Research Funding For Undergrads: MRSEC Summer Materials Undergraduate Research Fellowships

The Division of Science wishes to announce that, in 2017, we will offer seven MRSEC Summer  Materials Undergraduate Research Fellowships (SMURF) for Brandeis students doing undergraduate research, sponsored by the Brandeis Materials Research Science and Engineering Center.

The fellowship winners will receive $5,000 stipends (housing support is not included) to engage in an intensive and rewarding research and development program that consists of full-time research in a MRSEC lab, weekly activities (~1-2 hours/week) organized by the MRSEC Director of Education, and participation in SciFest VII on Aug 3, 2017.

The due date for applications is February 27, 2017, at 6:00 PM EST.

To apply, the application form is online and part of the Unified Application: https://goo.gl/9LcSpG (Brandeis login required).


Eligibility

Students are eligible if they will be rising Brandeis sophomores, juniors, or seniors in Summer 2017 (classes of ’18, ’19, and ’20). No prior lab experience is required. A commitment from a Brandeis MRSEC member to serve as your mentor in Summer 2017 is required though. The MRSEC faculty list is: http://www.brandeis.edu/mrsec/people/index.html

Conflicting Commitments
SMURF recipients are expected to be available to do full time laboratory research between May 30 – August 4, 2017. During that period, SMURF students are not allowed to take summer courses, work another job or participate in extensive volunteer/shadowing experiences in which they commit to being out of the lab for a significant amount of time during the summer. Additionally, students should not be paid for doing lab research during this period from other funding sources.

Application Resources
Interested students should apply online (Brandeis login required). Questions that are not answered in the online FAQ may be addressed to Steven Karel <divsci at brandeis.edu>.

Recycling is good for your brain

If you were able to remember where you put your keys on your way out the door this morning, it’s because – somehow – synapses in your brain changed their properties to encode this information and store it until you needed it. This process, known as “synaptic plasticity”, is essential for the continuity of our memory and sense of self, and yet we are only beginning to grasp the molecular mechanisms that enable this amazing feat of constant information storage and retrieval. Now a collaborative paper from the Turrigiano and Nelson labs just published in Cell Reports sheds important new light into how experience interacts with the genome to allow synapses to change their strength to store information.

Synapses are the connections between neurons, and it has long been appreciated that information is stored in large part through changes in the strength of these connections. Changes in strength at many synapses are in turn determined by the number of neurotransmitter receptors that are clustered at synaptic sites – the more receptors synapses have, the easier it is for neurons to excite each other to transmit information. Synapses are highly complicated molecular machines that utilize at least 300 different proteins that interact to traffic these receptors to synapses and sequester them there, and exactly how a change in experience alters the function of this nano-machine to enhance the number of synaptic receptors is still a matter of puzzlement.

In this study the Brandeis team devised a way to screen for candidate proteins that are critical for a particular form of synaptic plasticity: “synaptic scaling”, thought to be especially important for maintaining brain stability during learning and development. They were able to induce synaptic scaling within specific labelled neurons in the intact mouse brain (layer 4 star pyramidal neurons), and then sort out those labelled neurons from the rest of the brain and probe for changes in gene expression that were correlated with (and potentially causally involved in) the induction of plasticity.  This approach produced a small number of candidate genes that were up- or down-regulated during plasticity, to produce more or less of a given protein.  The team then went on to show that – when upregulated – one of these candidates (known as µ3A) acts to prevent neurotransmitter receptors from going into the cellular garbage bin (the lysosomes, where proteins are degraded) and instead recycles them to the synapse. Thus increased µ3A flips a switch within cells to enhance receptor recycling, and this in turn increases synaptic strength.

µ3A plays a critical role in the recycling of AMPA-type neurotransmitter receptors

A screen for genes with altered expression during synaptic plasiticity in specific neurons revealed that µ3A plays a critical role in the recycling of AMPA-type neurotransmitter receptors at the synapse. When this protein is upregulated, it prevents receptors from being trafficked into lysosomes, and instead allows them to be recycled back to synapses, increasing synapse number and enhancing synaptic strength.

It turns out that many other forms of synaptic plasticity use the same receptor recycling machinery as synaptic scaling, so it is likely that this mechanism represents  an important and general way for neurons to alter synaptic strength. This study also raises the possibility that defects in this pathway might contribute to the genesis of neurological disorders in which the stability of brain circuits is disrupted, such as epilepsy and autism. So next time you complain about having to sort your garbage, consider that your neurons do it all the time –  and what’s good for the planet turns out to be good for your brain as well.

Steinmetz CC, Tatavarty V, Sugino K, Shima Y, Joseph A, Lin H, Rutlin M, Lambo M, Hempel CM, Okaty BW, Paradis S, Nelson SB, Turrigiano G. Upregulation of μ3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway. Cell reports. 2016.

