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Leading Science: Magnifying the Mind

December 14, 2018 By

Brandeis Magnify the Mind

Written by Zosia Busé, B.A. ’20

Joshua Trachtenberg, graduated from Brandeis in 1990 and is a leader in studying the living brain in action using advanced imaging technology. After establishing his research laboratory at UCLA, he founded a company – Neurolabware – in order to build the sophisticated custom research microscopes that are needed to perform groundbreaking work in understanding how the brain develops and how diseases and injuries interrupt its normal functioning. His company is created by scientists and for scientists, and is unique in creating high quality microscopes that are easy to use but also have the flexibility to be used in creative ways in innovative experiments, and in combination with a variety of other devices.

Brandeis University is now seeking to acquire one of these advanced microscopes that can observe fundamental processes inside the living brains of animals engaged in advanced behaviors. The resonant scanning two-photon microscope from Neurolabware allows researchers to understand and image large networks of neurons in order to visualize which cells and networks are involved with specific memories or how these processes go awry in disease. “This approach is unparalleled. There is no other technique around that could possibly touch this,” Trachtenberg says.

Previous two-photon technologies permitted only very slow imaging, allowing scientists to take a picture about every two seconds, but the resonant two-photon technology is a major breakthrough that allows scientists to take pictures at about 30 frames per second. This speed increase is a major game changer. Not only can one observe activity in the brain at a higher speed, but it is possible to take pictures at a speed that is faster than the movement artifacts that must be accounted for, such as breathing or heart beats. Because one can see the movement, it can be corrected, allowing high resolution functional imaging of structures as small as single synaptic spines in the living brain. Further, advances in laser technology and fluorescent labels now allow scientists to see deeper into the brain than ever before, compounding the recent advantages of increased speed.

[Read more…]

Filed Under: labs, Neuroscience Tagged With: , , , ,

Paradis and Van Hooser labs collaborate on eLife paper

July 3, 2018 By
Figure 3 from research paper

Figure 3. Rem2 is required for late-phase critical period ocular dominance plasticity.

“Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits.” Anna R Moore, Sarah E Richards, Katelyn Kenny, Leandro Royer, Urann Chan, Kelly Flavahan, Stephen D Van Hooser, Suzanne Paradis. eLife 2018;7:e33092.

Throughout our waking hours, we experience an ever-changing stream of input from our senses. The brain responds to this varying input by adjusting its own activity levels and even its own structure. It does this by changing the strength of the connections between neurons, or the properties of the neurons themselves. Known as plasticity, this process of continuous change enables the brain to develop, learn and to recover from injury.

The visual systems of mammals are particularly well suited to studying how sensory experience alters the brain. Studies in animals show that lack of sensory input to one or both eyes during a critical period in development causes long-lasting changes in the brain’s visual circuits. Similarly, children with the condition amblyopia or ‘lazy eye’ – in which one eye has impaired vision and the brain ignores input from that eye – can end up with permanent deficits in their vision if the condition is not treated during childhood. Changes in sensory input are thought to trigger plasticity in the brain by altering the activity of specific genes. But exactly how this process works is unclear.

Anna Moore, Sarah Richards et al. now show that a gene called Rem2 has an important role in regulating visual plasticity. In the key experiments, young mice had their vision in one eye blocked for a few days. Analysis of their brains showed that mice that had been genetically modified to lack the Rem2 gene responded differently to this change in their environment (i.e. the loss of input to one eye) than their normal counterparts. Further experiments suggest that Rem2 regulates the excitability of individual neurons: that is, how much the neurons respond to any given input. In the absence of Rem2, neurons in visual areas of the brain become hyperactive. This prevents them from adjusting their activity levels in response to changes in sensory input, which in turn leads to impaired plasticity.

Being able to harness the brain’s visual plasticity mechanisms on demand, for example by regulating Rem2 activity, could benefit individuals with disorders such as amblyopia. Rem2 is also active in many other parts of the brain besides those that support vision. This suggests that manipulating this gene could affect numerous forms of plasticity. However, various barriers must be overcome before we could use this approach to treat brain disorders. These include obtaining a more in depth understanding of the role of the Rem2 gene in the human brain.

Filed Under: labs, Neuroscience Tagged With: , ,

Learning to see

June 5, 2017 By

How do we learn to see? Proper visual experience during the first weeks and months of life is critical for the proper development of the visual system. But how does experience modify neural circuits so that they exhibit the proper responses to visual stimuli? Knowledge of the mechanisms by which the brain is constructed early in development should inspire new therapies for repairing the brain if it develops improperly or is damaged by disease or injury.

At the present time, it is not possible to directly view all or even most connections within a living neural circuit. Therefore, neuroscientists often build computational models to study how these circuits may be constructed and how they may change with experience. A good model allows scientists to understand how these circuits may work in principle, and offers testable predictions that can be examined in the living animal to either support or refute the model.

