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Cellular level neuroscience for everyone.

TheCellularScale
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January 22, 2013
05:47 PM
158 views

How to Build a Neuron: Step 5

by TheCellularScale in The Cellular Scale

And now, the final step in how to build your computational model of a neuron: Add Synaptic Channels. All the steps in this series can be found here.Synapses connect neurons (source)So you already have a neuron, and you've added intrinsic channels to it. The next thing you want to do is add synaptic channels so you can hook this neuron up to other cells.The main synaptic channels you want to add are the excitatory channels: NMDA and AMPA and the inhibitory channel GABA. These channels don't have the same kind of activation and inactivation curves and the intrinsic channels do because they aren't activated by voltage, they are activated by a neurotransmitter. AMPA and NMDA receptors are activated primarily by glutamate, and cause an influx of sodium and calcium ions. Since both sodium and calcium ions are positively charged, this depolarizes the cell membrane and brings it closer to firing an action potential.AMPA receptors (source)GABA receptors, on the other hand are primarily activated by GABA, and cause and influx of chloride ions into the cell. Because chloride ions are negatively charged, this hyperpolarizes the cell membrane and brings it further away from firing an action potential.So if you want to have a realistic model of a neuron, you need to add an approximation of these channels. This is easier than adding intrinsic channels, because it is an on/off style (binary) rather than an analogue activation. So basically you just put in the parameters you want like how fast does the channel open and close, how much current does it allow through when activated, and where are they on the neuron.Of course deciding these parameters is not always easy. A paper out this year in PLoS Computational Biology describes 4 different ways the NMDA receptor can be configured and analyzes the consequences during different stimulation patterns. Evans et al., (2012) Figure 3The 4 NMDA configurations (based on the 4 different GluN2 subunits) vary in their sensitivity to a magnesium block, how fast they decay, and their maximal current. Above are their responses to the same stimulation patterns (an STDP protocol). Even though they were all receiving the same input pattern, they each show a very different response.So when considering adding synaptic channels to your model neuron, take the time to find out what the configuration of the receptors should actually be in the type of neuron you are building. © TheCellularScaleIf you are good at following clues, you will realize that I am very, very familiar with this paper. Evans RC, Morera-Herreras T, Cui Y, Du K, Sheehan T, Kotaleski JH, Venance L, & Blackwell KT (2012). The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons. PLoS computational biology, 8 (4) PMID: 22536151... Read more »

Evans RC, Morera-Herreras T, Cui Y, Du K, Sheehan T, Kotaleski JH, Venance L, & Blackwell KT. (2012) The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons. PLoS computational biology, 8(4). PMID: 22536151

January 19, 2013
01:27 PM
171 views

LMAYQ: Why do I like that?