SciFest VI recap and stats

photo credit: Mike Lovett

photo credit: Mike Lovett

The Brandeis University Division of Science held its annual undergraduate research poster session SciFest VI on August 4, 2016, as a record number of student researchers presented posters with the results of their summer’s (or last year’s) worth of independent research. We had a great audience of grad students, postdocs, faculty, proud parents, and senior administrators.

More pictures and abstract books are available at the SciFest site.

SciFest VI by numbers

Neurons that make flies sleep

Sleep is known to be regulated by both intrinsic (what time is it?) and environmental factors (is it hot today?). How exactly these factors are integrated at the cellular level is a hot topic for investigation, given the prevalence of sleep disorders. Researchers in the Rosbash and Griffith labs are pursuing the question in the fruit fly Drosophila melanogaster, to take advantage of the genetic tools in the model system and the excellent understanding of circadian rhythms in the fly.

Like other animals, the fruit fly displays a robust activity/sleep pattern, which consists of a morning (M) activity peak, a middle-day siesta, an evening (E) activity peak and nighttime sleep. M and E peaks are controlled by different subgroups of circadian neurons such as wake-promoting M and E clock cells.

In a paper just published in Nature, Brandeis postdoctoral fellow Fang Guo and coworkers identify a small group of circadian neurons, a subset of the glutamatergic DN1 (gDN1s) cells, which have a critical role in both types of regulation. The authors manipulated the gDN1s activity by using recently developed optogenetics tools, and found activity of those neurons is both necessary and sufficient to promote sleep.

circadian-feedback

The cartoon model illustrates how the circadian neuron negative feedback set the timing of activity and siesta of Drosophila. The arousal-promoting M cells (sLNv) release pigment-dispersing factor (PDF) peptide to promote M activity at dawn. PDF peptide can activate gDN1s, which release glutamate to inhibit arousal-promoting M and E (LNds) cells and cause a middle-day siesta. At evening, the gDN1s activity is reduced to trough levels and release E cell activity from inhibition.

DN1s enhance baseline sleep by acting as feedback inhibitors of previously identified wake-promoting M and E clock cells, making them the first known sleep-promoting neurons in this circadian circuit. It is already known that M cell can activate gDN1s at dawn. Thus the daily activity-sleep pattern of Drosophila is timed by the circadian neuron negative feedback circuitry (see Figure).  More interestingly, by using in vivo calcium reporters, the authors reveal that the activity of the gDN1s is also shown to be sexually dimorphic, explaining the well-known difference in daytime sleep between males and females. DN1s also have a key role in mediating the effects of temperature on daytime sleep. The circadian and environmental responsiveness of gDN1s positions them to be key players in shaping sleep to the needs of the individual animal.

Authors on the paper include postdocs Guo, Junwei Yu and Weifei Luo, staff member Kate Abruzzi, and Brandeis graduate Hyung Jae Jung ’15 (Biology/HSSP).

Guo F, Yu J, Jung HJ, Abruzzi KC, Luo W, Griffith LC, Rosbash M. Circadian neuron feedback controls the Drosophila sleep-activity profile. Nature. 2016.

Amy Lee Joins Biology Faculty

On August 1, Amy Lee joined the Biology department as an Assistant Professor. Previously, Amy was an American Cancer Society Postdoctoral Scholar in Jamie Cate’s lab at University of California, Berkeley. She received her Ph.D. in Virology from Harvard University in Sean Whelan’s lab and her Bachelors of Science in Biology from Massachusetts Institute of Technology.

Stx.key

eIF3d structure, see Figure 2 at http://rdcu.be/jzDD

Amy’s research focuses on understanding how gene regulation shapes cell growth and differentiation, and how dysregulation leads to human diseases like carcinogenesis and neurodegeneration. She is interested in discovering new mechanisms of mRNA translation initiation and novel functions of RNA-binding proteins and eukaryotic translation factors. Her research combines genome-wide and computational approaches together with molecular genetics, cell biology, biochemistry, and structural biology techniques.

Amy recently published a paper in Nature together with the Jamie Cate, Jennifer Doudna, and Philip Kranzusch describing the discovery of a new translation pathway that controls the production of proteins critical to regulating the growth and proliferation of cells. Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. One key insight more than 40 years ago was that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

Amy and her colleagues discovered that for a certain specialized subset of mRNAs – most of which have been linked somehow to cancer – initiation is triggered by a different protein, called eIF3d. The finding was a surprise because the protein is part of an assembly of 13 proteins called eIF3 -eukaryotic initiation factor 3 – that has been known and studied for nearly 50 years, and no one suspected its undercover role in the cell. This may be because eIF3’s ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3d that then latches onto the end-cap of mRNA to trigger the translation process. Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the cap-binding pocket. eIF3d thus presents a promising new drug target in cancer, as a drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016.

