Thomas Insel
NIMH
This week’s issue of Nature has a special section dedicated to research progress on schizophrenia.i There have been few such issues dedicated to any medical disorder, so this is a landmark for schizophrenia research, a follow-up perhaps to an editorial in Nature at the beginning of this year predicting a “decade for psychiatric disorders”.ii But beyond the mere fact that schizophrenia has been singled out for this distinction, the contents document remarkable progress on a disorder that has been such a conundrum for the past century.
For one thing, schizophrenia can now be described as a brain disorder or, more precisely, as a disorder of brain circuits. With neuroimaging, several of the major nodes in the circuit have been identified, especially within the prefrontal cortex. A major advance has been linking changes in circuit function to cognition and behavior. As a result, we are increasingly focusing on the cognitive deficits of schizophrenia as the core problem, preceding and perhaps leading to the more obvious positive symptoms of hallucinations and delusions.
Another area of unambiguous progress has been genomics. Five years ago the field was frustrated by the lack of replicated findings. With the creation of international consortia sharing data from thousands of patients, we can now see several of the major risk genes. They are not the usual suspects, such as genes involved in dopamine or serotonin neurotransmission. Common variants in genes from the MHC complex, which is important for immune self-recognition, a gene for a transcription factor called TCF4, and several genes that encode synaptic proteins have all been found to confer increased risk. The list is probably not complete as together these explain only a fraction of the genetic risk for the disorder. Many rare variants have also been described in the past year, adding to the known major structural lesions like DISC1 and the 22q11 deletion. These rare events may explain only a small fraction of cases, but as with hypertension and cancer, even rare mutations that cause disease can yield important clues to the pathophysiology underlying more common forms of disease.
From genomics have come clues to the importance of reconceptualizing schizophrenia as a neurodevelopmental disorder. Many of the genetic factors are involved with neurodevelopment; hardly surprising as thousands of genes must be expressed in a carefully choreographed sequence to develop a healthy brain. What is unexpected is that many of the genetic variations associated with schizophrenia appear to disrupt fragments of proteins expressed only in fetal development. And experimental reductions of DISC1 transiently during fetal development in mice have profound effects on physiology and behavior, emerging only in early adulthood. These kinds of observations, along with reports of prenatal and perinatal environmental factors that increase risk for schizophrenia, point to a model of schizophrenia that begins early in life, with subtle cognitive effects through much of development, and emergence of psychosis as a late stage in early adulthood.
If psychosis is a late stage of schizophrenia, analogous to myocardial infarction in coronary artery disease, then we need to develop biomarkers for early detection and treatments that can preempt psychosis. This is where the next decade of research could lead. If the core deficits are cognitive, the “biomarker” for detection might be a working memory task or some assessment of executive function. And the treatments to preempt psychosis might not resemble anti-psychotic medications. Instead of medication, imagine brain training to rewire the circuitry just as we use exercise to reduce cardiac risk. Continuing the coronary artery disease analogy, drugs such as marijuana might be, for someone at risk for psychosis, analogous to the high lipid diet for someone at risk for coronary disease: something that needs to be avoided.
Over the past half-century, we have learned to diagnose coronary artery disease well before a heart attack using tests of cardiovascular risk factors and function. We have averted millions of cardiac deaths through preventive measures such as diet, exercise, and medications for those at risk. For the past century, schizophrenia has been defined by psychosis and we have made too little progress for too many people challenged by this disorder. This issue of Nature marks new hope that we can develop a preemptive approach to schizophrenia, as done for cardiac disease.
There have been many apparent breakthroughs for schizophrenia over the past several decades, followed by non-replication or findings suggesting lack of treatment effectiveness. Finally, we are making real progress on many fronts, from cognition to genomics. As the articles in Nature note, we still have a long way to go. But this is an important moment to recognize – the “decade for psychiatric disorders” has begun.
Source link: http://www.nimh.nih.gov/about/director/2010/from-cognition-to-genomics-progress-in-schizophrenia-research.shtml
Thursday, November 25, 2010
Sunday, November 14, 2010
Spotlight on Postpartum Depression
Thomas Insel
National Institute of Mental Health (NIMH)
The postpartum period is a time of major adjustment for new parents. Biological changes in mothers that occur after childbirth are often accompanied by significant changes in family roles and responsibilities as well. Generally, postpartum depression (PPD) is thought to be associated with the drastic changes in hormone levels that occur during and just after pregnancy. Couple that with the daunting challenges associated with caring for a newborn, and the estimated 7 to 13 percent prevalence rate i becomes less surprising. And likely, that number is on the low side because like many mental disorders, PPD is generally under-recognized and under-treated. Recently, disorders during the postpartum period have also been described in new fathers. ii
Congress has taken note of the seriousness of PPD as well. The Affordable Care Act of 2010 specifically mentions the need “to continue activities on postpartum [conditions]…including research to expand the understanding of the causes of, and treatments for, postpartum conditions." iii
Consistent with Congressional interest, NIMH recently convened a workshop to encourage innovative research in PPD and other mood disorders that emerge during and after pregnancy. Participants discussed ways to optimize the use of currently available treatments based on a better understanding of individual differences among women. Studies of these individual differences, based on biomarkers, personal history or clinical features, will pave the path to personalized medicine. Meeting participants also discussed how to align new PPD research approaches with broader NIMH priority areas. These include research on comparative effectiveness, cost effectiveness, and global mental health.