Undergraduate Ian Christie ’16 was interested in understanding how neural circuits in the ferret visual system become selective to visual motion. At the time of eye opening, neurons in ferret visual cortex respond to an object moving in either of two opposite directions. With about a week of visual experience, each neuron develops a preference for only one of these directions, and greatly reduces its responses to the opposite direction.

Previous models of this process posited that the primary source of the change was in the organization and pattern of inputs to the cortex. But, recent experiments from the Van Hooser lab (Roy/Osik/Ritter et al., 2016) showed that stimulating the cortex by itself was sufficient to cause the development of motion selectivity, which suggests that some changes within the cortex itself must be underlying the increase in selectivity, at least in part. Further, other experiments in the lab of former Brandeis postdoc Arianna Maffei (Griffen et al., 2012) have shown that the cortex becomes less excitable to focal stimulation over the first weeks after eye opening.

Ian constructed families of computational models that could account for both of these observations. In the model, columns of neurons in the cortex already receive input that is slightly selective for motion in one of two opposite directions, but the connections between these cortical columns are so strong that both columns respond to both directions. However, the activity that is caused by simulated visual experience activates synaptic plasticity mechanisms in the model, that served to greatly reduce the strength of these connections between the columns, allowing motion selectivity to emerge in the cortical columns. The project was supervised by faculty members Paul Miller and Stephen Van Hooser, and the results were published in Journal of Neurophysiology (Christie et al., 2017).

Future experiments will now look for evidence of weaker connectivity between cortical neurons with visual experience.

This work was supported by the “Undergraduate and Graduate Training in Computational Neuroscience” grant to Brandeis University from NIH, and by the National Eye Institute grant EY022122. It also used the Brandeis University High Performance Computing Cluster.

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Sleep suppresses brain rebalancing

March 18, 2016 By

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.

Filed Under: grad students, Neuroscience, postdocs, Undergrads Tagged With: , , , , ,

How seeing can change what you see

December 21, 2012 By

We sometimes take it for granted how the way we see enables us to perceive and interact with the world, but how our visual system works is amazing. It’s an intricately choreographed process – from the light that comes into our eyes, to the way that our brains carry that information and form it into an image we can understand. If brain cells are improperly connected during growth and development, or if part of the system is destroyed by injury, all kinds of visual havoc can be a result. But how does a brain get wired properly in the first place?

 In a paper in the Journal of Neuroscience last week, Professor Steve Van Hooser’s lab reported some of the effects of experience on development. The new paper shows evidence that neurons in all layers of the visual cortex aren’t just ‘born’ with the right connections between the parts of the brain that control vision. According to their data, the act of seeing itself makes changes in how the neurons process visual information. The lab is continuing their studies of brain circuits to uncover how, during development, the act of seeing changes how you see.
Clemens JM, Ritter NJ, Roy A, Miller JM, and Van Hooser SD. The Laminar Development of Direction Selectivity in Ferret Visual Cortex. J. Neurosci. 12 December 2012, 32(50): 18177-18185. 
Filed Under: Biology, labs Tagged With: , , , ,

Illuminating career paths in the sciences for high school students

November 16, 2010 By

On November 5th, the Van Hooser lab in the Biology Department hosted nine high school students from Hyde Park’s Boston Preparatory Charter Public School (BPCPS) for both a tour of the lab and an open question session about the specific goals of the lab’s research, and about science careers in general.

Boston Prep serves students from disadvantaged areas of Boston, with 76% qualifying for free and reduced price lunch and 92% being of minority racial backgrounds. As part of a rigorous educational program that seeks to prepare them for college and beyond, BPCPS sophmores visit various area businesses twice a year for hands-on learning about the careers open to them. The school has been nationally recognized for its academic excellence. It also bucks trends in the sciences — while nationwide there is a noted drop-off in interest in the sciences as students enter high school, particularly among young women,  (Osborne, Simon, and Collins 2003; American Assoc. of University Women, 1992), students at Boston Prep retain a high interest in the sciences throughout their tenure there, and female students actually become more interested in the sciences in high school.

Assistant Professor Steve Van Hooser led the students through a brief introduction to life in an academic science lab and his personal career path, before discussing his lab’s focus on the visual system and the impact that basic research has on everyday life and understanding. The students then took a tour of the lab, and were able to visualize neurons under the lab’s 2-photon microscope. After the visit, Steve noted, “It was terrific to be able to talk with such promising young people and to share a little of the brain science we are doing here at Brandeis.  The students asked really insightful questions about our studies, the use of animals in research, and the clinical applications of basic research.  It is exciting to think about what these students will be doing in 15 years.”

Those interested in hosting a future visit from students can contact Jenn Wolff from the Van Hooser lab (jwolff at brandeis.edu), or contact Danielle Pape at BPCPS directly ( dpape at bostonprep.org (617)333-6688 ext. 126 )

Filed Under: Biology, labs, Neuroscience, outreach Tagged With: ,

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