The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

benefits-midage

They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

Sleep suppresses brain rebalancing

Why humans and other animals sleep is one of the remaining deep mysteries of physiology. One prominent theory in neuroscience is that sleep is when the brain replays memories “offline” to better encode them (“memory consolidation”). A prominent and competing theory is that sleep is important for re-balancing activity in brain networks that have been perturbed during learning while awake. Such “rebalancing” of brain activity involves homeostatic plasticity mechanisms that were first discovered at Brandeis University, and have been thoroughly studied by a number of Brandeis labs including the Turrigiano lab. Now, a study from the Turrigiano lab just published in the journal Cell shows that these homeostatic mechanisms are indeed gated by sleep and wake, but in the opposite direction from that theorized previously: homeostatic brain rebalancing occurs exclusively when animals are awake, and is suppressed by sleep. These findings raise the intriguing possibility that different forms of brain plasticity – for example those involved in memory consolidation and those involved in homeostatic rebalancing – must be temporally segregated from each other to prevent interference.

sleeprats

The requirement that neurons carefully maintain an average firing rate, much like the thermostat in a house senses and maintains temperature, has long been suggested by computational work. Without homeostatic (“thermostat-like”) control of firing rates, models of neural networks cannot learn and drift into states of epilepsy-like saturation or complete quiescence. Much of the work in discovering and describing candidate mechanisms continues to be conducted at Brandeis. In 2013, the Turrigiano Lab provided the first ­in vivo evidence for firing rate homeostasis in the mammalian brain: lab members recorded the activity of individual neurons in the visual cortex of freely behaving rat pups for 8h per day across a nine-day period during which vision through one eye was occluded. The activity of neurons initially dropped, but over the next 4 days, firing rates came back to basal levels despite the visual occlusion. In essence, these experiments confirmed what had long been suspected – the activity of neurons in intact brains is indeed homeostatically governed.

Due to the unique opportunity to study a fundamental mechanism of brain plasticity in an unrestrained animal, the lab has been probing the possibility of an intersection between an animal’s behavior and homeostatic plasticity. In order to truly evaluate possible circadian and behavioral influences on neuronal homeostasis, it was necessary to capture the entire 9-day experiment, rather than evaluate snapshots of each day. For this work, the Turrigiano Lab had to find creative computational solutions to recording many terabytes of data necessary to follow the activity of single neurons without interruption for more than 200 hours. Ultimately, these data revealed that the homeostatic regulation of neuronal activity in the cortex is gated by sleep and wake states. In a surprising and unpredicted twist, the homeostatic recovery of activity occurred almost exclusively during periods of activity and was inhibited during sleep. Prior predictions either assumed no role for behavioral state, or that sleeping would account for homeostasis. Finally, the lab established evidence for a causal role for active waking by artificially enhancing natural waking periods during the homeostatic rebound. When animals were kept awake, homeostatic plasticity was further enhanced.

This finding opens doors onto a new field of understanding the behavioral, environmental, and circadian influences on homeostatic plasticity mechanisms in the brain. Some of the key questions that immediately beg to be answered include:

  • What it is about sleep that precludes the expression of homeostatic plasticity?
  • How is it possible that mechanisms requiring complex patterns of transcription, translation, trafficking, and modification can be modulated on the short timescales of behavioral state-transitions in rodents?
  • And finally, how generalizable is this finding? As homeostasis is bidirectional, does a shift in the opposite direction similarly require wake or does the change in sign allow for new rules in expression?

Authors on the paper include postdoctoral fellow Keith Hengen, Neuroscience grad student Alejandro Torrado Pachedo, and Neuroscience undergraduate James McGregor ’14 (now in grad school at Emory).

Hengen KB, Torrado Pacheco A, McGregor JN, Van Hooser SD, Turrigiano GG. Neuronal Firing Rate Homeostasis is Inhibited by Sleep and Promoted by Wake. Cell. 2016.

Introduction to Microfluidics Technology – June 13-17, 2016

2016 MRSEC Summer Course Announcement

Registration for our annual, one-week summer course, “Introduction to Microfluidics Technology” at Brandeis University, near Boston, MA, is now open. The application deadline is March 31, 2016.

Introduction to Microfluidics Technology is a hands-on laboratory course sponsored by the National Science Foundation’s Bioinspired Soft Materials Research Science and Engineering Center (MRSEC) at Brandeis. It will be offered during the week of June 13 ‐ 17, 2016. The course is intended for graduate students, post docs, faculty, and industrial scientists/engineers interested in utilizing microfluidic technology in their work, both in the physical and life sciences. The course does not assume any specific prerequisites.

“Introduction to Microfluidics Technology” (June 13 – 17, 2016)
will be taught by Dr. Nathan Tompkins.

The $750 fee covers course tuition, housing in double-occupancy rooms, and breakfast/lunch/coffee from Monday through Friday. Single rooms are not available. Local students who do not need housing will pay a non-resident fee of $500 (cash and check only please).

More information is available.

Data Diving for Genomics Treasure

Laboratories around the world and here at Brandeis are generating a tsunami of deep-sequencing data from organisms large and small, past and present. These sequencing data range from genomes to segments of chromatin to RNA transcripts. To explore this “big data” ocean, one can navigate the portals of the National Computational Biotechnology Institute’s (NCBI’s) two signature repositories, the Sequencing Read Archive (SRA) and the Gene Expression Omnibus (GEO).  With the right bioinformatics tools, scientists can explore and discover freely-available data that can lead to new biological insights.