The current recommended treatments for women with PPD generally follow the course for any type of major depressive disorder (MDD) and include medication and psychotherapy. We now know that pregnancy is not protective against mental health disorders, and stopping antidepressants during pregnancy may lead to relapse. iv In addition, a mother’s depression can have physical effects on the fetus. But questions remain about how antidepressants affect a growing fetus or nursing baby. v Many pregnant or postpartum women choose not to take these medications. And although psychotherapy has been shown to be effective, getting access to evidence-based treatment can be difficult. So the need for alternatives, better treatments, and better delivery of services is great.
What new treatments are on the horizon? In preliminary trials, 17-beta estradiol, a form of estrogen, was shown to have a relatively rapid antidepressant effect in women with PPD, faster than typical antidepressant medications like SSRIs, which can take up to 8 weeks to start working. And unlike antidepressants, evidence suggests that the increased levels of estrogen associated with the treatment are not detected in breast milk, and therefore presumably do not pass to the nursing newborn. vi
Another NIMH study is modeling the effects of the normal hormonal changes in pregnancy and the postpartum period in non-pregnant women with a history of PPD, and comparing their progress with healthy volunteers. The study is testing whether hormonal events during the postpartum period trigger mood changes in women with PPD. It will serve as a source of information about both the biology of PPD and the factors that could put a woman at risk for developing it. Both of these studies provide evidence that the change in estrogen levels during the postpartum period may be a primary hormonal trigger for PPD.
Other studies are looking at the pathophysiology of PPD by identifying changes in the pregnant and postpartum brain that may help us better understand the neurochemical vulnerability to this disorder. vii In particular, neurosteroids, some of which are the products of progesterone, have long been suspected as mediators of anxiety and recently have been implicated in PPD. In animal studies, the normal massive increase in neurosteroids during pregnancy and precipitous decline at childbirth is usually compensated by a change in GABA receptors in the cortex of the brain. Mice without this compensatory GABA receptor change manifest many of the features of postpartum depression, including profound deficits in maternal care.
We know that women with a history of depression are at higher risk for PPD. What can we do to prevent it? Prevention is still a “work in progress." For example, current NIMH-funded research is investigating cognitive therapy and exercise programs to prevent PPD in pregnant women who are at high risk for PPD. NIMH is also funding studies to improve screening for PPD, web-based interventions and treatment models that use home visits.
These studies are a good start. But we still have a long way to go in treating and preventing PPD, and understanding its long-term impact on families.
Source link: http://www.nimh.nih.gov/about/director/2010/spotlight-on-postpartum-depression.shtml
National Institute of Mental Health (NIMH)
The postpartum period is a time of major adjustment for new parents. Biological changes in mothers that occur after childbirth are often accompanied by significant changes in family roles and responsibilities as well. Generally, postpartum depression (PPD) is thought to be associated with the drastic changes in hormone levels that occur during and just after pregnancy. Couple that with the daunting challenges associated with caring for a newborn, and the estimated 7 to 13 percent prevalence rate i becomes less surprising. And likely, that number is on the low side because like many mental disorders, PPD is generally under-recognized and under-treated. Recently, disorders during the postpartum period have also been described in new fathers. ii
Congress has taken note of the seriousness of PPD as well. The Affordable Care Act of 2010 specifically mentions the need “to continue activities on postpartum [conditions]…including research to expand the understanding of the causes of, and treatments for, postpartum conditions." iii
Consistent with Congressional interest, NIMH recently convened a workshop to encourage innovative research in PPD and other mood disorders that emerge during and after pregnancy. Participants discussed ways to optimize the use of currently available treatments based on a better understanding of individual differences among women. Studies of these individual differences, based on biomarkers, personal history or clinical features, will pave the path to personalized medicine. Meeting participants also discussed how to align new PPD research approaches with broader NIMH priority areas. These include research on comparative effectiveness, cost effectiveness, and global mental health.
