Piatti V.C.,Leloir Institute |
Davies-Sala M.G.,Leloir Institute |
Esposito M.S.,Leloir Institute |
Mongiat L.A.,Leloir Institute |
And 2 more authors.
Journal of Neuroscience | Year: 2011
The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturationwhentheir intrinsic electrical activity was reduced by the cell-autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus. © 2011 the authors.
Stella F.,International School for Advanced Studies |
Si B.,Weizmann Institute of Science |
Kropff E.,Leloir Institute |
Treves A.,International School for Advanced Studies |
Treves A.,Norwegian University of Science and Technology
Behavioral and Brain Sciences | Year: 2013
We show that, given extensive exploration of a three-dimensional volume, grid units can form with the approximate periodicity of a face-centered cubic crystal, as the spontaneous product of a self-organizing process at the single unit level, driven solely by firing rate adaptation. Copyright © 2013 Cambridge University Press.
Fresno C.,Catholic University of Córdoba |
Llera A.S.,CONICET |
Llera A.S.,Leloir Institute |
Girotti M.R.,CONICET |
And 10 more authors.
Computers in Biology and Medicine | Year: 2012
Set enrichment analysis (SEA) is used to identify enriched biological categories/terms within high-throughput differential expression experiments. This is done by evaluating the proportion of differentially expressed genes against a background reference (BR). However, the choice of the ". appropriate" BR is a perplexing problem and results will depend on it.Here, a visualization procedure that integrates results from several BRs and a stability analysis of enriched terms is presented as a tool to aid SEA. The multi-reference contrast method (MRCM) combines results from multiple BRs in a unique picture. The application of the proposed method was illustrated in one proteomic and three microarray experiments. The MRCM facilitates the exploration task involved in ontology analysis on proteomic/genomic experiments, where consensus terms were found to validate main experimental hypothesis. The use of more than one reference may provide new biological insights. The tool automatically highlights non-consensus terms assisting SEA. © 2011 Elsevier Ltd.
News Article | October 27, 2016
Babies and children undergo massive brain restructuring as they mature, and for good reason—they have a whole world of information to absorb during their sprint toward adulthood. This mental renovation doesn’t stop there, however. Adult brains continue to produce new cells and restructure themselves throughout life, and a new study in mice reveals more about the details of this process and the important role environmental experience plays. Through a series of experiments, researchers at the Leloir Institute in Buenos Aires showed that when adult mice are exposed to stimulating environments, their brains are able to more quickly integrate new brain cells into existing neural networks through a process that involves new and old cells connecting to one another via special helper cells called interneurons. The adult mammalian brain, long believed to lack the capacity to make new cells, has two main areas that continuously produce new neurons throughout life. One of these areas, the hippocampus (which is involved in memory, navigation, mood regulation and stress response) produces new neurons in a specialized region called the dentate gyrus. Many previous studies have focused on how the dentate gyrus produces new neurons and what happens to these neurons as they mature, but Alejandro Schinder and his colleagues at Leloir wanted to go one step further and understand how new neurons produced by the dentate gyrus are incorporated into the existing neural networks of the brain, and whether environment affects this process. The researchers placed adult mice in an enriched environment, a cage filled with enticing, novel objects such as clear crawl tubes, chew toys and a shelter carved to look like a block of Swiss cheese. As the mice explored, their dentate gyri activated. “They have to create a map of the new environment,” Schinder explains, “So this is a spatial learning process.” Next, the researchers injected the mice with a harmless virus that labeled the new neurons produced by the dentate gyrus with a red fluorescent protein. Over the next two weeks they placed groups of mice in an enriched environment for different two-day periods; after three weeks they compared the new neurons of the enriched mice to those of control mice that lived in an unadorned cage. The researchers found the new neurons in the enriched mice looked structurally different—they had longer dendrites (the neurons’ input cables that collect information from other parts of the brain) and more spines (locations where neurons connect to one another), which indicate faster growth. Additionally, an analysis of the electrical properties of these new neurons revealed they were more connected to their surrounding cells. According to Schinder, these experiments show “exposing the mice to the enriched environment for two days is sufficient to trigger a process in the cell that will push the cell to connect faster to the preexisting network.” Armed with this knowledge, the researchers set out to understand the mechanics of how new neurons connect. First they gave some of the mice a treatment that made existing neurons hyperactive for a two-day period, and found that this caused the new neurons to connect to the existing network more quickly, just as when mice experienced an enriched environment. Then they established that intermediate cells, called parvalbumin interneurons, are responsible for conveying signals from old neurons to the new ones, to connect the latter to the existing network. The researchers found that when they made the interneurons hyperactive for two days without placing mice in an enriched environment, the new neurons still connected to the existing network more quickly. When they silenced the interneurons completely but placed the mice in an enriched environment, the new neurons did not connect any more quickly than they did in the control mice. “This is important because now we are saying that the experience that the animal is undergoing is translated to the new cells through these parvalbumin interneurons,” Schinder explains. The results suggest “the process of neurogenesis, which is putting whole new neurons into the hippocampus, is sensitive to really subtle stimuli such as going from a very boring environment to a very rich environment.” The complex environment makes the neurons connect faster, and may prime them for encoding new information. Hongjun Song, a neuroscientist at Johns Hopkins University who was not involved in the study, finds the results very interesting. His own research has shown these same interneurons play a role in controlling the activation of stem cells and regulating new neuron survival. He says the big takeaway is that everyday experiences can continuously shape physical brain structure. “I think that’s striking,” he says. He adds that the work may have implications for brain disorders such as epilepsy or Alzheimer’s. “What's intriguing is that this type of neuron is vulnerable to disease,” he says, “So I think this paper not only shows how normally an experience can impact the circuit formation continuously in the brain, but also hints at how brain disorders in cells can also cause abnormal regulation of the process.” Heather Cameron, who studies neuroplasticity at the National Institute of Mental Health and also was not part of the research, is impressed by the way the study “takes things people have said in different contexts—for instance, that interneurons are the first to connect to the young neurons or that enriched environment affects the development or affects neurogenesis, and puts them all together in one complete picture of how this circuit affects new neuron development.” And although the study is in mice, not humans, Cameron points out that there are a lot of brain similarities between the two species. “We know that the anatomy of the hippocampus and its inputs and outputs are very similar in the two species, and we know that there is ongoing neurogenesis in humans,” she says, “So it's a good bet that these mechanisms seen in mice are also occurring in humans.”