by TheCellularScale in The Cellular Scale

Again it is time for me to answer some questions. As always, these are real true 'search terms' that have resulted in some one finding The Cellular Scale. While some questions (like 'how do you build a model of a neuron') are answered by this blog, the ones I answer is these LMAYQ posts are almost certainly not. All the questions and answers in this series can be found in the Let Me Answer Your Questions index.Drawing by Grave Unicorn1. "Why do I like ketamine so much?"This is actually a pretty interesting question. Ketamine is a psychoactive drug known to cause hallucinations and feelings of dissociation, but it's not thought to be super-addictive in the same way that heroin or cocaine are thought to be. So why do you like it? First let me get a 'safety warning' out of the way. Even though research is currently being conducted to investigate ketamine as an acute anti-depressant and to investigate its possible role in neurogenesis, it is not all considered a safe drug. It can seriously damage your urinary system for one thing, and probably damages your brain. Don't take it. Ketamine (source)Having said that, ketamine might give you a 'good feeling' because it is a partial agonist (meaning helps activate) the dopamine D2 receptor and the serotonin 5-HT2 receptor. In 2002, Kapur and Seeman published a paper showing that ketamine (and PCP) affects the dopamine and serotonin system by binding to these specific receptors. However dopamine is a confusing molecule and the idea that ketamine activates the D2 dopamine receptors does not necessarily mean 'pleasure.'A classic test of 'wanting something' in rats is the self-administration paradigm, where rats can press a lever and get a dose of some drug or an electrical stimulation directly into the brain. A recent paper by De Luca and Badiani (2011) shows that rats will self administer ketamine when given the chance. Interestingly, they found that the amount of self-administration was much higher when they took the rat out of its cage and put it somewhere new for the self-administration session. When the rat was allowed to self-administer ketamine in its home cage it just didn't give itself as much.So your 'liking' of ketamine might have to do with where you are when you do it.Kapur S, & Seeman P (2002). NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Molecular psychiatry, 7 (8), 837-44 PMID: 12232776De Luca MT, & Badiani A (2011). Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology, 214 (2), 549-56 PMID: 210695152. "What do neurons like?"This question cracks me up because it reminds me of two personal anecdotes. First it reminds me of one of my professors who just can't stand when people say "the neurons behaved this way or that way." The idea being that behavior is a thing animals do, not a thing that neurons do. I basically agree that neurons don't behave per se, but I also don't really care if someone wants to 'be cute' by anthropomorphizing a cell.Second, thinking about neurons 'liking' things or being happy reminds me of a yoga class when during the final relaxation segment, the teacher started saying things like 'You are happy. Your cells are happy, they are all smiling at each other.' It was hard for me to relax and let my cells smile at each other when all my willpower was being engaged preventing me from bursting into laughter. Regardless, I will do my best to answer this question. I suppose, neurons 'like' glucose, which gives them energy. Other than that I don't think it's meaningful to talk about neurons liking things.3. "Why do men like big women?" This is one of a long string of questions that resulted from me having the words 'small', 'men', 'like', 'big', and 'women' all in the title of a post. As you might imagine, this is far from the worst 'search term' that has dropped people onto that page.And believe it or not, this question has a scientific answer.A paper this year by Swami and Tovee (2012) investigates the influence of stress in men's judgement of women's bodies. They found that men who were stressed for just 15 minutes (by being forced to give a speech explaining how suitable they are for a job) found 'bigger' women more attractive than the men who were not stressed did. Poor guy, if only he had a nice motherly type to cook him a pie. (source)The 'explanation' could be (though this is speculation, of course) that bigger women represent more 'security.'"The Environmental Security Hypothesis [15]–... Read more »

Kapur S, & Seeman P. (2002) NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Molecular psychiatry, 7(8), 837-44. PMID: 12232776

De Luca MT, & Badiani A. (2011) Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology, 214(2), 549-56. PMID: 21069515

Swami V, & Tovée MJ. (2012) The impact of psychological stress on men's judgements of female body size. PloS one, 7(8). PMID: 22905153

January 15, 2013
08:39 PM
253 views

How big is the GIANT Squid Giant Axon?