The current recommended treatments for women with PPD generally follow the course for any type of major depressive disorder (MDD) and include medication and psychotherapy. We now know that pregnancy is not protective against mental health disorders, and stopping antidepressants during pregnancy may lead to relapse. iv In addition, a mother’s depression can have physical effects on the fetus. But questions remain about how antidepressants affect a growing fetus or nursing baby. v Many pregnant or postpartum women choose not to take these medications. And although psychotherapy has been shown to be effective, getting access to evidence-based treatment can be difficult. So the need for alternatives, better treatments, and better delivery of services is great.
What new treatments are on the horizon? In preliminary trials, 17-beta estradiol, a form of estrogen, was shown to have a relatively rapid antidepressant effect in women with PPD, faster than typical antidepressant medications like SSRIs, which can take up to 8 weeks to start working. And unlike antidepressants, evidence suggests that the increased levels of estrogen associated with the treatment are not detected in breast milk, and therefore presumably do not pass to the nursing newborn. vi
Another NIMH study is modeling the effects of the normal hormonal changes in pregnancy and the postpartum period in non-pregnant women with a history of PPD, and comparing their progress with healthy volunteers. The study is testing whether hormonal events during the postpartum period trigger mood changes in women with PPD. It will serve as a source of information about both the biology of PPD and the factors that could put a woman at risk for developing it. Both of these studies provide evidence that the change in estrogen levels during the postpartum period may be a primary hormonal trigger for PPD.
Other studies are looking at the pathophysiology of PPD by identifying changes in the pregnant and postpartum brain that may help us better understand the neurochemical vulnerability to this disorder. vii In particular, neurosteroids, some of which are the products of progesterone, have long been suspected as mediators of anxiety and recently have been implicated in PPD. In animal studies, the normal massive increase in neurosteroids during pregnancy and precipitous decline at childbirth is usually compensated by a change in GABA receptors in the cortex of the brain. Mice without this compensatory GABA receptor change manifest many of the features of postpartum depression, including profound deficits in maternal care.
We know that women with a history of depression are at higher risk for PPD. What can we do to prevent it? Prevention is still a “work in progress." For example, current NIMH-funded research is investigating cognitive therapy and exercise programs to prevent PPD in pregnant women who are at high risk for PPD. NIMH is also funding studies to improve screening for PPD, web-based interventions and treatment models that use home visits.
These studies are a good start. But we still have a long way to go in treating and preventing PPD, and understanding its long-term impact on families.
Source link: http://www.nimh.nih.gov/about/director/2010/spotlight-on-postpartum-depression.shtml
Saturday, October 30, 2010
In children, hallucinations are not always a sign of psychosis
Current Psychiatry
Vol. 9, No. 10 / October 2010
Although hallucinations frequently are considered synonymous with psychotic disorders, in children this rare. Neurobiologic studies (fMRI) of adults show activation of Broca’s area (left inferior frontal gyrus) seconds before patients perceive auditory verbal hallucinations, which suggests that auditory hallucinations may be misidentified self-talk.a,b According to Piaget,c children age <7 may have difficulty distinguishing between events occurring while dreaming and awake. He further theorized that nonpathologic hallucinations could become pathologic when combined with trauma such as abuse. Straussd suggested that psychosis might lie on a continuum with normal phenomenon. In a case series, Wilking and Paulie described how developmental difficulties, deprivation, sociocultural conditions, and family relationships could contribute to impaired reality testing. Imaginary friends or companions are common among all children. Children who have imaginary friends are more likely to report hearing “voices.”f Imaginary friends: * appear, function, and disappear at the wish of the child * pose no threat and often are a source of comfort * often can be described in detail * are not ego-dystonic Also, children with imaginary friends will not show evidence of a thought disorder.
Full text: http://www.currentpsychiatry.com/article_pages.asp?aid=8973
Vol. 9, No. 10 / October 2010
Although hallucinations frequently are considered synonymous with psychotic disorders, in children this rare. Neurobiologic studies (fMRI) of adults show activation of Broca’s area (left inferior frontal gyrus) seconds before patients perceive auditory verbal hallucinations, which suggests that auditory hallucinations may be misidentified self-talk.a,b According to Piaget,c children age <7 may have difficulty distinguishing between events occurring while dreaming and awake. He further theorized that nonpathologic hallucinations could become pathologic when combined with trauma such as abuse. Straussd suggested that psychosis might lie on a continuum with normal phenomenon. In a case series, Wilking and Paulie described how developmental difficulties, deprivation, sociocultural conditions, and family relationships could contribute to impaired reality testing. Imaginary friends or companions are common among all children. Children who have imaginary friends are more likely to report hearing “voices.”f Imaginary friends: * appear, function, and disappear at the wish of the child * pose no threat and often are a source of comfort * often can be described in detail * are not ego-dystonic Also, children with imaginary friends will not show evidence of a thought disorder.
