Neurotalk S2E5: Graeme Davis

Each week the Stanford Neurosciences Institute (SNI) invites a prominent scientist to come to campus and share their most recent work with the Stanford community. Each week, as part of the Neuwrite West podcast NeuroTalk, we engage the SNI speaker in an informal interview/conversation. This week, we talk to Graeme Davis about teaching neurobiology at Wood's Hole, how a synapse maintains homeostasis, and more!

Dr. Davis is a professor of neuroscience at UC San Francisco.

Listen to NeuroTalk S2E5 Graeme Davis by NeuWriteWest | Explore the largest community of artists, bands, podcasters and creators of music & audio.

Listening options: Our conversation with professor Davis can be streamed or downloaded here: NeuroTalk S2E5 Graeme Davis You can also subscribe to NeuroTalk though iTunes by searching for "Neuwritewest" in the iTunes store and subscribing to our channel.

NeuroTalk S2E4 Gail Mandel

Each week the Stanford Neurosciences Institute (SNI) invites a prominent scientist to come to campus and share their most recent work with the Stanford community. Each week, as part of the Neuwrite West podcast NeuroTalk, we engage the SNI speaker in an informal interview/conversation. This week, we talk to Gail Mandel about her long, and winding journey into neuroscience, what makes a neuron a neuron, how astrocytes contribute to neurological disorder, and more!

Dr. Mandel is a Senior Scientist at the Vollum Institute and a Professor in the Department of Biochemistry and Molecular Biology at the Oregon Health and Science University, as well as an HHMI investigator.

Gail Mandel talks about her long, and winding journey into neuroscience, what makes a neuron a neuron, how astrocytes contribute to neurological disorder, and more! Dr. Mandel is a Senior Scientist at the Vollum Institute and a Professor in the Department of Biochemistry and Molecular Biology at the Oregon Health and Science University, as well as an HHMI investigator.

Listening options:

Our conversation with professor Mandel can be streamed or downloaded here: 

NeuroTalk S2E4 Gail Mandel

You can also subscribe to NeuroTalk though iTunes by searching for "Neuwritewest" in the iTunes store and subscribing to our channel.

NeuroTalk S2E3 Penguins & Pajamas

 This week on NeuroTalk, we bring you a special report about a scientific sleepover hosted by the California Academy of Science called Penguins & Pajamas! Stanford postdocs from a variety of disciplines presented on their research, and we bring stories from the event, and speak with Mary Cavanagh and Antoine de Morree from the Stanford postdoc association. Below, you'll also find full interviews with many of the postdocs at the event.  

This week we bring you a special report about a scientific sleepover hosted by the California Academy of Science called Penguins & Pajamas! Stanford postdocs from a variety of disciplines presented on their research, and we bring stories from the event, and speak with Mary Cavanagh and Antoine de Morree from the Stanford postdoc association.

David Zhang talks about the science behind cloning, and the ongoing efforts to clone a woolly mammoth.

Felice Kelly and Fiona Strouts talk about how live bacteria and yeasts transform simple ingredients into more complex flavors.

Gazi Yildirim talks about the Quake Catcher Network, the world's largest, low-cost strong-motion seismic network.

Learn more about the Quake Catcher Network here: http://qcn.stanford.edu/

Jenny Lumb describes the science of hula-hooping!

Jolyn Gisselberg

Merav Vonshak talks about the worldwide domination of invasive ants and consequences for biodiversity.

Rico Rojas talks about cholera, climate change, and the ecological relationships between humans and their pathogens.

Zeeshan Maan talks about translating research from the bench to the bedside.

Urvi Vyas talks about conducting brain surgery without ultrasound.

Viola Caretti talks about a novel approach to studying brain cancer by using light-activated neuronal stimulation.

Stefano Bonetti explains how to use magnetism to get a levitating train.

Avi Adhikari talks about the neurobiology underlying anxiety.

All pictures by Mark Padolina and Luqia Hou.