by TheCellularScale in The Cellular Scale

With all the hubbub about the first every video of an attacking giant squid in the wild about to unveiled, I started wondering about the giant axon of the giant squid... I mean it would be huge right?...Giant Squid, Giant Axon? (source)Squid are special creatures to neuroscientists. Specifically to neurophysiologists, who study the electrical activity of neurons.Squid Axon locationAtlantic squid have this huge (1mm) amazing axon running down each side of their mantle which allowed for the first recordings of action potentials in the 1930s.Here is a really nice 5 minute video showing how with (by today's standards) very crude techniques, the electrical signal could be recorded from these axons. So the squid giant axon is neat, and modern neurophysiology would probably not exist with out it. But what about the GIANT squid giant axon? Wouldn't that be an electrophysiologist's dream? If it scaled proportionally to say, mantle length, the 1foot long Atlantic squid with a 1mm diameter axon would become a 16 foot long GIANT squid with a 16mm giant axon. Let's think about this for a minute, 16mm is about 5/8 of an inch. US coins for size reference That is like the diameter of a dime! For those not familiar with US coins, it's like the size of a bead on a necklace... a big bead, like a nice-sized pearl. Basically HUGE considering that most axons in vertebrates are not even visible without a microscope. However,before you all start running out to hunt the giant squid for its precious precious axon...the truth is that the giant squid does not have a super-giant dime-sized axon. The giant squid axon actually has a smaller diameter than the 'normal' squid axon. Surprising right?Do the giant squid just have more axons there, so they don't need one gigantic one? Or is this axon somehow magically myelinated (probably not)? Or does the giant squid just not need one?First, let me explain that this information was pretty hard to come by and basically anecdotal. I watched a few dissections of giant squid. And while these were really amazing (look at the hooks on the colossal squid's tentacles!), they said very little about the giant axon or how it was modified in these larger animals. hooks of the colossal squid tentacles, yikes! (source)This information comes from a comment quoting JZ Young at a 1977 symposium describing his dissection of a 125cm (about 4 feet) long giant squid. I could not get access to this manuscript, so I have to trust the commenter with his quote:“Everyone wants to know whether giant squids have giant giant fibres. We have no material of the central nervous system but some years ago I was able to dissect the stellate ganglion of an animal washed up at Scarborough in 1933 and sent to the British Museum. The mantle length was 125 cm. The nerves of the mantle muscles are arranged in this genus differently from any other I have seen. Those in the front part of the mantle arise from a relatively small stellate ganglion, in the usual way. The hinder part of the mantle, perhaps more than half of the whole, is suspended from a distinct median nerve, running with the fin nerve and giving off a series of branches to the mantle.Each of the nerves arising from the ganglion contains one or two large fibres, ranging in diameter from about 80 micrometers in the more anterior ones to a maximum of 250 micrometers further back. The median nerve was further preserved but one fibre of about 250 micrometers could be seen. Two of the more posterior branches contained fibres of about 200 micrometers each. None of the nerves examined contained the exceptionally large fibres reported by Aldrich & Brown (1967). We may conclude that Architeuthis is not an especially fast-moving animal. This would agree with evidence that it is neutrally buoyant with a high concentration of ammonium ions in the mantle and arms (Denton, 1974).”Young explains that the axon network is set up differently in the giant squid (Architeuthis). He reasons that because the axon is not especially large, it could only conduct so fast, and therefore the fast escape reflex which it causes in the normal squid is just not that fast in the giant squid. This sort of makes sense, in that the giant squid might not benefit from escape as much as the normal squid. The giant squid might be better served by having razor sharp teeth on its suckers or terrifying pain causing-hooks so it could fight away a predator. The biggest axon award goes to the Humboldt Squid which has an axon the 'size of spaghetti.' And while the first ever video of a giant squid just came out, the first ever photographs from the wild were published in 2005. © TheCellularScaleKubodera T, & Mori K (2005). First-ever observations of a live giant squid in the wild. Proceedings. Biological sciences / The Royal Society, 272 (1581), 2583-6 PMID: ... Read more »

Kubodera T, & Mori K. (2005) First-ever observations of a live giant squid in the wild. Proceedings. Biological sciences / The Royal Society, 272(1581), 2583-6. PMID: 16321779

January 11, 2013
11:08 AM
222 views

On Selling and Over-Selling Science

by TheCellularScale in The Cellular Scale

Science!!! (source)Science communication is a persistent topic of ... well communication. Who is responsible for communicating science? How can science be best communicated to the public? What can we to do stop sensationalist and misleading articles from controlling what findings are generally accepted in the public sphere?All these questions rise up in science blogs and on twitter and then fade back into the background. Then something happens and a flurry of posts about communicating science float to the surface again. I have decided to join this party, and have written a Guest Editorial at the Biological Bulletin.It's called "On Selling and Over-Selling Science" and is about trying to find that perfect balance between communicating a scientific finding accurately and accessibly.I'd love to hear new opinions on this. So feel free to follow the link and leave a comment about it here. © TheCellularScaleI was not able to use my 'blogging name' like Neuroskeptic was, so here is the article and my identity along with it:Evans RC (2012). Guest editorial on selling and over-selling science. The Biological bulletin, 223 (3), 257-8 PMID: 23264470... Read more »