Full text: http://www.currentpsychiatry.com/article_pages.asp?aid=8973
Brain Molecule May Offer Key to Erasing Fearful Memories
by Jon Hamilton
Scientists have discovered a molecule in the brain that may help erase the fearful memories that afflict people with post-traumatic stress disorder.
The substance, described in an online edition of the journal Science, was found in mice. But it's part of a memory system that seems to work the same way in people.
Roger Clem and Richard Huganir of the Johns Hopkins University School of Medicine made the discovery while studying mice conditioned to associate a particular sound with an electric shock.
"If they hear the tone the next day, or even weeks later, the mouse will freeze" because it will bring up the fearful memory of the shock, Huganir tells Shots.
Clem and Huganir wanted to understand how that fearful memory is created.
So they studied the brains of mice that had just gone through fear conditioning. And they noticed that an unusual protein appeared in the amygdala, a part of the brain involved in emotions.
That molecule remained for only a few days and appeared to strengthen the brain circuit responsible for maintaining the fearful memory.
But when the researchers eliminated the protein during this period, mice lost their fearful memory. Forever.
The trick was to eliminate the protein soon after a fearful incident, Huganir says.
"Maybe this is a window of time when behavioral therapy would work much better," Huganir says, adding that it may also be possible to eliminate the protein with drugs.
And he says research on people suggests that it may be possible to create a new window for treatment by having people deliberately recall a fearful memory.
Researchers from New York University found that when people did that, there was a 6-hour window in which the original memory could be altered permanently through behavioral techniques.
Experiments in rodents suggest that's because the molecule involved in fear memories appears once again in the amygdala, Huganir says.
If so, he says, it may be possible to eliminate a person's unwanted memory during the critical period by giving a drug that interferes with the fear molecule.
Source link: http://www.npr.org/blogs/health/2010/10/29/130913234/brain-molecule-may-offer-key-to-erasing-fearful-memories-treating-ptsd?ft=1&f=1007
Scientists have discovered a molecule in the brain that may help erase the fearful memories that afflict people with post-traumatic stress disorder.
The substance, described in an online edition of the journal Science, was found in mice. But it's part of a memory system that seems to work the same way in people.
Roger Clem and Richard Huganir of the Johns Hopkins University School of Medicine made the discovery while studying mice conditioned to associate a particular sound with an electric shock.
"If they hear the tone the next day, or even weeks later, the mouse will freeze" because it will bring up the fearful memory of the shock, Huganir tells Shots.
Clem and Huganir wanted to understand how that fearful memory is created.
So they studied the brains of mice that had just gone through fear conditioning. And they noticed that an unusual protein appeared in the amygdala, a part of the brain involved in emotions.
That molecule remained for only a few days and appeared to strengthen the brain circuit responsible for maintaining the fearful memory.
But when the researchers eliminated the protein during this period, mice lost their fearful memory. Forever.
The trick was to eliminate the protein soon after a fearful incident, Huganir says.
"Maybe this is a window of time when behavioral therapy would work much better," Huganir says, adding that it may also be possible to eliminate the protein with drugs.
And he says research on people suggests that it may be possible to create a new window for treatment by having people deliberately recall a fearful memory.
Researchers from New York University found that when people did that, there was a 6-hour window in which the original memory could be altered permanently through behavioral techniques.
Experiments in rodents suggest that's because the molecule involved in fear memories appears once again in the amygdala, Huganir says.
If so, he says, it may be possible to eliminate a person's unwanted memory during the critical period by giving a drug that interferes with the fear molecule.
Source link: http://www.npr.org/blogs/health/2010/10/29/130913234/brain-molecule-may-offer-key-to-erasing-fearful-memories-treating-ptsd?ft=1&f=1007
Thursday, October 28, 2010
Reversal of Depressed Behaviors in Mice by p11 Gene Therapy in the Nucleus Accumbens
Sci Transl Med 20 October 2010: Vol. 2, Issue 54, p. 54ra76
ABSTRACT
The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT1B)] and serotonin 4 (5-HT4) receptor–binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)–mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.
Source link: http://stm.sciencemag.org/content/2/54/54ra76.abstract
Full Text: http://stm.sciencemag.org/content/2/54/54ra76.full
ABSTRACT
The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT1B)] and serotonin 4 (5-HT4) receptor–binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)–mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.