You can find more information about the Stanford Postdoc Association on their website: http://www.stanford.edu/group/supd/

or their Facebook page: https://www.facebook.com/StanfordUniversityPostdoctoralAssociation

You can find more information about Penguins & Pajamas on the California Academy of Sciences website: http://www.calacademy.org/events/sleepovers/

For more information about Stanford's involvement in Penguins & Pajamas, and other events, you can also contact Mary Cavanagh directly at museumpostdocs@gmail.com

NeuroTalk S2E2: Diana Bautista

Each week the Stanford Neurosciences Institute (SNI) invites a prominent scientist to come to campus and share their most recent work with the Stanford community. Each week, as part of the Neuwrite West podcast NeuroTalk, we engage the SNI speaker in an informal interview/conversation, with the aim of gaining a better insight into the speaker’s personality, and providing a platform for the kinds of stories which are of interest to us but are often left out of more formal papers or presentations. This week, we talk to Diana Bautista about the difference between itch and pain, the curious organ of the star-nosed mole, and more! Dr. Bautista is an assistant professor of molecular and cellular biology at the University of California at Berkeley.

This week, we talk to Diana Bautista about the difference between itch and pain, the curious organ of the star-nosed mole, and more! Dr. Bautista is an assistant professor of molecular and cellular biology at the University of California at Berkeley.

Other listening options: Our conversation with professor Bautista can be streamed or downloaded here: NeuroTalk S2E2 Diana Bautista You can also subscribe to NeuroTalk though iTunes by searching for "Neuwritewest" in the iTunes store and subscribing to our channel.

Please let us know if you have any trouble accessing the podcast.

Thanks, and enjoy!

On behalf of NeuWrite West, Erica Seigneur Forrest Collman Mark Padolina

NeuroTalk S2E1: Yun Zhang

Welcome to the new year of school, and a new year of NeuroTalk! In the first episode of our second season, our guest is Yun Zhang, an associate professor of biology at Harvard University. We speak with professor Zhang about growing up in science, and studying learning and behavior in C.elegans!

Note to listeners: we had some connectivity issues while conducting the interview, so the audio quality is not as good in some places.

Welcome to the new year of school, and a new year of NeuroTalk! In our first episode of our second season, we speak with Yun Zhang about growing up in science, and learning and behavior in the nematode C.elegans! Yun Zhang is an associate professor of biology at Harvard University.

You can also stream or download this NeuroTalk here: 

NeuroTalk S2E1 Yun Zhang

Season 1 of NeuroTalk is still available for your listening pleasure here:

NeuroTalk Archive

Thinking outside the gene

  Our DNA contains the code that builds the bodies we call ourselves. These days, we are used to hearing about genes: phrases of DNA, read out by cellular machinery to construct the components of our bodies. We are used to the idea that mutations in our genes, changes or mistakes in the code, can make people sick. But the code written into our DNA is not as static or inflexible as we might imagine and it is not only your genetic sequence that has an effect on your physical traits (phenotype). Cells have layer upon layer of processes that control when and how much a gene is expressed, introducing complexity at multiple levels. Not only (as it often seems) to frustrate scientists, but rather to confer the redundancy, flexibility and robustness that allow development and survival to continue in the face of environmental change. One group at Columbia University is now looking at the role played by these extra levels of regulation in age-related memory loss. The reason some people experience memory loss in old age and others don’t, may have nothing to do with which genes you have. Rather, the difference may lie in how and when your cells express those genes.

We have a storage problem. At the risk of repeating a decades-old factoid, the DNA contained within a single cell is around 2 metres long. The average diameter of a human cell is 10 micrometres giving a shortfall of space in the order of two hundred thousand. Somehow all that DNA has to fit inside the cell, and histone proteins are the contortionists that make that possible. By winding DNA around itself, then around histone proteins, then winding those around each other, then winding that again a few more times, our cells can cram in all the DNA necessary to code for everything that makes us human. But now we have a new problem. If the code we need is in the middle of a tangled mess of other code and wrapped around bulky proteins, which are then crammed together even further, how can that code be accessed? This is where epigenetics comes in. Epigenetics is a rather vague term used to describe a whole host of strategies used by cells to regulate the expression of genes. But why do cells have to regulate gene expression? And how does that relate to the problem of genetic storage? Every single cell in your body* contains all of your genetic information. In other words, a single cell in your skin (or anywhere else, for that matter) contains all the information necessary to make any other cell in the body and, theoretically, could be reprogrammed to become any other cell. But a skin cell has no use for, say, proteins used to send nervous impulses, and can exploit this position of limited need to tackle the problem of genetic storage. Cells don’t need to access the entire genetic code all of the time. There are things in there, for example, that are used when we’re developing in the womb, but have no function once we’re out in the wide world. These genes, then, can be archived – set aside to be passed on to our offspring for their in utero development. By selecting which genes are buried away and which are close to the surface, ready to be decoded, the cell can perform efficiently and still house the entire human genome.