Evans RC. (2012) Guest editorial on selling and over-selling science. The Biological bulletin, 223(3), 257-8. PMID: 23264470

January 7, 2013
04:07 PM
226 views

Does a high fat diet lead to a less 'rewarding' life?

by TheCellularScale in The Cellular Scale

Some interesting research out of the University of Pennsylvania suggests that a high fat diet can disrupt dopamine signalling. This high-fat fed rat sure looks happy to me (source)As I briefly discussed during my SfN Neuroblogging binge, a high fat diet can alter dopamine levels in the brain. To expand on this, we'll look at new research on how exactly this might happen and which specific areas of the brain are affected. Vucetic et. al. (2012) tested the levels of dopamine-related gene expression (via mRNA) in the hypothalamus and the ventral tegmental area (VTA). The hypothalamus is important because it controls your levels of hunger as well as many other things. The VTA is important because it is the main source of dopamine to the ventral striatum (AKA the Nucleus Accumbens). The VTA-nucleus accumbens pathway is generally thought to signify 'reward' when it is activated. Sex, Drugs, Music, and lots of other 'pleasurable' activities all activate this pathway. So alterations in the dopamine levels here might change how 'rewarded' a person (or mouse in this case) feels in response to pleasurable stimuli.So Vucetic et al., (2012) found that in the VTA, the levels of tyrosine hydroxylase ("TH", an enzyme indicative of how much dopamine can be made) and dopamine active transporter ("DAT", which gets rid of excess dopamine at the synapse) are both reduced in the mice eating the high fat diet. Vucetic et al. (2012) Figure 1By contrast, in the hypothalamus, TH and DAT are both increased due to the high fat diet.So what does this mean? The authors point out that increased dopamine in the hypothalamus actually promotes eating. Consistent with this idea, the authors show that mice eating the high fat diet actually ate more frequently and ate more total food. Secondly, when there is less dopamine in the VTA, it is likely that a rewarding stimuli will seem less rewarding. In the author's words:"Collectively, these behaviors have the potential to promote obesity in two distinct ways: (i) through an increase in food intake and (ii) by increasing the drive for palatable food, as the animal with a blunted response to palatable foods may seek and/or consume these food relatively more than a normal animal in order to reach the same rewarding response. "So basically the mice aren't obese because the food they are eating is high fat, they are obese because they are eating MORE food. But of course, they are eating more food because the high fat diet makes them 'want' to eat more food, so the high fat diet is indirectly causing the weight gain.It is truly a vicious cycle. *Note: They also look at epigenetic effects on the TH and DAT promoter DNA. If you are interested in that aspect of the study, comment and I can do a follow-up post explaining it, or you can just read the study for yourself, following the link below. © TheCellularScaleVucetic Z, Carlin JL, Totoki K, & Reyes TM (2012). Epigenetic dysregulation of the dopamine system in diet-induced obesity. Journal of neurochemistry, 120 (6), 891-8 PMID: 22220805... Read more »

Vucetic Z, Carlin JL, Totoki K, & Reyes TM. (2012) Epigenetic dysregulation of the dopamine system in diet-induced obesity. Journal of neurochemistry, 120(6), 891-8. PMID: 22220805