Source link: http://stm.sciencemag.org/content/2/54/54ra76.abstract
Full Text: http://stm.sciencemag.org/content/2/54/54ra76.full
Tuesday, October 26, 2010
Nature Neuroscience: November 2010, Volume 13 No 11 pp1299-1440
Current issue
November 2010, Volume 13 No 11 pp1299-1440
Life experiences affect behavior, in part by altering DNA via epigenetic modifications. These epigenetic changes include histone or chromatin modifications and can silence genes or make them easier to read. Recently, neuroscientists have also begun to explore epigenetic mechanisms to help explain the influence of experiences on not only long-term behavior, but also on neural development and function. Nature Neuroscience presents a special focus on this growing field of neural epigenetics consisting of commentaries, perspectives and reviews. These articles highlight the latest advances in our understanding of these epigenetic mechanisms, their regulation and their role in the nervous system.
Editorial
Focus on Epigenetics
Focus on epigenetics - p1299
doi:10.1038/nn1110-1299
We present a special focus on epigenetics in the nervous system, highlighting recent advances in our understanding of epigenetic mechanisms and their regulation in neurons, as well as their role in nervous system function.
Book Review
Taking animal rights personally - p1301
An Odyssey with Animals: A Veterinarian's Reflections on the Animal Rights & Welfare Debate by Adrian R Morrison
doi:10.1038/nn1110-1301
News and Views
Bringing SOD1 into the fold - pp1303 - 1304
Sami Barmada & Steven Finkbeiner
doi:10.1038/nn1110-1303
Could similar changes in superoxide dismutase 1 (SOD1) underlie both familial and sporadic amyotrophic lateral sclerosis (ALS)? A new study finds that wild-type SOD1 from sporadic ALS tissues shows conformational changes similar to those seen in familial ALS and may be pathogenic as a result of the same mechanism.
See also: Article by Bosco et al.
Categorizing speech - pp1304 - 1306
Sophie K Scott & Samuel Evans
doi:10.1038/nn1110-1304
Using direct electrode recordings in patients undergoing preoperative surgery, a new study demonstrates that neural responses in the secondary auditory cortex mirror perception, showing categorical responses to continuous stimuli.
See also: Article by Chang et al.
“Yes! We're all individuals!”: redundancy in neuronal circuits - pp1306 - 1307
Timothy E Holy
doi:10.1038/nn1110-1306
In the mouse olfactory bulb, cells with common input respond to odors with similar firing rates but with different timing. This suggests that such 'sister' cells make independent and unique connections with local interneurons.
Full Text - “Yes! We're all individuals!”: redundancy in neuronal circuits | PDF (260 KB) - “Yes! We're all individuals!”: redundancy in neuronal circuits
See also: Article by Dhawale et al.
Making glutamatergic neurons from GABAergic progenitors - pp1308 - 1309
Magdalena Götz
doi:10.1038/nn1110-1308
The mature phenotype of CNS neurons is thought to be set at an early progenitor stage. A study now shows that expression of Fezf2 alone can turn striatal GABAergic precursors into glutamatergic corticofugal neurons.
Full Text - Making glutamatergic neurons from GABAergic progenitors | PDF (183 KB) - Making glutamatergic neurons from GABAergic progenitors
See also: Brief Communication by Rouaux & Arlotta
I see where you're hearing: how cross-modal plasticity may exploit homologous brain structures - pp1309 - 1311
Daphne Bavelier & Elizabeth A Hirshorn
doi:10.1038/nn1110-1309
Sensory deprivation such as deafness or blindness leads to specific functional and neural reorganization. A new study gives insight into why and how certain abilities change, while others remain unaltered after the loss of a sense.
Full Text - I see where you're hearing: how cross-modal plasticity may exploit homologous brain structures | PDF (456 KB) - I see where you're hearing: how cross-modal plasticity may exploit homologous brain structures
See also: Article by Lomber et al.
The importance of degradation - p1311
Annette Markus
doi:10.1038/nn1110-1311
See also: Article by Hoeck et al.
Commentary
Focus on Epigenetics
Epigenetic regulation of the neural transcriptome: the meaning of the marks - pp1313 - 1318
Michael J Meaney & Anne C Ferguson-Smith
doi:10.1038/nn1110-1313
This commentary provides a nuanced discussion on the conceptual framework to study epigenetic mechanisms that regulate brain function and plasticity. By drawing from examples in genomic imprinting, the authors highlight the challenges facing epigenetics research in the context of neuroscience.
Perspectives
Focus on Epigenetics
DNA methylation and memory formation - pp1319 - 1323
Jeremy J Day & J David Sweatt
doi:10.1038/nn.2666
Disruption of DNA methylation in the brain can impair learning and memory in rodents. In this Perspective, Day and Sweatt provide an overview of evidence that implicates this epigenetic mechanism in memory processes and discuss how past controversies can be explained in light of recent findings.
