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.

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.

Gina Turrigiano Named One of the “30 Most Influential Neuroscientists Alive Today”

Gina Tturrigiano405urrigiano has been named one of the “30 Most Influential Neuroscientists Alive Today” by the Online Psychology Degree Guide.

The guidelines for selecting the neuroscientists include: leadership, applicability (neuroscientists that have created technologies that have improved people’s lives); awards & recognition by the international science community and other notable accomplishments such as personal or educational achievements.

Gina Turrigiano is the author of numerous papers, has been awarded a MacArthur Foundation fellowship and the HFSP Nakasone Award, and in 2013 was elected to the National Academy of Sciences.

Fast-spiking interneurons and the critical period

How do children learn to play instruments and speak languages so much easier than adults, and why does brain damage result in worse outcomes in the mature brain vs. the young brain?  These questions are central to the study of how “critical periods” are regulated in the brain.

fs-interneuron

Electron micrograph from a single 70 nm cross-section through a fast-spiking parvalbumin-containing (gold labeling = white dots) presynaptic terminal forming a synapse (red dots) with a pyramidal soma. Original colors are inverted, contours have been raised and membranous structures are highlighted in aqua for ease of visualization. Presynaptic vesicles (colored ovals) within perisomatic fast spiking terminals mostly cluster within ∼200 nm of the synapse, with a few close enough (≤2 nm) to be deemed docked.

Critical periods in brain development define temporal windows when neuronal physiology and anatomy are most sensitive to changes in sensory input or experience (e.g. sound, touch, light, etc.).  The maturation of inhibitory cells that release the neurotransmitter GABA, especially a subset called fast-spiking (FS) interneurons, is thought to gate this period of neuronal ‘plasticity’ in the mammalian primary visual cortex.  However, it has remained unclear what aspects of FS cell development are important for permitting this period of neuronal malleability in the visual cortex. A new paper in Journal of Neuroscience from the Turrigiano lab addresses the question.

To explore how FS cell development might be linked to critical period plasticity, Brandeis postdoc Marc Nahmani and Professor Gina Turrigiano employed a well-established assay for cortical plasticity in visual cortex called monocular deprivation (MD), and measured FS cell connections using confocal and electron microscopy, as well as optogenetic stimulation of the FS cell population (i.e. shining light onto FS cells possessing light-gated channels to make them fire action potentials).

Following up on previous work from the Turrigiano lab (Maffei et al., 2006), they found that MD induces a coordinated increase in FS interneuron to pyramidal cell (the major excitatory output cells of the cortex) pre- and postsynaptic strength.  These changes occur if MD is performed during, but not before the critical period in visual cortex, suggesting they may play a role in gating this period of heightened neuronal plasticity.  Future studies are aimed at determining the timeline for these changes across the extent of the critical period in visual cortex.

see: Nahmani M, Turrigiano GG (2014) Deprivation-Induced Strengthening of Presynaptic and Postsynaptic Inhibitory Transmission in Layer 4 of Visual Cortex during the Critical Period. Journal of Neuroscience 34:2571-2582.

DeRosier wins Distinguished Scientist Award from Microscopy Society of America

Professor Emeritus of Biology (and current Turrigiano lab “postdoc”) David DeRosier received the Distinguished Scientist Award (for Biological Science) at this year’s annual meeting of the Microscopy Society of America.

 

Turrigiano elected to NAS

Professor of Biology Gina Turrigiano has been elected to the National Academy of Sciences this month. Turrigiano, a neuroscientist, is interested in synaptic scaling and remodeling, and in the tension between plasticity and stability in neurons during learning and development.

For more information, see the story at Brandeis NOW or the Turrigiano lab website.

American Academy of Arts & Sciences elects Turrigiano, Luo and Berger.

The American Academy of Arts & Sciences recently announced its 2012 class of Fellows, including 3 current and former Brandeis scientists.

Professor of Biology Gina Turrigiano and graduate alumnus Liqun Luo (PhD ’92, Biology) were elected in the Neurosciences, Cognitive Sciences, and Behavioral Biology section. Undergraduate alumna Bonnie Berger ’83 was elected in the Mathematics section.

Turrigiano’s lab works on the plasticity of synaptic and intrinsic properties of cortical neurons and circuits. Turrigiano has been previously honored with a MacArthur Fellowship and with the Human Frontier Science Program Nakasone Award for “frontier-moving research in biology“. Luo, who did his graduate research with Kalpana White at Brandies,  is now Professor of Biology at Stanford University and an HHMI Investigator. His lab studies how neural circuits are organized and assembled during development. Berger discovered her interest and talent for math as an undergraduate at Brandeis, graduating with a degree in computer science. She obtained her PhD at MiT, where she is now Professor of Applied Mathematics and head of the Computation and Biology group at the MIT Computer Science and Artificial Intelligence Laboratory (CSAIL). Berger has continued to support Brandeis through her active membership in the Brandeis University Science Advisory Council.

The American Academy of Arts & Sciences elects leaders in the academic disciplines, the arts, business, and public affairs. Among the others elected this year are Mel Brooks, Clint Eastwood, Frederica von Stade, Melinda Gates and Hilary Clinton.

See also Brandeis NOW.

UPDATE (5/1/2012): Liqun Luo was elected to the National Academy of Sciences this year.

Sprout Grants Awarded to Seven Groups

Another Brandeis NOW story covers the results of the 2012 Sprout Grant competition. Of 20 applications received, half were software related, half life sciences and physical science-related, so the groups were judged separately. Thirteen groups were asked to return for a second round of interviews, coaching and presentations to outside panels of industry judges.  Seven groups were awarded grants:

2012 Sprout Grant winners, life and physical sciences:

  • 
Radiation detector, Wellenstein, PI $20,000
  • Tuberculosis treatment, therapeutic, Hedstrom, PI $17,000
  • Cold Stage for Light Microscopy, microscope tools, Turrigiano, PI $16,000
  • Conditional gene silencing, research tool, Lau PI, $6,000

2012 Sprout Grant winners, software:

  • Innermost Labs, social network. Sahar Massachi and Adam Hughes, $7,500
  • Digital Learning Analytics, learning analytics, Larusson PI  $6,000
  • Campus Bash, social network, Y. Sebag, and M. Jafferji $6,500

For more information about the projects and the judging process, read the story at Brandeis NOW.

Protected by Akismet
Blog with WordPress

Welcome Guest | Login (Brandeis Members Only)