BISA features latetst NEWS in the field of Science
Their discovery has important implications for understanding the underlying causes of neurological diseases such as Alzheimer's disease and for restoring memory in areas of the brain that are necessary for orientation.
"This work is the first to demonstrate that oscillatory activity has a well-defined function in brain areas that store memories," says Stefan Leutgeb, an assistant professor of biology at UCSD who headed the team of researchers.
News in Brief: Body & Brain Electrical Oscillations Found to Be Critical for Storing Spatial Memories in Brain
The scientists report in the April 29 issue of the journal Science that neurons called "grid cells" that create maps of the external environment in one portion of our brain require precisely timed electrical oscillations in order to function properly from another part of the brain that serves as a kind of neural pacemaker.Their discovery has important implications for understanding the underlying causes of neurological diseases such as Alzheimer's disease and for restoring memory in areas of the brain that are necessary for orientation.
"This work is the first to demonstrate that oscillatory activity has a well-defined function in brain areas that store memories," says Stefan Leutgeb, an assistant professor of biology at UCSD who headed the team of researchers.
Herpes sheds anytime
People carrying the contagious virus that causes genital herpes can unwittingly shed the pathogen and expose sex partners even if they never have symptoms, researchers at the University of Washington in Seattle and colleagues report in the April 13 Journal of the American Medical Association. But people who do get symptoms shed the virus more often. The scientists asked 410 people with symptomatic herpes and 88 infected people without symptoms to take daily swabs of their genital areas. These samples showed that the symptomatic people shed the virus on 20 percent of days compared with 10 percent of days in the people who showed no symptoms. It is estimated that 16 percent of U.S. adults have herpes simplex-2, but less than one-quarter of that group gets symptoms. —Nathan Seppa
More bad news on ecstasy
The club drug ecstasy may carry long-term cognitive risks, a Dutch research team finds. The scientists conducted magnetic resonance imaging on 10 young men who on average had taken 281 ecstasy tablets each over the previous six years, and also tested seven men who didn’t use the drug but who were similar to the users in other respects. The MRI brain scans showed that the users had roughly 5 percent less brain gray matter by volume than the nonusers. Reporting online April 6 in the Journal of Neurology, Neurosurgery and Psychiatry, the researchers also noted that volume of the hippocampus — the part of the brain that stores long-term memories — was 10 percent smaller in the drug users. —Nathan Seppa
High-fat diet’s quick effects on heart and brain
A high-fat, low-carb diet can trigger worrisome changes in the body in less than a week. University and hospital researchers in Oxford, England, fed 16 college-age men two different diets for five days each. One diet derived 75 percent of its calories from fat, the other got just 23 percent from fat. “Cognitive tests showed impaired attention, speed and mood after the high-fat, low-carbohydrate diet,” the researchers report in the April American Journal of Clinical Nutrition. Moreover, the scientists found that the high-fat diet boosted chemical markers of impaired heart metabolism and function in the volunteers. —Janet Raloff
Small body, big world
SAN FRANCISCO — When people are tricked into thinking their bodies are the size of Barbie’s boyfriend Ken, their world seems much bigger, a new study finds. And when the fake body is the size of a 4-meter-tall giant, the world seems to shrink. Researchers led by Henrik Ehrsson of the Karolinska Institute in Stockholm used sophisticated head-mounted cameras and simultaneous touches to a doll and the study volunteer to induce the body-swapping illusion. People who had been shrunk judged objects to be much larger than the objects were, and judged distances to be farther, too. The opposite was true for people who had been giant-sized. The results were presented April 2 at the annual meeting of the Cognitive Neuroscience Society. —Laura Sanders
Resetting elderly sleep clocks
Blame the early-bird special on a hormone imbalance. As people get older, they get up earlier, go to bed earlier and need more naps. Scientists used to think the change in sleep habits happened because molecular clocks that govern the body’s daily rhythms broke down. But researchers in Switzerland report online April 11 in the Proceedings of the National Academy of Sciences that early-to-bed, early-to-rise is in the blood. Older people’s daily, or circadian, clocks work fine; they are just being set wrong by some still-unknown hormone. The finding suggests sleep problems in the elderly might be fixable with therapies. —Tina Hesman Saey
The aging brain is perhaps the most fragile of tissues, with a population of structurally elaborate and metabolically demanding neurons that are seldom replenished during adulthood. Neurodegenerative disorders such as Alzheimer's disease (AD) and acute insults such as an ischemic stroke lead to seemingly irreparable damage that impairs cognitive and/or motor function. Considerable evidence suggests that the vulnerability of neurons to aging and associated disorders can be modified by environmental factors including dietary energy intake and exercise [1,2,3]. Energy (caloric) restriction (CR) and exercise induce the expression of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), cytoprotective protein chaperones, and proteins that can prevent apoptosis. The mechanisms responsible for the neuro-protective effects of CR and exercise are mediated, in part, by changes in gene transcription [3]. However, new findings reported in this issue of Aging suggest a role for down-regulation of microRNAs (miRNAs) that target mRNAs encoding cell survival proteins in the beneficial effects of CR on the aging brain [4].