Focus on Epigenetics
Plasticity and specificity of the circadian epigenome - pp1324 - 1329
Selma Masri & Paolo Sassone-Corsi
doi:10.1038/nn.2668
This perspective discusses the role of epigenetic mechanisms in regulating circadian rhythms, and emphasizes that the role of peripheral machinery is key for a fuller understanding of this regulation.
Reviews
Focus on Epigenetics
Dynamic epigenetic regulation in neurons: enzymes, stimuli and signaling pathways - pp1330 - 1337
Antonella Riccio
doi:10.1038/nn.2671
This Review discusses the current knowledge regarding regulation of epigenetic modifications and mechanisms in the nervous system in response to dynamic signals such as developmental stage, growth factors and synaptic activity.
Focus on Epigenetics
Epigenetic choreographers of neurogenesis in the adult mammalian brain - pp1338 - 1344
Dengke K Ma, Maria Carolina Marchetto, Junjie U Guo, Guo-li Ming, Fred H Gage & Hongjun Song
doi:10.1038/nn.2672
This review examines evidence supporting diverse roles for epigenetic mechanisms in regulating specific aspects of adult neurogenesis and their implications.
Brief Communications
Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo - pp1345 - 1347
Caroline Rouaux & Paola Arlotta
doi:10.1038/nn.2658
Rouaux and Arlotta show that expression of a single transcription factor, Fezf2, suffices to turn ventral forebrain progenitors committed to a striatal GABAergic fate into glutamatergic corticofugal projection neurons—which nevertheless migrate to the striatum.
Abstract - Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo | Full Text - Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo | PDF (1,240 KB) - Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo | Supplementary information
See also: News and Views by Götz
N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release - pp1348 - 1350
Alexander M Weber, Fiona K Wong, Adele R Tufford, Lyanne C Schlichter, Victor Matveev & Elise F Stanley
doi:10.1038/nn.2657
The established conductance hierarchy of voltage-gated calcium channels, where conductance of CaV1 is greater than CaV2, which is in turn greater than CaV3, was determined using nonphysiological divalent ion concentrations. Weber et al. find that CaV2.2 conductance is greater than that of CaV1 and CaV3 and investigate implications for Ca2+ nanodomain signaling.
Abstract - N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release | Full Text - N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release | PDF (431 KB) - N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release | Supplementary information
Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice - pp1351 - 1353
Evan Elliott, Gili Ezra-Nevo, Limor Regev, Adi Neufeld-Cohen & Alon Chen
doi:10.1038/nn.2642
Corticotrophin releasing factor (CRF) and its receptors are involved in the neuroendocrine and behavioral responses to stress. Here, Elliot and colleagues describe alterations in DNA methylation of the Crf gene that regulate its expression and show that these alterations correlate with resilience to social stress.
Abstract - Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice | Full Text - Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice | PDF (383 KB) - Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice | Supplementary information
The habenula is crucial for experience-dependent modification of fear responses in zebrafish - pp1354 - 1356
Masakazu Agetsuma, Hidenori Aizawa, Tazu Aoki, Ryoko Nakayama, Mikako Takahoko, Midori Goto, Takayuki Sassa, Ryunosuke Amo, Toshiyuki Shiraki, Koichi Kawakami, Toshihiko Hosoya, Shin-ichi Higashijima & Hitoshi Okamoto
doi:10.1038/nn.2654
Agetsuma and colleagues find that the pathway between the lateral subnucleus of the dorsal habenula (dHbL) and the interpeduncular nucleus is involved in mediating experience-dependent fear responses in zebrafish. Genetic inactivation of the dHbL biased fish towards freezing, rather than the typical flight behavior, in response to a conditioned fear stimulus.
Abstract - The habenula is crucial for experience-dependent modification of fear responses in zebrafish | Full Text - The habenula is crucial for experience-dependent modification of fear responses in zebrafish | PDF (587 KB) - The habenula is crucial for experience-dependent modification of fear responses in zebrafish | Supplementary information
Articles
APC/CFzr/Cdh1-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS - pp1357 - 1364
Marion Silies & Christian Klämbt
doi:10.1038/nn.2656
For young glia to migrate along motor axons in the developing fly, their adhesion to the axon must be broken. Silies and Klämbt show that this is accomplished by removal of Fas2 from the axonal membrane, involving a ubiquitin ligase complex that has previously been implicated only in cell cycle regulation.
