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  • studied two different strains of mice genetically engineered to develop Alzheimer s symptoms plus a group of healthy mice All of these mice when exposed to a chamber where they received a foot shock showed fear when placed in the same chamber an hour later However when placed in the chamber again several days later only the normal mice still showed fear The Alzheimer s mice did not appear to remember the foot shock Short term memory seems to be normal on the order of hours But for long term memory these early Alzheimer s mice seem to be impaired Roy says An access problem The researchers then showed that while the mice cannot recall their experiences when prompted by natural cues those memories are still there To demonstrate this they first tagged the engram cells associated with the fearful experience with a light sensitive protein called channelrhodopsin using a technique they developed in 2012 Whenever these tagged engram cells are activated by light normal mice recall the memory encoded by that group of cells Likewise when the researchers placed the Alzheimer s mice in a chamber they had never seen before and shined light on the engram cells encoding the fearful experience the mice immediately showed fear Directly activating the cells that we believe are holding the memory gets them to retrieve it Roy says This suggests that it is indeed an access problem to the information not that they re unable to learn or store this memory The researchers also showed that the engram cells of Alzheimer s mice had fewer dendritic spines which are small buds that allow neurons to receive incoming signals from other neurons Normally when a new memory is generated the engram cells corresponding to that memory grow new dendritic spines but this did not happen in the Alzheimer s mice This suggests that the engram cells are not receiving sensory input from another part of the brain called the entorhinal cortex The natural cue that should reactivate the memory being in the chamber again has no effect because the sensory information doesn t get into the engram cells If we want to recall a memory the memory holding cells have to be reactivated by the correct cue If the spine density does not go up during learning process then later if you give a natural recall cue it may not be able to reach the nucleus of the engram cells Tonegawa says This is a remarkable study providing the first proof that the earliest memory deficit in Alzheimer s involves retrieval of consolidated information says Rudolph Tanzi a professor of neurology at Harvard Medical School who was not involved in the research As a result the implications for treatment of memory deficits Alzheimer s disease based on strengthening synapses are extremely exciting Long term connection The researchers were also able to induce a longer term reactivation of the lost memories by stimulating new connections between the entorhinal cortex and the hippocampus To achieve

    Original URL path: https://picower.mit.edu/cms/20160316/lost-memories-can-be-found/ (2016-04-25)
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  • Picower Institute and the paper s lead author Only the lonely Matthews first identified the loneliness neurons somewhat serendipitously while studying a completely different topic As a PhD student at Imperial College London she was investigating how drugs affect the brain particularly dopamine neurons She originally planned to study how drug abuse influences the DRN a brain region that had not been studied very much As part of the experiment each mouse was isolated for 24 hours and Matthews noticed that in the control mice which had not received any drugs there was a strengthening of connections in the DRN following the isolation period Further studies both at Imperial College London and then in Tye s lab at MIT revealed that these neurons were responding to the state of isolation When animals are housed together DRN neurons are not very active However during a period of isolation these neurons become sensitized to social contact and when the animals are reunited with other mice DRN activity surges At the same time the mice become much more sociable than animals that had not been isolated When the researchers suppressed DRN neurons using optogenetics a technique that allows them to control brain activity with light they found that isolated mice did not show the same rebound in sociability when they were re introduced to other mice That suggested these neurons are important for the isolation induced rebound in sociability Tye says When people are isolated for a long time and then they re reunited with other people they re very excited there s a surge of social interaction We think that this adaptive and evolutionarily conserved trait is what we are modeling in mice and these neurons could play a role in that increased motivation to socialize Social dominance The researchers also found that animals with a higher rank in the social hierarchy were more responsive to changes in DRN activity suggesting that they may be more susceptible to feelings of loneliness following isolation The social experience of every animal is not the same in a group Tye says If you re the dominant mouse maybe you love your social environment And if you re the subordinate mouse and you re being beat up every day maybe it s not so fun Maybe you feel socially excluded already The findings represent an amazing cornerstone for future studies of loneliness says Alcino Silva a professor of neurobiology psychiatry and psychology at the David Geffen School of Medicine at UCLA who was not involved in the research There is something poetic and fascinating about the idea that modern neuroscience tools have allowed us to reach to the very depths of the human soul and that in this search we have discovered that even the most human of emotions loneliness is shared in some recognizable form with even one of our distant mammalian relatives the mouse Silva says The researchers are now studying whether these neurons actually detect loneliness or are responsible for driving the response