 

Inside the Marder Lab

Marder Office MobileProfessor Eve Marder’s office door is unmistakable. Tucked between the certificates, accolades, official photos, and award plaques that plaster her lab’s walls, her office door is decorated with a collage of fading photos of students and yellowing cartoons of lobsters and crabs. Inside the office, the shelves are crammed with neuroscience books and stacks of primary and review articles published by her lab throughout her career. But among all of the awards and publications there’s something else that draws your eye. Hanging just above her computer is a homemade mobile built by a former student. Dangling from the mobile are photos of lab members and important scientific figures, faces and images gently pirouetting and circling around one another just above Marder’s head.

Now Marder has another award to add to her vast collection. In June 2016, she was announced as a winner of the Kavli Prize in Neuroscience. Marder shares the Prize with Carla Shatz, of Stanford University, and Michael Merzenich, of the University of California, San FMarder Office Doorrancisco. The award was given to these scientists “for the discovery of mechanisms that allow experience and neural activity to remodel brain function.” The Prize includes a gold medal ceremony and a one-million-dollar award (to be split among the winners), which will be conferred by His Majesty King Harald V of Norway in Oslo in September 2016. First awarded in 2008, the Kavli Prize was established to recognize scientific achievement and to honor creative scientists in the fields of Neuroscience, Astrophysics, and Nanoscience.

The illustrations of lobsters and crabs on Marder’s office door pay homage to the creatures that her lab has used as research subjects to shed light on the fundamental rules that govern how nervous systems function. Her life’s work has been studying a group of neurons called the stomatogastric ganglion (STG). These neurons control rhythmic chewing and filtering of food through the stomachs of crustaceans like crabs and lobsters. The STG is a relatively small (~30 neurons) circuit of cells. It can be dissected out from the animal and placed in a dish, where it can continue to function for up to weeks at a time. In the dish, the neurons will continue to produce electrical rhythms as if the stomach were still chewing and filtering. These electrical rhythms can be studied using a technique called electrophysiology where changes in cell voltage are measured and recorded. The STG contains well-studied central pattern generators (CPGs), circuits that produce rhythmic patterns without sensory feedback. In fact, insight gained from studying the general principles involved in STG activity has given neuroscientists a better understanding of CPGs involved in human behaviors including walking, sleeping, and breathing.

pyloric rhythm

From The Cancer borealis STG guide (Rutgers University)

Because the STG is robust and relatively simple, it makes an excellent model to study how neural circuits work. Gina Turrigiano, a colleague at Brandeis, has written that the ideas Marder and her lab developed from studying this system have “catalyzed paradigm shifts in fields as diverse as neural circuit function, computational neuroscience, and neuronal homeostasis…Her ideas have proved to be highly generalizable, and have fundamentally changed the way neuroscientists think about these problems.”

Neuroscientists used to think that the brain was wired like an electronic circuit board. In other words, neurons were wired together via simple connections that could only be “on” or “off.” When all the connections were turned on, the circuit produced a single behavior. Understanding the brain was thought to be as simple as determining how each neuron was physically connected to all others. While working as a graduate student at the University of California San Diego, Marder made a discovery that questioned this dogma. She found that neurons in the STG release acetylcholine in addition to the already known neurotransmitter, glutamate. This result, published in 1974, suggested that neuronal connections could be turned on in more than one way. Her discovery was instrumental in shifting how neuroscientists think about nervous systems. It could no longer be assumed that a simple connection diagram was sufficient.

Further work uncovered many different neuromodulators (neurotransmitters and peptides hormones) that could modulate or alter the neurons’ rhythms of the STG. Dr. Marder found that release of these neuromodulators could shift the activity of the neural circuit without changing any physical connections. This shift can happen very quickly and be long lasting. In addition, neuromodulation can also induce certain neurons to synchronize with different circuits switching their activity to coordinate with one circuit (like the ‘chewing’ circuit) and then to another (like the ‘filtering’ circuit). Both of these findings opened new questions for the entire field of neuroscience. A neural circuit with the same physical connections could have many different output activities so that even simple neural circuits could accomplish a surprising variety of tasks.

Partial Summary of Neuromodulation of the STG, see Marder (2012) Neuron 76:1–11.

Much of the Marder lab’s work in recent years has grown from this initial work in neuromodulation. With so much flexibility of activity, it became important to explore how these systems are able to maintain stability. Although a neuron can live over 100 years, the components of that neuron, including proteins that make up ion channels, constantly change on a timescale of seconds to weeks. Marder worked in collaboration with Larry Abbott and his lab to study how neurons maintain appropriate activity despite such rapid turnover. This work resulted in theoretical models suggesting that neurons have an intrinsic “set-point.” An individual neuron mediates changes in ion channels to produce a specific desirable activity output. This work informed our understanding of how neurons and nervous systems are able to be both plastic, but also to remain functional in a constantly changing environment. It has given rise to work investigating how synapses are able to respond to changing activity or “synaptic scaling” and research into how neurons determine their “set-point” at a molecular level.