Abstract - APC/CFzr/Cdh1-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS | Full Text - APC/CFzr/Cdh1-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS | PDF (2,543 KB) - APC/CFzr/Cdh1-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS | Supplementary information
Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun - pp1365 - 1372
Joerg D Hoeck, Anett Jandke, Sophia M Blake, Emma Nye, Bradley Spencer-Dene, Sebastian Brandner & Axel Behrens
doi:10.1038/nn.2644
This study demonstrates that Fbw7, a component of ubiquitin ligase complex, regulates neural progenitor cell viability and differentiation by controlling Notch and JNK/c-Jun signaling.
Abstract - Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun | Full Text - Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun | PDF (3,220 KB) - Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun | Supplementary information
See also: News and Views by Markus
The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching - pp1373 - 1379
Freddy Jeanneteau, Katrin Deinhardt, Goichi Miyoshi, Anton M Bennett & Moses V Chao
doi:10.1038/nn.2655
How extracellular signals, such as BDNF, regulate axonal branching is unclear. Here, Jeanneteau et al. find that MAP kinase phosphatase 1 expression is induced by BDNF signaling to deactivate JNK. This negatively regulates phosphorylation of JNK substrates that impinge on microtubule destabilization. Neurons from mkp-1 null mice were unable to produce BDNF-induced axon branches.
Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway - pp1380 - 1387
Coralie Fassier, James A Hutt, Steffen Scholpp, Andrew Lumsden, Bruno Giros, Fatiha Nothias, Sylvie Schneider-Maunoury, Corinne Houart & Jamilé Hazan
doi:10.1038/nn.2662
Hereditary spastic paraplegia (HSP) is manifested as motor dysfunction stemming from axonal degeneration. Of the known 19 spastic paraplegia genes (SPGs), SPG3a encodes a multimeric integral membrane protein Atlastin. Here, the authors use zebrafish system to demonstrate the interplay between Atlastin and bone morphogenic protein signaling in motor axon development and stability.
Abstract - Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway | Full Text - Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway | PDF (2,208 KB) - Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway | Supplementary information
A crosstalk between β1 and β3 integrins controls glycine receptor and gephyrin trafficking at synapses - pp1388 - 1395
Cécile Charrier, Patricia Machado, Ry Y Tweedie-Cullen, Dorothea Rutishauser, Isabelle M Mansuy & Antoine Triller
doi:10.1038/nn.2645
Integrins connect cells to the extracellular matrix and mediate neuron-neuron or neuron-glia interactions during synapse maturation and synaptic plasticity. Here, Charrier et al. find that integrins β1 and β3 exert opposing actions via CaMKII to regulate glycine receptor lateral diffusion and gephyrin trafficking at the inhibitory synapses in spinal cord neurons.
Abstract - A crosstalk between [beta]1 and [beta]3 integrins controls glycine receptor and gephyrin trafficking at synapses | Full Text - A crosstalk between β1 and β3 integrins controls glycine receptor and gephyrin trafficking at synapses | PDF (1,258 KB) - A crosstalk between β1 and β3 integrins controls glycine receptor and gephyrin trafficking at synapses | Supplementary information
Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS - pp1396 - 1403
Daryl A Bosco, Gerardo Morfini, N Murat Karabacak, Yuyu Song, Francois Gros-Louis, Piera Pasinelli, Holly Goolsby, Benjamin A Fontaine, Nathan Lemay, Diane McKenna-Yasek, Matthew P Frosch, Jeffrey N Agar, Jean-Pierre Julien, Scott T Brady & Robert H Brown Jr
doi:10.1038/nn.2660
Could similar changes in SOD1 underlie both familial and sporadic ALS? Here, Bosco et al. find that wild-type SOD1 from sporadic ALS tissues shows conformational changes similar to those seen in familial ALS and that aberrant wild-type SOD1 can be pathogenic, potentially as a result of the same SOD1-dependent mechanism seen in familial ALS.
Abstract - Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS | Full Text - Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS | PDF (1,376 KB) - Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS | Supplementary information
See also: News and Views by Barmada & Finkbeiner
Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse - pp1404 - 1412
Ashesh K Dhawale, Akari Hagiwara, Upinder S Bhalla, Venkatesh N Murthy & Dinu F Albeanu
doi:10.1038/nn.2673
Using optogenetic techniques, Dhawale et al. find that, although sister mitral cells (which receive input from the same olfactory glomerulus) have highly correlated average spike rate responses, their spike timing with respect to respiration differs. This suggests that sister cells carry both correlated and independent information.
Abstract - Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse | Full Text - Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse | PDF (1,695 KB) - Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse | Supplementary information
See also: News and Views by Holy
The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits - pp1413 - 1420
Hysell V Oviedo, Ingrid Bureau, Karel Svoboda & Anthony M Zador
doi:10.1038/nn.2659
Primary auditory cortex is organized tonotopically along one axis. Using laser scanning photostimulation in acute slices, the authors find that local connections along the tonotopic axis differ from those along the orthogonal, isofrequency axis.