    Original URL path: https://picower.mit.edu/cms/20160211/pinpointing-loneliness-in-the-brain/ (2016-04-25)
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  • range of disorders from drug addiction to mental illness The key to enabling plasticity in the adult brain is understanding which elements of a brain circuit are changeable and which aren t and under what circumstances says study author Elly Nedivi Picower researcher and professor of neuroscience in the MIT Department of Brain and Cognitive Sciences The good news is that while parts of the circuit are hard wired others are not they retain a capacity for remodeling Gaining and losing connections A neuron is bombarded with signals from hundreds of presynaptic partners Synapses act as conduits for these incoming signals Excitatory neurotransmitters flow from the presynaptic to the postsynaptic neuron at synaptic locations that are on bulbous protrusions with a rounded head and thin neck termed spines The long branching dendrites of a single neuron can display hundreds of spines like leaves on a tree branch When spines appear and disappear a neuron can gain new connections or lose existing ones If spines disappear they rarely come back to the same location new spines seek out alternative locations says biology graduate student Katherine Villa co first author on the study It s as if after deciding that a connection is not worth keeping neurons will try to replace it with a different contact Seeing spines at work Using cutting edge imaging techniques developed in collaboration with Peter So MIT professor of mechanical and biological engineering Nedivi s team tracked the daily dynamics of all the dendritic spines on a single neuron in the living mouse brain as well as all the excitatory and inhibitory synapses on these neurons The ability to label inhibitory synapses in live animals is fairly recent even today it is notoriously difficult to witness excitatory and inhibitory synapses working side by side Directly visualizing inhibitory synapses revealed the surprising fact that while many reside on the shaft of dendritic branches approximately 30 percent reside on dendritic spines alongside excitatory synapses Another surprise was that when inhibitory synapses are removed they return again and again to the same location Clearly the goal here is not to change partners as we see for excitatory connections says biology graduate student Kalen Berry Villa s co first author We think that inhibitory synapses can act as a kind of gatekeeper flickering on and off to shut down excitatory connections as needed Interestingly the dual purpose spines are large and extremely stable as are the excitatory connections onto them This is essentially a hard wired part of the circuit Nedivi says But we still have the potential to modify it via the nearby inhibitory synapse These findings raise questions about why some excitatory connections on singly innervated spines can be restructured while those on dually innervated spines cannot How does the structural plasticity of inhibitory synapses alter excitatory circuit properties and what enables their rapid insertion and removal at stable sites The answers to these questions could shed light on ways to enhance plasticity in the adult brain and synapse

    Original URL path: https://picower.mit.edu/cms/20160204/a-day-in-the-life-of-a-synapse-reveals-new-facets-of-the-adult-brain/ (2016-04-25)
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  • the presynaptic to the postsynaptic neuron This communication allows the brain to coordinate activity and store information such as new memories Previous studies have shown that postsynaptic cells can actively pull in some of their receptors in a phenomenon known as long term depression LTD This important process allows cells to weaken and eventually eliminate poor connections as well as to recalibrate their set point for further excitation It can also protect them from overexcitation by making them less sensitive to an ongoing stimulus Pulling in receptors requires the cytoskeleton which provides the physical power and a specialized complex of proteins known as the endocytic machinery This machinery performs endocytosis the process of pulling in a section of the cell membrane in the form of a vesicle along with anything attached to its surface At the synapse this process is used to internalize receptors Until now it was unknown how the cytoskeleton and the endocytic machinery were linked In the new study Nedivi s team found that the CPG2 protein forms a bridge between the cytoskeleton and the endocytic machinery CPG2 acts like a tether for the endocytic machinery which the cytoskeleton can use to pull in the vesicles Nedivi says The glutamate receptors that are in the membrane will get pinched off and internalized They also found that CPG2 binds to the endocytic machinery through a protein called EndoB2 This CPG2 EndoB2 interaction occurs only during receptor internalization provoked by synaptic stimulation and is distinct from the constant recycling of glutamate receptors that also occurs in cells Nedivi s lab has previously shown that this process which does not change the cells overall sensitivity to glutamate is also governed by CPG2 This study is intriguing because it shows that by engaging different complexes CPG2 can regulate different types of endocytosis says Linda Van Aelst a professor at Cold Spring Harbor Laboratory who was not involved in the research When synapses are too active it appears that an enzyme called protein kinase A PKA binds to CPG2 and causes it to launch activity dependent receptor absorption CPG2 may also be controlled by other factors that regulate PKA including hormone levels Nedivi says Link to bipolar disorder In 2011 a large consortium including researchers from the Broad Institute discovered that a gene called SYNE1 is number two on the hit list of genes linked to susceptibility for bipolar disorder They were excited to find that this gene encoded CPG2 a regulator of glutamate receptors given prior evidence implicating these receptors in bipolar disorder In a study published in December Nedivi and colleagues including Loebrich and co lead author Mette Rathje identified and isolated the human messenger RNA that encodes CPG2 They showed that when rat CPG2 was knocked out its function could be restored by the human version of the protein suggesting both versions have the same cellular function Rathje a Picower Institute postdoc in Nedivi s lab is now studying mutations in human CPG2 that have been linked to bipolar

