to deeply buried structures and achieve high enough resolution to study cells, molecules and genes, they had to cut brain tissue into extremely thin sections (each a fraction of a millimeter thick), deforming it. Loss of an intact brain also makes it difficult to relate such micro-level findings to more macro-level information about wiring and circuitry, which cuts across slices.

In tackling this challenge, the researchers saw opportunity in the fact that the fats, or lipids, that physically support the brain’s working components, such as neurons and their connections, also block chemical probes and the passage of light. So replacing the lipids with something clear and permeable – that would also hold everything else in place – might make it possible to perform the same tests in an intact brain that previously could only be done with brain tissue slices.

Deisseroth’s team infused into brain a high-tech cocktail, including a plastic-like material and formaldehyde. When heated, it formed a transparent, porous gel that biochemically integrated with, and physically supported, the brain’s working tissue – while excluding the lipids, which were safely removed via an electrochemical process. The result was a brain transformed for optimal accessibility.

They called the new method Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel – CLARITY, for short.

Using CLARITY, the researchers imaged the entire brain of a mouse that had been genetically engineered to express a fluorescent protein. A conventional microscope revealed glowing details, such as proteins embedded in cell membranes and individual nerve fibers, while an electron microscope resolved even ultra-fine structures, such as synapses, the connections between neurons.

In a series of experiments using CLARITY in mouse brain, the researchers demonstrated that, for the first time, standard immune- and genetics-based tests can be performed repeatedly in the same intact brain. Tracer molecules, such as antibodies, can be readily delivered for staining tissue – or removed – leaving brain tissue undisturbed.

The researchers found that CLARITY outperformed conventional methods across a range of previously problematic technical challenges.

When they used CLARITY to analyze a post-mortem human brain of a person who had autism, even though it had been hardening in formaldehyde for six years, they were able to trace individual nerve fibers, neuronal cell bodies and their extensions.

Videos

Reference

Structural and molecular interrogation of intact biological systems. Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Nature. 2013 Apr 10. doi: 10.1038/nature12107. [Epub ahead of print] PMID:23575631

Grant numbers: 1 R01 MH099647 01

See Director’s Blog: New Views into the Brain

###

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The NIH Common Fund encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. These new programs are funded through the Common Fund, and managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Why are rates of schizophrenia and autism higher in males? New evidence implicates an enzyme expressed in the placenta that helps protect the developing fetal brain from adverse effects of maternal stress early in pregnancy. Video: NIMH grantee Tracy Bale, Ph.D., of the University of Pennsylvania, discussed her line of research into how maternal stress might differentially affect the developing male brain during an interview at the 2011 Society for Neuroscience meeting.

Since then, Bale and colleagues discovered in mice that the gene that makes the enzyme, called OGT, is expressed less in placentas of male than in female offspring. Moreover, OGT was also expressed at relatively lower levels in placentas from stressed mothers. When they looked at evidence of its expression in human placentas, they saw a similar pattern of sex differences. Further experiments in mice confirmed that OGT plays a pivotal role in regulating the turning on-and-off of hundreds of brain genes and in protecting the developing brain from insults. The researchers suggest that OGT epigeneticallyExternal Link: Please review our disclaimer. places male fetuses at a disadvantage in adapting to environmental changes – a possible mechanism underlying males’ increased vulnerability to enduring effects of maternal stress on brain development.

See U PENN press release: Mom’s Placenta Reflects Her Exposure to Stress, Penn Vet Team FindsExternal Link: Please review our disclaimer.

Grant 5 R01 MH091258 04

Howerton CL, Morgan CP, Fischer DB, Bale TL. O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. PNAS, March 5, 2013

Five major mental disorders share some of the same genetic risk factors, the largest genome-wide study of its kind has found.  Evidence for such genetic overlap had previously been limited to pairs of disorders. 

National Institutes of Health-funded researchers discovered that people with disorders traditionally thought to be distinct – autism, ADHD, bipolar disorder, major depression and schizophrenia – were more likely to have suspect genetic variation at the same four chromosomal sites. These included risk versions of two genes that regulate the flow of calcium into cells.

Jordan Smoller, M.D.,
Massachusetts General Hospital

“These results will help us move toward diagnostic classification informed by disease cause,” said Jordan Smoller, M.D.External Link: Please review our disclaimer., of Massachusetts General Hospital, Boston, a coordinator of the study, which was supported by NIH’s National Institute of Mental Health. “Although statistically significant, each of these genetic associations individually can account for only a small amount of risk for mental illness, making them insufficient for predictive or diagnostic usefulness by themselves.”

Smoller, Kenneth Kendler, M.D.,External Link: Please review our disclaimer., Virginia Commonwealth University, Richmond; Nicholas Craddock, PhD.External Link: Please review our disclaimer., Cardiff University, England; Stephan Ripke, M.D.External Link: Please review our disclaimer., Massachusetts General, Patrick Sullivan, M.D.External Link: Please review our disclaimer., University of North Carolina at Chapel Hill, and colleagues in the Cross-Disorder Group of the Psychiatric Genomics Consortium, report on their findings February 28, 2013 in The Lancet.

Prior to the study, researchers had turned up evidence of shared genetic risk factors for pairs of disorders, such as schizophenia and bipolar disorder, autism and schizophrenia and depression and bipolar disorder. Such evidence of overlap at the genetic level has blurred the boundaries of traditional diagnostic categories and given rise to research domain criteria, or RDoC, an NIMH initiative to develop new ways of classifying psychopathology for research based on neuroscience and genetics as well as observed behavior.

To learn more, the consortium researchers analyzed the five key disorders as if they were the same illness. They screened for evidence of illness-associated genetic variation across the genomes of 33,332 patients with all five disorders and 27,888 controls, drawing on samples from previous consortium mega-analyses.

For the first time, specific variations significantly associated with all five disorders were among several suspect genomic sites that turned up. These included variation in two genes that code for the cellular machinery for regulating the flow of calcium into neurons. Variation in one of these, called CACNA1C, which had previously been implicated in susceptibility to bipolar disorder, schizophrenia and major depression, is known to impact brain circuitry involved in emotion, thinking, attention and memory – functions disrupted in mental illnesses. Variation in another calcium channel gene, called CACNB2, was also linked to the disorders.

Alterations in calcium-channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology, suggest the researchers.

They also discovered illness-linked variation for all five disorders in certain regions of chromosomes 3 and 10. Each of these sites spans several genes, and the specific causal factors within them remain elusive. However, one region, called 3p21, which produced the strongest signal of illness association, harbors suspect variations identified in previous genome-wide studies of bipolar disorder and schizophrenia.

References

Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet, February 28, 2013

Grant # 1 U01 MH085520 01

Video

Bruce Cuthbert, Ph.D., director of NIMH’s Division of Adult Translational Research, explains the significance of the Consortium study findings for diagnosis and treatment of mental illnesses.