Epigenetic_mechanisms

Figure from http://www.beginbeforebirth.org/the-science/epigenetics

The amount of control imparted by epigenetic mechanisms is only just beginning to be appreciated. Perhaps from fear of a return to Lamarckism, there was a reluctance in the scientific community to attribute heritable changes to anything other than mutations in DNA. However, we now know that differences in phenotype can be the result of processes other than changes in genetic sequence. These epigenetic mechanisms have been shown not only to influence an organism’s phenotype, but also to have the capacity to be inherited by offspring. That is to say that two organisms can have a different phenotype, not because their genetic sequence is different, but because their parents regulated the expression of that gene in different ways. One highly visual example of this is the Agouti mouse, in which the coat colour of the offspring can be influenced by supplements given to the mother during pregnancy. Expose the mother to bisphenol A (BPA) and her offspring are more likely to be yellow. Without BPA, they come out brown [1].

Agouti_2

Figure modified from reference 1.

In this recent paper on memory loss [2], the authors wanted to look at what causes age-related memory loss and how it differs, if indeed it does differ, from Alzheimer’s disease. Previous studies have suggested that Alzheimer’s primarily affects an area of the hippocampus called the entorhinal cortex. In contrast, normal ageing (which is also associated with memory loss) involves changes in a different part of the hippocampus – the dentate gyrus [3]. With this in mind, the authors took brain tissue from post-mortem samples of healthy people to look for differences between the entorhinal cortex and the dentate gyrus. They looked at changes in gene expression that were associated with age by measuring how much of each gene was being expressed in each brain region and matching expression level to the age of the person. One difference they saw was in the dentate gyrus, which showed a large, age-related decrease in the expression of an enzyme (RbAp48) that modifies histone proteins. These, remember, provide a scaffold for DNA and help to determine which genes are accessible and which are archived. This finding suggested that age-related memory loss may not be the result of a person having a defective gene, but rather the result of incorrect genetic archiving. As is usual in this kind of study, they turned to a mouse model to look at this enzyme in more detail. By breeding mice unable to make RbAp48, they were able to show that this enzyme is necessary for normal memory: mice lacking RbAp48 performed worse on memory tests (navigating a maze or recognising an unfamiliar object). As mice get older, their memory appears to deteriorate based on tests like this, and mice lacking RbAp48 experienced this deterioration at a younger age than mice with normal levels of RbAp48. When looking at human brains, the decrease in RbAp48 wasn’t seen in the area of the brain associated with Alzheimer’s disease, suggesting that age-related memory loss has a unique starting point and is not just an early sign of Alzheimer’s. This could have important consequences in the future for diagnostics.

The more we learn about epigenetics, the more obvious it becomes that there is more to go wrong than we thought. You not only need the right genes, but you need the right control mechanisms in place to make sure have the right amount of each gene in each cell at all times throughout life. At the same time, we know that most people manage this, reflecting the amazing robustness of the system. Increasing our understanding of these control mechanisms has implications for treatment too. By looking at the underlying cause of a disease, we can treat it more effectively. This has been going on for decades in infection research, but may be applied more to other diseases in the future. For example, two patients presenting with fever and breathing difficulties will be tested for pneumonia. One may have a fungal infection and the other a bacterial infection. These need to be treated very differently, but only a knowledge of the underlying cause can tell us how to treat each patient. Similarly, treatment may be very different for someone lacking a gene completely compared with someone who has the gene in an inaccessible place. Both patients would have the same symptoms, but an analysis of the underlying causes could completely change the nature of the treatment. It is this sort of personalised diagnosis that could help to provide the right treatment for a patient; which would not only help the patient recover more quickly, but could also help to reduce the amount of money wasted on ineffective treatments.

*There are a few notable exceptions. Red blood cells have no nucleus and contain no genetic DNA. Egg/sperm cells have half the amount of DNA as the rest of your cells to make sure an embryo has the correct amount after fusion.

Jargon box

Histone: a type of protein used as a scaffold for DNA. DNA molecules wind themselves around histones to reduce the amount of space needed to house the genome.

Phenotype: observable characteristics of an organism from visible traits e.g. hair colour to cellular traits e.g. cell shape or structure.