News Article | April 6, 2016
Researchers in Argentina say they have genetically modified an adenovirus - which can cause colds, conjunctivitis and bronchitis - to home in on cancer, killing tumor cells in patients without harming healthy tissue. Scientists have long been intrigued by the idea of using viruses to alert the immune system to seek and destroy cancerous cells. That interest has taken off in recent years as advances in genetic engineering allow them to customize viruses that target tumors. Dr. Osvaldo Podhjacer, Chief of the Laboratory of Molecular and Cellular Therapy at the Fundacion Instituto Leloir in Buenos Aires, and his team developed an 'oncolytic' virus designed to target both malignant cells and tumor-associated stromal cells. In February, Unleash Immuno Oncolytics announced it had entered a license agreement with Leloir Institute to develop immuno-oncology products for cancer treatment in Saint Louis. Unleash's leading product, developed thanks to work by Podhjacer, is called UIO-512. Dr. Podhjacer explained how the virus helps to attack cancer. "This is a virus, which, by genetic modification, we have restricted their infectivity exclusively to malignant cells, in spite of the fact, originally, the virus can infect normal cells and cause colds, conjunctivitis and bronchitis. Why immunotherapy? Because in addition to the changes we have made to restrict the infection only to malignant cells, it also has a gene that exacerbates the immune response. Then there is a direct attack on the tumor initial and an additional immunological response which in principle eliminates the residual tumor, which was not eliminated by the virus and disseminated metastases," Dr. Podhjacer said. Scientific journal Nature reported in October last year that cancer-fighting viruses had started to win approval. Researchers hope that ongoing clinical trials of similar oncolytic viruses and their approval will generate the enthusiasm and cash needed to spur further development of the approach. "These viruses are very effective in pre-clinical models of cancer, we have tested and in particular, ovarian cancer and melanoma but we also have other viruses for pancreatic and colon rectal cancer. These are non-toxic and they are as important as their therapeutic efficacy, where we have managed to reverse the levels of liver enzymes to a normal level with animals that have a tumor. These levels become very high due to the toxicity. In general terms, it allows us to qualify this virus as an ideal candidate to be taken to a clinical trial in humans beings," Dr. Podhjacer, said. Professor Lawrence Young, a cancer specialist from the University of Warwick, said that while similar research has been ongoing for many years, Podhjacer's team had added a mechanism to influence the cells surrounding the cancer tumor. "To be honest, it's not particularly novel. What they have done, however, which is a bit interesting is introduce a new bell or a new whistle, if you like, in terms of the virus, which is to also have an effect on some of the supporting cells. So one of the things that's very exciting about current cancer biology is an increased understanding of the fact that while you've got cancer cells and tumor cells, which are important targets; actually there's a lot of supporting cells around the cancer that also get modified in that environment and start to mis-behave," Young told Reuters. Podhajcer said that the virus attacks the entire tumor mass, not only the malignant cells themselves but also the stromal cells that support cancer dissemination. "We have prepared a virus with the ability to study everything that is characteristic of the tumor and to attack all the cells of the tumor. In other words, we have an approach different to what has been done to this day today, even within what is being used in the oncolytic therapy using these viruses which also generate secondary immune responses. In other words, it is a disruptive technology and we also add something that is unique to our research," Podhajcer said. Professor Young cautioned that there are a number of hurdles for the therapy to overcome. In addition to the cost implications for eventually making it widely available, he said that the body's own immune system could make subsequent doses of a treatment increasingly less effective. "Some of those immune responses will target the tumor, some won't. And so the degree to which you can re-use these viruses is a problem because as you get an immune response to them, as soon as you then expose a patient to a second or third dose their immune system starts to think "wait a minute, we've seen that before, we're going to wipe it out". So these are very challenging therapies," he said. According to the journal Nature, the strategy builds on a phenomenon which has been recognized for more than a century. Physicians in the 1800s first noted their cancer patients sometimes unexpectedly went into remission after experiencing a viral infection. Based on these reports, doctors in the 1950s and 1960s were then inspired to start injecting cancer patients with a menagerie of viruses. Sometimes the therapy destroyed the tumor, and on occasion it killed the person instead. According to Professor Young, however, the field of immunotherapy has advanced rapidly in the past ten years and there is a great deal of positivity for what the future holds in the fight against cancer. "I think that there's so much excitement about this now, and so much excitement about being able to use non-viral approaches to delivering drugs and genes, that it's quite clear that over the next ten years or so, we're going to see more of these therapies, especially in the more difficult to manage tumors," he said.