Abstract - The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits | Full Text - The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits | PDF (2,543 KB) - The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits | Supplementary information
Cross-modal plasticity in specific auditory cortices underlies visual compensations in the deaf - pp1421 - 1427
Stephen G Lomber, M Alex Meredith & Andrej Kral
doi:10.1038/nn.2653
Lomber and colleagues find that enhanced visual localization and motion detection in deaf cats is subserved by cross-modal reorganization of cortex that is typically dedicated to auditory function. Furthermore, the authors localize the individual visual functions to discrete portions of reorganized auditory cortex.
Abstract - Cross-modal plasticity in specific auditory cortices underlies visual compensations in the deaf | Full Text - Cross-modal plasticity in specific auditory cortices underlies visual compensations in the deaf | PDF (1,097 KB) - Cross-modal plasticity in specific auditory cortices underlies visual compensations in the deaf | Supplementary information
See also: News and Views by Bavelier & Hirshorn
Categorical speech representation in human superior temporal gyrus - pp1428 - 1432
Edward F Chang, Jochem W Rieger, Keith Johnson, Mitchel S Berger, Nicholas M Barbaro & Robert T Knight
doi:10.1038/nn.2641
A continuum of acoustically varying speech sounds is not perceived as a continuum, but as distinct phonetic categories. Chang et al. recorded directly from human posterior superior temporal gyrus and found that this area has a similarly discontinuous coding of objectively continuous sound, matching perception and indicating higher-level processing.
Abstract - Categorical speech representation in human superior temporal gyrus | Full Text - Categorical speech representation in human superior temporal gyrus | PDF (691 KB) - Categorical speech representation in human superior temporal gyrus | Supplementary information
See also: News and Views by Scott & Evans
Technical Report
Functional imaging of hippocampal place cells at cellular resolution during virtual navigation - pp1433 - 1440
Daniel A Dombeck, Christopher D Harvey, Lin Tian, Loren L Looger & David W Tank
doi:10.1038/nn.2648
Dombeck and colleagues describe a method for two-photon calcium imaging using a genetically encoded indicator in the hippocampus of awake, behaving mice. This powerful approach permits the recording of multiple hippocampal place cells' activity with subcellular resolution as the mice run on a track in a virtual reality environment.
Abstract - Functional imaging of hippocampal place cells at cellular resolution during virtual navigation | Full Text - Functional imaging of hippocampal place cells at cellular resolution during virtual navigation | PDF (1,597 KB) - Functional imaging of hippocampal place cells at cellular resolution during virtual navigation |
Meridia (sibutramine): Market Withdrawal Due to Risk of Serious Cardiovascular Events
FDA U.S. Food and Drug Administration
AUDIENCE: Primary Care, Consumers
ISSUE: Abbott Laboratories and FDA notified healthcare professionals and patients about the voluntary withdrawal of Meridia (sibutramine), an obesity drug, from the U.S. market because of clinical trial data indicating an increased risk of heart attack and stroke.
BACKGROUND: Meridia was approved November 1997 for weight loss and maintenance of weight loss in obese people, as well as in certain overweight people with other risks for heart disease. The approval was based on clinical data showing that more people receiving sibutramine lost at least 5 percent of their body weight than people on placebo who relied on diet and exercise alone. FDA has now requested market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT is part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of the drug. The trial demonstrated a 16 percent increase in the risk of serious heart events, including non-fatal heart attack, non-fatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine compared with another given placebo. There was a small difference in weight loss between the placebo group and the group that received sibutramine.
RECOMMENDATION: Physicians are advised to stop prescribing Meridia to their patients, and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs.
Source link: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm228830.htm
AUDIENCE: Primary Care, Consumers
ISSUE: Abbott Laboratories and FDA notified healthcare professionals and patients about the voluntary withdrawal of Meridia (sibutramine), an obesity drug, from the U.S. market because of clinical trial data indicating an increased risk of heart attack and stroke.
BACKGROUND: Meridia was approved November 1997 for weight loss and maintenance of weight loss in obese people, as well as in certain overweight people with other risks for heart disease. The approval was based on clinical data showing that more people receiving sibutramine lost at least 5 percent of their body weight than people on placebo who relied on diet and exercise alone. FDA has now requested market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT is part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of the drug. The trial demonstrated a 16 percent increase in the risk of serious heart events, including non-fatal heart attack, non-fatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine compared with another given placebo. There was a small difference in weight loss between the placebo group and the group that received sibutramine.
RECOMMENDATION: Physicians are advised to stop prescribing Meridia to their patients, and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs.
Source link: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm228830.htm
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