miRNAs are short non-coding RNAs that typically bind to scores of transcripts an inhibit translation of the targeted mRNA [5]. Khanna et al found that levels of three miRNAs (miR-34a, miR30e and miR181-a-1*) are significantly lower in brain tissue samples from old mice (24-28 months-old) that had been maintained on a CR diet (40% CR beginning at 4 months of age) compared to mice on the usual ad libitum diet. Interestingly, all three of these miRNAs were predicted to have at least one target site for Bcl2, an anti-apoptotic protein previously been shown to increase with CR. The authors confirmed the repressive action of these miRNAs on Bcl2. These changes in miRNA expression were validated in both cortical and hippocampal tissues, suggesting a more global repression of these miRNAs in the CNS due to CR.
Although the authors chose to solely investigate Bcl2 as a target of these three miRNAs in mediating the beneficial effects of CR, eight additional shared mRNA targets were found using multiple target-prediction algorithms. One of these targets, cAMP response element binding protein 1 (CREB1), is an important activator of several immediate response genes that are critical to synaptic plasticity [6]. Repression of CREB1 by these three age-dependent miRNAs could play a role in the cognitive decline observed with aging. Additionally, huntingtin (Htt) is a predicted target of these miRNAs, and this possible interaction may play a role in the beneficial effects of dietary energy restriction in Htt mutant mice, a model of Huntington's disease [7]. Moreover, previous research demonstrated that miR-30a, which has an identical seed region to miR-30e acts to functionally repress BDNF expression in the cortex [8]. Up-regulation of BDNF by CR has been shown to mediate, in part, the increased neurogenesis by CR and is also thought to play an important role in learning and memory [9,10]. Although not explored by Khanna and colleagues in the context of CR, the regulation of BDNF by the miR-34 family represents yet another potential avenue for miRNAs as mediators of effects of dietary energy intake on neuronal vulnerability in aging and disease.
It will be important to determine whether changes in the expression of miRNAs 34a, 30e, and 181a do in fact mediate effects of energy intake on neuronal vulnerability. This might be accomplished by overexpressing or knocking down each of these miRNAs in neurons of interest in animal models of Alzheimer's, Parkinson's and Huntington's diseases. Whether Bcl-2 is a pivotal target of this miRNAs could be determined in experiments with Bcl-2 deficient mice. It seems likely that the findings of Khanna et al. [4] represent the ‘tip of the iceberg' with regards to miRNAs in brain aging and disease as there are undoubtedly numerous other miRNAs and target mRNAs involved in regulating neuronal survival and plasticity. This arena of research is a promising area for the development of novel therapeutic interventions in neurodegenerative disorders. Indeed, multiple miRNAs appear to be dysregulated in neurological diseases [5]. Initial studies in non-human primates have further emphasized the potential for miRNA-based theraputics [11]. The work by Khanna and colleagues suggest a potential for miRNA-based therapies that utilize the same anti-apoptic mechanisms as CR. However, as a single miRNA can regulate hundreds of transcripts, systemic delivery of a miRNA mimetic or sponge may result in undesirable off-target and tissue specific effects.
REFERENCES
- Stranahan AM, Mattson MP. Impact of energy intake and expenditure on neuronal plasticity. Neuromolecular Med. 2008; 10: 209-218.
- Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev. 2006; 5: 332-353.
- Stranahan AM, Mattson MP. Bidirectional metabolic regulation of neurocognitive function. Neurobiol Learn Mem. 2011 Jan 12. [Epub ahead of print].
- Khanna A, Muthusamy S, Liang R, Sarojini H, Wang E. Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging 2011; this issue.
- Hutchison ER, Okun E, Mattson MP. The therapeutic potential of microRNAs in nervous system damage, degeneration, and repair. Neuromolecular Med. 2009; 11: 153-161.
- Deisseroth K, Mermelstein PG, Xia H, Tsien RW. Signaling from synapse to nucleus: the logic behind the mechanisms. Curr Opin Neurobiol. 2003; 13: 354-365.
- Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A. 2003; 100:2911-2916.
- Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S. A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Hum Mol Genet. 2008; 17: 3030-3042.
- Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002; 82: 1367-1375.
- Mattson MP, Duan W, Wan R, Guo Z. Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations. NeuroRx. 2004; 1: 111-116.
- Elmén J, Lindow M, Schütz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjärn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S. LNA-mediated microRNA silencing in non-human primates. Nature. 2008; 452: 896-899.
'Thunder' Protein Regulates Memory Formation
Researchers at Johns Hopkins have discovered in mice a molecular wrecking ball that powers the demolition phase of a cycle that occurs at synapses -- those specialized connections between nerve cells in the brain -- and whose activity appears critical for both limiting and enhancing learning and memory.