January 4, 2013
10:44 AM
273 views

Cellular Recap of 2012 #2: favorites

by TheCellularScale in The Cellular Scale

As promised, here are my favorite posts from each month.January: The Human Neuron" not so special after all?Butti C, Santos M, Uppal N, & Hof PR (2011). Von Economo neurons: Clinical and evolutionary perspectives. Cortex; a journal devoted to the study of the nervous system and behavior PMID: 22130090February: If you give a mouse a placebo...Wise RA, Wang B, & You ZB (2008). Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release. PloS one, 3 (8) PMID: 18682722 March: Plant neurons: Sensation and Action in the Venus FlytrapBenolken RM, & Jacobson SL (1970). Response properties of a sensory hair excised from Venus's flytrap. The Journal of general physiology, 56 (1), 64-82 PMID: 5514161Volkov AG, Adesina T, & Jovanov E (2007). Closing of venus flytrap by electrical stimulation of motor cells. Plant signaling & behavior, 2 (3), 139-45 PMID: 19516982 Forterre Y, Skotheim JM, Dumais J, & Mahadevan L (2005). How the Venus flytrap snaps. Nature, 433 (7024), 421-5 PMID: 15674293... Read more »

Butti C, Santos M, Uppal N, & Hof PR. (2011) Von Economo neurons: Clinical and evolutionary perspectives. Cortex; a journal devoted to the study of the nervous system and behavior. PMID: 22130090

Benolken RM, & Jacobson SL. (1970) Response properties of a sensory hair excised from Venus's flytrap. The Journal of general physiology, 56(1), 64-82. PMID: 5514161

Volkov AG, Adesina T, & Jovanov E. (2007) Closing of venus flytrap by electrical stimulation of motor cells. Plant signaling , 2(3), 139-45. PMID: 19516982

Forterre Y, Skotheim JM, Dumais J, & Mahadevan L. (2005) How the Venus flytrap snaps. Nature, 433(7024), 421-5. PMID: 15674293

Kindt M, Soeter M, & Vervliet B. (2009) Beyond extinction: erasing human fear responses and preventing the return of fear. Nature neuroscience, 12(3), 256-8. PMID: 19219038

Kim IJ, Zhang Y, Yamagata M, Meister M, & Sanes JR. (2008) Molecular identification of a retinal cell type that responds to upward motion. Nature, 452(7186), 478-82. PMID: 18368118

Kay JN, De la Huerta I, Kim IJ, Zhang Y, Yamagata M, Chu MW, Meister M, & Sanes JR. (2011) Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(21), 7753-62. PMID: 21613488

Kraskov A, Dancause N, Quallo MM, Shepherd S, & Lemon RN. (2009) Corticospinal neurons in macaque ventral premotor cortex with mirror properties: a potential mechanism for action suppression?. Neuron, 64(6), 922-30. PMID: 20064397

Casile A, Caggiano V, & Ferrari PF. (2011) The mirror neuron system: a fresh view. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 17(5), 524-38. PMID: 21467305

Blackiston DJ, Silva Casey E, & Weiss MR. (2008) Retention of memory through metamorphosis: can a moth remember what it learned as a caterpillar?. PloS one, 3(3). PMID: 18320055

Marx M, Günter RH, Hucko W, Radnikow G, & Feldmeyer D. (2012) Improved biocytin labeling and neuronal 3D reconstruction. Nature protocols, 7(2), 394-407. PMID: 22301777

Finger TE, & Kinnamon SC. (2011) Taste isn't just for taste buds anymore. F1000 biology reports, 20. PMID: 21941599

Triana-Del Rio R, Montero-Domínguez F, Cibrian-Llanderal T, Tecamachaltzi-Silvaran MB, Garcia LI, Manzo J, Hernandez ME, & Coria-Avila GA. (2011) Same-sex cohabitation under the effects of quinpirole induces a conditioned socio-sexual partner preference in males, but not in female rats. Pharmacology, biochemistry, and behavior, 99(4), 604-13. PMID: 21704064

Labour MN, Banc A, Tourrette A, Cunin F, Verdier JM, Devoisselle JM, Marcilhac A, & Belamie E. (2012) Thick collagen-based 3D matrices including growth factors to induce neurite outgrowth. Acta biomaterialia, 8(9), 3302-12. PMID: 22617741

Fu M, Yu X, Lu J, & Zuo Y. (2012) Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature, 483(7387), 92-5. PMID: 22343892