    Original URL path: https://picower.mit.edu/cms/20160114/how-neurons-lose-their-connections/ (2016-04-25)
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  • repeatedly with different proteins labeled each time To achieve that the researchers devised a method for controlling the chemical reactions required for tissue preservation and labeling This allows them to first preserve the tissue then label a certain protein and image it They can then wash away the tagging molecule and label a different protein over and over again Controlling the chemical reactions requires a pair of buffers solutions of weak acids and bases that alter the tissue s environment One of the buffers known as SWITCH Off halts most chemical reactions in the tissue while the SWITCH On buffer allows them to resume To prepare the tissue samples the researchers first add the SWITCH Off buffer followed by chemicals necessary for tissue preservation the most important of which is glutaraldehyde Because the chemicals cannot react with any cells they diffuse evenly throughout the sample It s like these chemicals are in a stealth mode They are not detected by tissue Chung says When the researchers add the SWITCH On buffer the glutaraldehyde forms a gel that preserves the tissue The researchers also add detergent to destroy the lipids of the cell membranes making the cell interiors more visible to a light microscope Once the tissue is preserved and ready for imaging the researchers add the SWITCH Off buffer again With the tissue in an unreactive state they add labels such as antibodies or dyes which can be tailored to detect not only proteins but also DNA neurotransmitters or lipids Once the labels have diffused through the tissue adding the SWITCH On buffer allows all cells to be exposed to the labels simultaneously Protein analysis In the Cell study the researchers labeled 22 different proteins in a small section of human brain tissue roughly 3 millimeters by 3 millimeters by 0 1 millimeters After 22 rounds of labeling the tissue was still in good condition so the researchers believe this technique could be used to image even more proteins They also examined the distribution of six proteins in human visual cortex tissue and were able to label and image the myelinated fibers that connect different regions of the brain If you can visualize these fibers then you can really understand brain connectivity and the fundamental laws that govern how these wires are formed and connected Chung says The size of the tissue that can be imaged is limited only by the amount of time required for labeling the proteins and imaging the sample It takes about a month for each labeling molecule to diffuse through a cubic centimeter sized tissue sample but Chung and colleagues recently reported in the Proceedings of the National Academy of Sciences that they could speed this up dramatically by exposing the tissue to a randomly changing electric field This cuts the diffusion time to about a day The imaging time depends on the type of microscope used For this study the researchers used a light sheet microscope which can image samples about 100 times faster

    Original URL path: https://picower.mit.edu/cms/20151203/protein-imaging-reveals-detailed-brain-architecture/ (2016-04-25)
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  • receptors for neurotransmitters to its surface amplifying the signal it receives from the presynaptic cell This phenomenon known as long term potentiation LTP occurs following persistent high frequency stimulation of the synapse Long term depression LTD a weakening of the postsynaptic response caused by very low frequency stimulation can occur when these receptors are removed Scientists have focused less on the presynaptic neuron s role in plasticity in part because it is more difficult to study Littleton says His lab has spent several years working out the mechanism for how presynaptic cells release neurotransmitter in response to spikes of electrical activity known as action potentials When the presynaptic neuron registers an influx of calcium ions carrying the electrical surge of the action potential vesicles that store neurotransmitters fuse to the cell s membrane and spill their contents outside the cell where they bind to receptors on the postsynaptic neuron The presynaptic neuron also releases neurotransmitter in the absence of action potentials in a process called spontaneous release These minis have previously been thought to represent noise occurring in the brain However Littleton and Cho found that minis could be regulated to drive synaptic structural plasticity To investigate how synapses are strengthened Littleton and Cho studied a type of synapse known as neuromuscular junctions in fruit flies The researchers stimulated the presynaptic neurons with a rapid series of action potentials over a short period of time As expected these cells released neurotransmitter synchronously with action potentials However to their surprise the researchers found that mini events were greatly enhanced well after the electrical stimulation had ended Every synapse in the brain is releasing these mini events but people have largely ignored them because they only induce a very small amount of activity in the postsynaptic cell Littleton says When we gave a strong activity pulse to these neurons these mini events which are normally very low frequency suddenly ramped up and they stayed elevated for several minutes before going down Synaptic growth The enhancement of minis appears to provoke the postsynaptic neuron to release a signaling factor still unidentified that goes back to the presynaptic cell and activates an enzyme called PKA This enzyme interacts with a vesicle protein called complexin which normally acts as a brake clamping vesicles to prevent release neurotransmitter until it s needed Stimulation by PKA modifies complexin so that it releases its grip on the neurotransmitter vesicles producing mini events When these small packets of neurotransmitter are released at elevated rates they help stimulate growth of new connections known as boutons between the presynaptic and postsynaptic neurons This makes the postsynaptic neuron even more responsive to any future communication from the presynaptic neuron Typically you have 70 or so of these boutons per cell but if you stimulate the presynaptic cell you can grow new boutons very acutely It will double the number of synapses that are formed Littleton says The researchers observed this process throughout the flies larval development which lasts three to five days