Many of the numerous primary and review papers stacked in Marder’s office have been co-authored by some of her almost 80 graduate students and post-docs. These papers have been the work of both experimentalists, who gather data from real neurons, and theorists, who use computers to make hypothetical models of neurons. The collaborative working environment lends strength to the work completed in the Marder lab and forces students and post-docs to explain their work to peers with very different skill sets. It also gives lab members an opportunity to use both theory and experiments to cooperatively build stronger models and to design better experiments. As one example of this, Marder and Abbott together developed the dynamic clamp tool. Using this tool, real biological neurons are connected to model neurons generated within computer programs. This system, now used by scientists all over the world, makes well-controlled manipulations while still probing a dynamically complex biological system.

Wandering through the Marder lab on any given day, it is always buzzing with students and postdocs at computers, doing dissections, or popping into Marder’s office for a quick chat and some chocolate. Currently, the Marder lab is investigating variability in neural circuits. Scientists often view variability as a result of experimental error and attempt to minimize it through averaging over multiple trials. Marder’s approach has revealed that variability is a natural part of how neurons and circuits are constructed and can reveal very important information about how these systems work. Both experimental and theoretical work from the Marder lab has shown that neurons with widely varying characteristics can exhibit nearly identical activity patterns. Thus rather than finding the average properties of a neuron, it is crucial to understand how functionality is maintained in the presence of this variability.

Picture2

Dye fill of STG neuron by Marder lab members

One way the Marder lab currently studies this variability is using temperature change, a physiologically relevant stimulus for crabs who live in varying depths of water throughout the year. Understanding more about how different neuromodulators affect the activity rhythm continues to be an ongoing project since approximately 50 neuromodulators have been discovered in the STG. Other lab members are interested in observing variability in the morphology of different cell types. STG neurons visually have a cell body with a single axon that branches many times so that the cells look less like a traditional ‘neuron’ image but rather a cell body connected to something that looks like a tangled ball of hair. Other work in the lab is interested in investigating where different ion channels are located on this highly branched and complex structure.

To those scientists who have met Dr. Marder she is a source of inspiration and advice. She clearly enjoys engaging with younger scientists especially graduate students and postdocs and many of them have experienced her mentorship throughout their careers. Barbara Beltz of Wellesley College wrote of Marder “It has been clear to me for a long time that although I had PhD and postdoctoral advisors who were supportive and kind, it was Eve who was the most influential mentor in my career.” Marder provides supportive encouragement always paired with frank honesty sometimes in the form of tough love. Ted Brookings, a former Marder lab post-doc says that Marder takes mentorship very seriously and her greatest pride as an advisor is not in selecting the most brilliant people but instead seeing the evidence of how much they have grown during their time in the lab. Many female scientists in particular see her as a trail-blazer and those who have been to her office find the life-sized cutout of Xena Warrior Princess to be appropriate decor.

Working at her undergraduate alma mater, Brandeis University since 1978, Marder helped to build one of the first undergraduate neuroscience programs in the country and a highly regarded neuroscience PhD program. Even as a senior professor, Marder often teaches the Principles of Neuroscience course taken by upper-level undergraduates and required for incoming graduate students. She is unique among the faculty for teaching the course using the blackboard rather than Powerpoint and begins each year with a new bucket of large colorful sidewalk chalk. According to a former Marder lab graduate student, Marder’s teaching permeates everything she does, whether she’s in front of the classroom, having a personal sit down in her office or giving a grand seminar.

IMG_1984 (1)

Celebration party after Kavli Prize 2016 announcement. Photo by Steven Karel.

Marder received hundreds of congratulatory emails from colleagues and former students and post-docs after the announcement of the Kavli Prize. The extensive body of research from Marder and her students, using the STG, has revealed fundamental properties that apply to all nervous systems. One of her colleagues at Brandeis University, Leslie Griffith has written “Her work has provided a platform for much of our current cellular understanding of circuit function and stability and the mechanisms by which circuits negotiate the flexibility/stability trade-off.” The homemade mobile rotating above her head in her office appears to capture the essence of how Marder views her work and her lab – old and new people constantly in motion orbiting groundbreaking discoveries in neuroscience.

Drawing by Ben Marder

Drawing by Ben Marder

 

 

About the Author

Maria Genco is a PhD candidate in the Neuroscience Program working in the Griffith Lab at Brandeis University.

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