References

1)    Dolinoy et al. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. (2007) 104 (32): 13056–13061. Link. OPEN ACCESS!

2)    Pavlopoulos et al. Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48. Science Translational Medicine (2013) 200 (5): 200. Link.

3)    Small et al. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat. Rev. Neurosci. (2011) 12: 585–601. Link. OPEN ACCESS!

How To Train Your Brain (Part II)

Can playing a game improve your cognitive abilities or maintain them as you age? We learned from Erica Seigneur’s post on August 15 that evidence in the neuroscience literature is inconclusive. But a new paper in the September 5 issue of Nature claims to have a breakthrough (1). Dr. Joaquin Anguera and colleagues at UCSF trained older adults to multi-task with a custom-made video game called NeuroRacer and declared big improvements not just in multi-tasking but also in working memory and sustained attention. How are their experiments different from those that reported no effect of brain-training games? Anguera and colleagues focused narrowly on improving multi-tasking in older adults to or above the level of multi-tasking ability found in younger adults. They designed NeuroRacer to get participants to simultaneously drive a virtual car and respond to signs flashing on the computer screen. Both the driving and the responding to signs had many levels of difficulty. For each participant, the authors picked a difficulty level of driving and of responding that the participant could do with 80% accuracy. They defined multi-tasking ability as the difference in accuracy between only responding to signs and responding to signs while driving, with smaller difference indicating greater ability. After these preparations, they measured baseline multi-tasking ability for participants aged 20 to 79 and found a linear decline with age. Then they trained a different group of participants aged 60 to 85 with NeuroRacer for one hour three times a week for four weeks, adapting the difficulty levels as participants got better at the game. An active control group, also aged 60 to 85, played a version of NeuroRacer that would alternate between driving and responding to signs without multi-tasking, but was counseled to believe that they were also training in multi-tasking. A passive control group from the same age group did not play NeuroRacer. At the end of 4 weeks of training, both the experimental and the active control groups could multi-task better than passive controls, and the experimental group was better than active controls. About 6 months after training, the experimental group had lost some multi-tasking ability but was still better than not only both control groups but also a group of 20-year-olds that played NeuroRacer for the first time. On the basis of these results, Anguera and colleagues declared success in using NeuroRacer to improve multi-tasking in older adults.

But did the participants actually improve their cognitive abilities or just got really good at NeuroRacer? To address that, Anguera and colleagues put the participants they trained through more tests. They stuck electrodes to their scalps and measured electrical signals from the brain, called theta waves, that have been correlated with multi-tasking, sustained attention, working memory, and general cognitive control, which I interpret to mean healthy brain. They asked participants to complete another video-game-based test called the Test of Variables of Attention (TOVA), which is commonly used to diagnose ADHD (2). From the results, they declared improved sustained attention. Though they also claimed improvements in working memory, they offered only the briefest of descriptions for their method of testing it in Supplementary Figure 12, and it wasn’t sufficient for me to judge its merits. However, their measurements of theta waves are also supposed to support this claim. In all, Anguera and colleagues went to great lengths to demonstrate general cognitive benefit from NeuroRacer to older adults.

But Anguera and colleagues themselves cite a Nature paper from 2010 by Dr. Adrian M. Owen and others that tested many more participants with brain-training games similar to commercially available ones and reported no evidence of general cognitive benefit from their use. What’s going on here? Anguera and colleagues point out that, unlike Owen and co-workers who tested people from the general population, they trained members of a specific sub-population, older adults, in something where they had a measurable impairment, i.e. multi-tasking. They also stressed that because NeuroRacer adapts its difficulty to the abilities of each user, it provides a consistent challenge and more effective training. Anguera’s supervisor Dr. Adam Gazzaley co-founded Akili Interactive Labs to commercialize the concept of NeuroRacer, so perhaps in a few years we will be able to test it out for ourselves (4). In the meantime, let’s set aside the question of benefit from video games and just appreciate how much fun they are.

 Sources

1. Anguera J A et al. (2013). “Video game training enhances cognitive control in older adults.” Nature. 501:97-101. Paywall.

2. http://www.tovatest.com
3. Owen A M et al. (2010). “Putting brain training to the test.” Nature. 465:775–778.
4. http://www.ucsf.edu/news/2013/09/108616/training-older-brain-3-d-video-game-enhances-cognitive-control