    Original URL path: https://picower.mit.edu/cms/20151118/neuroscientists-reveal-how-the-brain-can-enhance-connections/ (2016-04-25)
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  • Engineering and Brain and Cognitive Sciences is one of 18 individuals chosen to receive a 2015 Packard Fellowship for Science and Engineering Every year the David Lucile Packard Foundation invites fifty universities to nominate early career professors from their institutions for the five year 875 000 grants that give emerging young scientists and engineers the freedom to take risks pursue innovative ideas and creatively explore new frontiers The Packard Foundation established the Fellowships in 1988 to allow the nation s most promising professors to pursue science and engineering research early in their careers with few funding restrictions and limited reporting requirements The program arose out of David Packard s commitment to strengthening university based science and engineering programs in recognition that the success of the Hewlett Packard Company which he cofounded derived in large measure from the research and development in university laboratories according to the Foundation s website Since 1988 the Foundation has awarded 362 million to support 541 scientists and engineers from 52 top national universities KC Chung s research focuses on developing and applying novel technologies for integrative and comprehensive understanding of large scale biological systems His lab explores methods that enable rapid extraction of structural molecular and genomic information from intact tissues Article also appeared on MIT News Tags David Lucile Packard Foundation IMES Kwanghun Chung MIT Picower Picower Institute for Learning and Memory Recommended Posts Lost memories can be found Pinpointing loneliness in the brain Bose s new beat News Topics Media Mentions Press Releases Neuroscience News Picower e Newsletter Publications Featured News Lab News Bear Lab News Brown Lab News Chung Lab News Flavell Lab News Heiman Lab News Littleton Lab News Miller Lab News Nedivi Lab News Sur Lab News Tonegawa Lab News Tsai Lab News Tye Lab News Wilson Lab News Xu

    Original URL path: https://picower.mit.edu/cms/20151019/congratulations-to-kwanghun-chung-2015-packard-fellowship-recipient/ (2016-04-25)
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  • diagnosed with autism These combined efforts are expected to enhance understanding of the underlying clusters of symptoms specifically associated with ASD which in turn will drive the development of more effective treatments ASD is a complex disorder Given the large number of genes potentially responsible for autism it is impossible to develop a one size fits all treatment On the other hand it is also unrealistic to expect specific interventions for every genetic cause It makes sense to focus on a few molecular and circuit pathways that can be targeted by a limited number of mechanism based treatments Current efforts are concentrating on single gene mutations that reveal a prevalence of ASD symptoms Designing successful clinical trials Sur and Sahin discuss obstacles faced in current research initiatives and propose recommendations for future clinical trials designed to deliver precision medicine Challenges include selecting the right group of patients defining the optimal duration for the trial ensuring that drugs engage their targets and optimizing animal models to ensure direct relevance for human outcomes Translatable biomarkers that can be employed in both mouse models and human subjects are particularly powerful according to the paper s co authors A critical feature of precision clinical trial design these biomarkers can effectively predict subjects most likely to respond confirm target engagement and detect early signs of efficacy A panel of significant biomarkers that provides a unique profile of a patient will allow scientists to interrogate the most relevant ASD related circuits which can assist in early diagnosis and assessing phonotype and severity The critical age window for treatment of autism remains unclear but there is no doubt that biomarkers will be important for ensuring effectiveness Sur and Sahin include two additional suggestions for clinical trials They recommend using available technology to observe the effects of test drugs on a patient s neurons before directly administering a pharmaceutical therapy They also caution researchers exploring gene therapy to carefully regulate dosage levels since elevated expression of particular genes can have harmful effects They predict that those who conduct trials based on a mechanistic understanding of autism performed on a well defined group of subjects with evidence of target engagement and supportive biomarkers are the most likely to succeed Treatment ramifications and challenges Today two FDA approved drugs are used to treat autism and both are aimed at relieving irritability rather than the core manifestations of the disorder Since single gene conditions involve multiple potential targets combination rather than singular drug therapies will likely be most effective Also while drug therapies may normalize neuronal abnormalities cognitive function depends on complex circuits and an individual s interaction with the environment Thus a drug therapy may correct synaptic abnormality and even accelerate the rate of learning but it may not result in behavioral changes A combination of behavioral and pharmacological interventions appears to comprise the most promising treatment approaches Yet even if neuroscientists are successful in enhancing their understanding of single gene syndromes that cause autism roadblocks will remain A comparative

    Original URL path: https://picower.mit.edu/cms/20151015/leveraging-genetic-diversity-to-drive-precision-medicine/ (2016-04-25)
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