The newly revealed protein, which the researchers named thorase after Thor, the Norse god of thunder, belongs to a large family of enzymes that energize not only neurological construction jobs but also deconstruction projects. The discovery is described in the April 15 issue of Cell.
"Thorase is vital for keeping in balance the molecular construction-deconstruction cycle we believe is required for memory formation," explains Valina Dawson, professor of neurology and neuroscience in the Johns Hopkins Institute of Cell Engineering. "It's a highly druggable target, which, depending on whether you enhance or inactivate it, may potentially result in new treatments for autism, PTSD, and memory dysfunction."
The enzyme is one of many AAA+ ATPases that drive the assembly of proteins needed to form specialized receptors at the surfaces of synapses. These receptors are stimulated by neighboring neurons, setting up the signaling and answering connections vital to brain function. The Hopkins team showed how thorase regulates the all-important complementary process of receptor disassembly at synapses, which ultimately tamps down signaling.
Prolonged excitation or inhibition of these receptors -- due to injury, disease, genetic malfunction or drugs -- has been implicated in a wide array of learning and memory disorders.
"Change in the strength of the connections between two nerve cells forms the basis of our ability to learn and remember," Dawson says. This phenomenon, called synaptic plasticity, depends upon a balanced alternation of excitation and inhibition of receptors, she adds.
Using a powerful microscope to look at labeled neurons from the brains of mice, the scientists saw that thorase was concentrated in the synaptic regions of cells, leading them to focus studies on the protein interactions that happen there.
First, they cut a protein aptly called GRIP1 -- it acts as scaffolding to hold GluR2 receptors to the surface -- into various chunks and combined it with thorase. Encouraged by the fact that thorase and the GRIP1 scaffold did indeed bind tightly, they teased out the physiology of that interaction in the presence of lots of thorase and then no thorase.
They discovered that the more thorase, the quicker the scaffolding deconstructed and the faster the surface receptors decreased. Thorase causes GluR2 receptors and GRIP1 to release their hold on each other, and therefore the receptor's grip at the surface of the synapse, they concluded.
To see if the deconstruction of the protein complex had any effect on nerve-signaling processes, they again used cells to record receptor activity by measuring electric currents as they fluxed through cells with and without thorase. In the presence of extra thorase, surface receptor expression was decreased, resulting in reduced signaling.
Next, the team measured the rates of receptor recycling by tagging the protein complex with a fluorescent marker. It could then be tracked as it was subsequently reinserted back into the surface membrane of a cell. In cells in which thorase was knocked out, there was very little deconstruction/turnover compared to normal cells. The scientists reversed the process by adding back thorase.
Finally, the team conducted a series of memory tasks in order to compare the behaviors of normal mice with those genetically modified to lack thorase. When the animals lacking thorase were put into a simple maze, their behaviors revealed they had severe deficits in learning and memory.
"Mice lacking thorase appear to stay in a constant state of stimulation, which prevents memory formation," Dawson explains. "Their receptors get up to the membrane where they are stimulated, but they aren't being recycled if thorase isn't present. If thorase doesn't stop the excitation by recycling the receptor, it continues on and has deleterious effects."
Support for this research came from the National Institute for Aging and the Intramural Research Program of the National Institute on Aging, McKnight Endowment for Neuroscience, American Heart Association and the Simon's Foundation Autism Research Initiative.
Authors of the paper, in addition to Valina Dawson, are Jianmin Zhang, Yue Wang, Zhikai Chi, Matthew J. Keuss, Ying-Min Emily Pai, Ho Chul Kang, Jooho Shin, Artem Bugayenko, Hong Wang, Yulan Xiong, Mikhail V. Pletnikov, Mark P. Mattson, and Ted M. Dawson, all of Johns Hopkins.
Obesity and the inflammasome
High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1β plays a role in insulin resistance, yet how IL-1β is induced by the fatty acids in an HFD, and how this alters insulin signaling, is unclear. We show that the saturated fatty acid palmitate, but not unsaturated oleate, induces the activation of the NLRP3-ASC inflammasome, causing caspase-1, IL-1β and IL-18 production. This pathway involves mitochondrial reactive oxygen species and the AMP-activated protein kinase and unc-51–like kinase-1 (ULK1) autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in several target tissues to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1β affects insulin sensitivity through tumor necrosis factor–independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D.
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Stem cell 'Itch'
Although hematopoietic stem cells (HSCs) are the most thoroughly characterized type of adult stem cell, the intricate molecular machinery that regulates their self-renewal properties remains elusive. Here we showed that the E3 ubiquitin ligase Itch negatively regulated the development and function of HSCs. Itch−/− mice had HSCs with enhanced frequency, competence and long-term repopulating activity. Itch-deficient HSCs showed accelerated proliferation rates and sustained progenitor properties, as well as more signaling by the transcription factor Notch1, due to more accumulation of activated Notch1. Knockdown of Notch1 in Itch-mutant HSCs resulted in reversion of the phenotype. Thus, we identify Itch as a previously unknown negative regulator of HSC homeostasis and function.
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