Nelson Lau’s lab in the Department of Biology at Brandeis has recently completed two such successful voyages of genomics data mining, with studies published in the Open Access journals of Nucleic Acids Research (NAR) and the Public Library of Science Genetics (PLoSGen).   Publication of both these two studies was supported by the Brandeis University LTS Open Access Fund for Scholarly Communications.

In this scientific journey, the Lau lab made use of important collaborations from across the globe. The NAR study employed openly shared genomics data from the United Kingdom (Casey Bergman lab) and Germany (Björn Brembs lab).  The PlosGen study employed contributions from Austria (Daniel Gerlach), Australia (Benjamin Kile’s lab), Nebraska (Mayumi Naramura’s lab), and next door neighors (Bonnie Berger’s lab at MIT).  This collaborative effort has been noted at Björn Bremb’s blog, who has been a vocal advocate for Open Access and Open Data Sharing to improve the speed and accessibility of communicating scientific research.

tidal fly banner

In the NAR study, postdoctoral fellow Reazur Rahman and the Lau team devised a program called TIDAL (Transposon Insertion and Depletion AnaLyzer) that scoured over 360 fly genome sequences publicly accessible in the SRA portal.  Their study discovered that transposons (jumping genetic parasites) formed different genome patterns in every fly strain.  Common fly strains with the same name but living in different laboratories turn out to have very different patterns of transposons. Simply noting “Canton-S” or “Oregon-R” strains are used may not be enough to fully characterize a strain.  The Lau lab hopes to utilize the TIDAL tool to study how expanding transposon patterns might alter genomes in aging fly brains.

animals

The piRNAs from these animals were compared in the PLoS Genetics story

In the PLoSGen study, visiting scientist Gung-wei Chirn and the Lau team developed a novel small RNA tracking program that discovered Piwi-interacting RNA loci expression patterns from many mammalian datasets extracted from the GEO portal.  Coupling these datasets with other small RNA datasets created in the Lau lab at Brandeis, the Lau group discovered a remarkable diversity of these RNA loci for each species. For example, the piRNA genomic loci made in humans were quite distinct from other primates like the macaque monkey and the marmoset.  However, a special set of these genomic loci have been conserved in their piRNA expression patterns, extending across humans, through primates, to rodents, and even to dogs, horses and pigs.

These conserved piRNA expression patterns span nearly 100 million years of evolution, which is quite a long time for these types of loci to be maintained for some likely important function in mammals.  To test this hypothesis that evolution preserved these piRNAs for their utility, the Lau lab analyzed two existing mouse mutations in these loci.  They showed that the mutations indeed affected the generation of the piRNAs, and these mice were less fertile because sperm count was reduced.  The future studies from the Lau lab will explore how infertility diseases may be linked to these specific piRNA loci.

TIDAL-Fly: a new database resource of Transposon Landscapes for understanding animal genome dynamics.

We tend to think of our genomes as nicely-ordered encyclopedias,  curated with only useful information that makes up our genes.  In actuality, nature and evolution is extremely sloppy.  All animal genomes, from us humans to the simple fruit fly, are littered with genetic baggage.  This baggage is sizeable, making up at least 11% of the fly genome and more than 45% of our genome.  The scientific term for this baggage is transposable elements (TEs) or transposons, which are mobile entities that must copy themselves to other places of the genome to ensure their survival during animal evolution.

Because there are so many copies of transposons, they can be difficult to analyze by most standard genetic methods. Brandeis postdoctoral fellow Reazur Rahman and a team in Nelson Lau’s lab have formulated a new tool called the Transposon Insertion and Depletion AnaLyzer (TIDAL). TIDAL aims to provide an accurate and user-friendly program to reveal how frequently transposons can move around in animal genomes.  Currently, the TIDAL tool has been applied to over 360 fruit fly genomes that have been sequenced and deposited in the NIH NCBI Sequencing Read Archive.  The outputs from this program are available to the whole genetics community through the TIDAL-FLY database.

tidal fly banner

The TIDAL-Fly database will allow geneticists to pick their favorite fly strain and see if a transposon has landed near to their gene and perhaps affect gene expression. Fruit flies are key model organisms utilized by many researchers, including here at Brandeis, to study human diseases, from infertility to insulin signaling to aging to sleep disorders.  Since these new transposon insertions are not available in the standard genome databases, this tool and website may provide answers to previously puzzling genetic effects not revealed by typical DNA sequencing studies.  It is Reazur’s and the Lau lab’s goal to continue updating the TIDAL-Fly database with more genomes as fly genome re-sequencing becomes easier and easier to perform.

see also: Rahman R, Chirn GW, Kanodia A, Sytnikova YA, Brembs B, Bergman CM, Lau NC. Unique transposon landscapes are pervasive across Drosophila melanogaster genomes. Nucleic Acids Res. 2015.

Summer 2015: “Introduction to Microfluidics Technology”

Students are in the cleanroom during training.

Students in the clean room during training

The annual one-week course offered during the summer of 2015 is “Introduction to Microfluidics Technology” (June 22 – 26). It will be held at Brandeis University and sponsored by the National Science Foundation’s Bioinspired Soft Materials Research Science and Engineering Center (MRSEC) at Brandeis. It is intended for graduate students, post docs, faculty and industrial scientists and engineers interested in utilizing microfluidic technology in their work, in both physical sciences and life sciences, and does not assume any specific prerequisites.

SUMMER COURSE ANNOUNCEMENT 2015

Microfluidic Xmas Tree

Protected by Akismet
Blog with WordPress

Welcome Guest | Login (Brandeis Members Only)