Turrigiano lab uncovers sources of neuronal heterogeneity

High activity neurons have greater instrinsic excitability and response to local inputs, but no difference in total input type or amount

Mammalian cortex has long been one of the most widely studied systems in neuroscience, dating back to the pioneering work of Santiago Ramon y Cajal in the late 19th century. The cortex is much larger in primates than other mammals, and is thought to be responsible for the advanced cognitive abilities of humans. Today, models of cortical connections and computations form the basis for some of the most powerful deep learning paradigms. However, despite this success, there is still much that is unknown about how cortex functions. One feature of cortex that has recently been discovered is that neurons that appear to be similar to each other can have very different baseline activity levels: some neurons are 100x more active than their neighbors. We don’t know how neurons that are otherwise highly similar in shape and genetic makeup can maintain such different activity levels, or if the neurons with high and low activity levels have different functions in the brain. These neurons are otherwise so similar to each other that it is difficult to tell them apart without recording their activity directly, and current techniques for recording the activity of many neurons simultaneously in live animals do not allow us to later re-identify them for further study.

In a paper recently published in Neuron, the Turrigiano lab, led by postdoctoral researcher Nick Trojanowski, reported a new approach for permanently labeling high and low activity neurons in live animals, and then determining what makes them different. To do this they used a fluorescent protein called CaMPARI2 that changes from green to red as activity increases, but only when exposed to UV light. By shining UV light into the brain, they caused neurons with high activity to turn red, while neurons with low activity remained green. This procedure allowed them to run a series of tests on high and low activity neurons to identify differences between them. They found that high activity neurons would intrinsically generate more activity than low activity neurons when presented with the same stimulus. These high activity neurons also receive more excitatory input specifically from nearby neurons of the same type. Surprisingly, however, they found that the total amount of excitatory and inhibitory input that high and low activity neurons received from other neurons was not a major factor in determining their activity levels. Together, these results tell us that the differences in activity between neurons are due to intrinsic differences, as well as their pattern of connectivity to their nearby partners. This has deep implications for how the networks that underlie cortical computations are built and maintained.

With these tools in hand, it is now possible to further explore the differences between high and low activity neurons. Do these neurons serve different functions? Are the baseline activity levels specified from birth? How do these activity levels affect the mechanisms of plasticity that are responsible for learning and memory? The recently published results represent just the tip of the iceberg of information that can be learned with this new technique, in the mammalian cortex as well as other brain regions.

Learning from how viruses assemble

Capsid image from paper

credit: eLife

Michael Hagan, Professor of Physics, is quoted extensively in the Chemical & Engineering News article, Lessons learned from watching viruses assemble. The paper discusses how scientists are studying the ability for viruses to self-assemble. During a viral infection, infected cells manufacture the genetic material and other components of the virus. These components then self-assemble, or build themselves into complex shapes, to form new viruses capable of infecting additional cells.

Many viruses contain their genetic material within a protective shell known as a capsid. Michael Hagan is one of the scientists studying how these capsids are formed by modeling the conditions and chemical properties that allow viruses to build themselves. Once understood, researchers hope this will help in drug design and delivery.

Article: Lessons learned from watching viruses assemble, Laura Howes, Chemical & Engineering News-C&EN,  December 15, 2020.

Grace Han named Landsman Career Development Chair in the Sciences

Grace Han, Assistant Professor of Chemistry, has been appointed the Landsman Career Development Chair in the Sciences. Lisa Lynch, Provost and Dorothy Hodgson, Dean of Arts and Sciences, noted that Han’s work as a “scholar, a teacher, and an advisor, makes [her] highly deserving of the Landsman Chair.”

Grace directs the Han Group at Brandeis. This lab, whose scientific inquiry focuses on light-matter interaction in various material systems that range from photo-switching molecules to inorganic 2D crystals.  Her team seeks to develop optically-controlled molecular switches for energy conversation and storage and optoelectronic applications.

Grace’s research has resulted in a project, “Optically-Controlled Functional Heat Storage Materials,” which was featured in Chemical and Engineering News upon being granted Brandeis SPROUT Awards in 2019 and again in 2020.  In this work, the Han Group developed materials that recycle waste heat from a running engine and warm up frozen oil upon triggering to facilitate car startups in northern climes.  The Han Group is currently developing the initial prototype for the device containing the functional energy material.

At Brandeis, Grace teaches “Inorganic Chemistry,” “Polymer and Inorganic Materials Chemistry,” and “Chemistry Colloquium.”  She is co-chair of the Graduate Student Admissions Committee and of the Departmental Colloquium Committee and is also a member of the Graduate Studies Committee. Grace has most recently co-authored articles for the Journal of the American Chemical Society, Chemistry of Materials, and ACS Nano.

The Landsman Chair was established in 2015 through a gift from Dr. Emanuel Landsman. The Landsman Chair reflects his deep commitment to nurturing rising young scientists.

Longtime supporters of the University, Manny and his wife, Sheila Landsman, also gifted the funds used to build the Landsman Research Facility. This is the structure that houses an 800 MHz magnetic resonance spectrometer. The 15,000-pound superconducting magnet is used by scientists to search for solutions to neurodegenerative diseases and cancer.  Dr. Landsman co-founded the American Power Conversion Corporation, served on the Brandeis University Science Advisory Council for many years, and was named a Brandeis Fellow in 2008.  The Landsmans’ grandson, Wiley Krishnaswamy, is a member of the Class of 2020.

Griffith lab finds that time-keeping brain protein influences memory

Figure from Griffith lab paperIn the Journal of Neuroscience, members of the Griffith Lab found that memory impairments can result from disruptions in the release of the peptide Pigment-dispersing factor (PDF). PDF aligns the brain’s time-keeping mechanism to the correct time of day.

Upsetting the brain’s timekeeping can cause cognitive impairments, like when jetlag makes you feel foggy and forgetful. These impairments may stem from disrupting a protein that aligns the brain’s time-keeping mechanism to the correct time of day, according to new research in fruit flies published in JNeurosci.

The brain contains ‘clock’ neurons that collectively mold circadian behaviors and link them to cues from the environment, like light and seasonal changes. In fruit flies, the peptide Pigment-dispersing factor (PDF) is released from the clock to both synchronize the activity of the clock neurons and to drive time-based behaviors like mating and sleep. PDF may also underlie memory formation, explaining the cognitive dysfunction that occurs when the clock is desynchronized from the environment.

Flyer-Adams et al. tested how well fruit flies with a functioning core clock, but lacking the PDF output signal, could learn. They found that without PDF signaling, flies had severely impaired memory. Interestingly, memory regulation by PDF likely occurs without direct signaling to the main memory structure of flies. Their results suggest that PDF from the clock may promote normal memory throughout the day by acting as a timestamp to learning. The VIP pathway in humans may play a similar role.

Publication:

Regulation of olfactory associative memory by the circadian clock output signal Pigment-dispersing factor (PDF). Johanna G. Flyer-AdamsEmmanuel J. Rivera-RodriguezJunwei YuJacob D. MardovinMartha L. Reed and Leslie C. Griffith. 

Hedstrom Receives NIH Director’s Transformative Research Award

Liz HedstromBrandeis University chemical biologist Lizbeth Hedstrom received one of nine Director’s Transformative Research Awards this year from the National Institutes of Health under its High-Risk, High-Reward Research Program.  The 5-year, $3.5 mil grant will support the development of new methods for drug design relying on targeted protein degradation.  This emerging strategy has several potential therapeutic advantages over traditional approaches, including the development of more potent, longer acting, drugs.

The rational design of ‘degraders’ has focused almost exclusively on degradation induced when the target protein is modified with ubiquitin.  In contrast, Hedstrom will be developing ubiquitin-independent strategies.

Susan Lovett elected to the American Academy of Arts and Sciences

Susan LovettSusan Lovett, the Abraham S. and Gertrude Burg Professor of Microbiology, has been elected to the American Academy of Arts and Sciences. She was among the 276 outstanding individuals that were elected to the Academy in 2020 and announced on April 23. Brandeis University Professor, Anita Hill, joins Professor Lovett as a 2020 member of AAAS.

The Lovett lab studies the fundamental mechanisms by which cells preserve genetic information by the study of DNA damage repair and mutation avoidance in the model organism Escherichia coli. Additionally, they research how cell cycle events including DNA replication and chromosome segregation are coupled to cellular physiology and to the status of the chromosome.

Lovett joins other Brandeis science faculty members: Jeff Gelles, Gina Turrigiano, James Haber, Michael Rosbash, Eve Marder, David Derosier, Gregory Petsko, Stanley Deser, and Edgar Brown, Jr.

Founded in 1780, the Academy recognizes the outstanding achievements of individuals in academia, the arts, business, government, and public affairs.

Read more: BrandeisNow

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