December 18, 2012
06:07 PM
246 views

How to Build a Neuron: step 4

by TheCellularScale in The Cellular Scale

And now, the next step in neuron building! You can see all the previous steps and shortcuts here. Step 4 is adding intrinsic channels to your neuron.Potassium Channel (source)Pretty much all neurons need sodium and potassium channels so they can fire action potentials, but other channels such as calcium channels are also commonly seen in computational models. To add these channels you have to extract the parameters from known data. This means extracting Boltzmann curves and time constant information so you can tell the channel which voltages activate it and inactivate it and how fast to open and close. Activation (Boltzmann) curve for fast sodium channelThis step is tricky and can take a long time, but there is some software that can help. The Enguage Digitizer is one tool I could not live without. Enguage is basically a tool that allows you to manually trace curves from published figures to get the curve data as an excel or .csv file. First you add axis points using the button at the top that has red plus signs on it. You tell the software what values each of the 3 corners of the graph are. Then you click the blue plus signs button and start to trace your graph, like so:using Enguage digitizer to extract channel dataThen you export the data as whichever type of file you want. Pretty nice!I like to have the data this way because then I can overlay this figure trace with any other trace I want and can manually fit an equation to it.Channels are a hugely important part of a computational model. A recent paper from Eve Marder's lab shows that even with a very simple morphological model (just a soma), interesting electrical characteristics can be seen simply by manipulating the channels. Kispersky et al., 2012 from Figure 1Kispersky et al., (2012) introduce an interesting paradox. They show that when you increase the sodium channel conductance you see more action potentials with low current injections (like 200pA). This is expected because the sodium channel is what causes the upswing of the action potential and more sodium is thought to mean more excitability. However, the authors find that when a high current injection is given (like 10nA), the increased sodium channel conductance actually decreases the firing rate. This is counter-intuitive because it goes against the more sodium=more excitability rule.This is a pretty cool finding published in the Journal of Neuroscience using only a simple one-compartment model. The finding is based entirely on channel manipulation, and demonstrates how important these intrinsic channels are to any computational model. © TheCellularScaleKispersky TJ, Caplan JS, & Marder E (2012). Increase in sodium conductance decreases firing rate and gain in model neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (32), 10995-1004 PMID: 22875933... Read more »

Kispersky TJ, Caplan JS, & Marder E. (2012) Increase in sodium conductance decreases firing rate and gain in model neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(32), 10995-1004. PMID: 22875933

December 9, 2012
03:36 PM
210 views

Cortical spine growth and learning how to eat pasta

by TheCellularScale in The Cellular Scale

There are two aspects to neuron shape. One is the pattern of dendritic or axonal branching, and the other is the pattern of spines. Spines are the little protrusions that come off of the dendrite often receiving synaptic inputs.spines on a pyramidal neuron (source)Because these spines are associated with excitatory synapses, and because synapse development is thought to be the cellular basis of learning, it makes sense that spines would grow when we learn.But how would they grow exactly? Using transcranial two-photon microscopy (a window into the brain of a living mouse), Fu et al. (2012) have caught images of neural learning in action. A window into the mouse brain (source) The authors used two learning tasks to investigate how spines grow during learning. In the "reaching" task, mice had to reach their paw into a slit and grab a seed. In the "capellini handling task" the mouse is given a 2.5 cm length of (I am not making this up) angel hair pasta and learns how to handle it for eating. learning is measured by how fast the mouse eats the pasta. learning how to eat pasta makes mouse cortical spines grow (source)They found that spines grow during learning (not too surprising). But spines also grow when the mouse is exposed to a motor-enriched environment (like a mouse-sized playground). Fu et al. 2012 (Figure 2C+D)The interesting difference between learning a specific task rather than just playing is that the spines grow in distinct clusters when the mice are taught a learning task. C shows the total spine growth, while D shows the proportion of clustered spines to total spines. Reach only means the mice were only taught the reaching task, and cross-training means they were taught both the reaching task and the pasta handling task. The authors explain two possible functions for these spine clusters:"Positioning multiple synapses between a pair of neurons in close proximity allows nonlinear summation of synaptic strength, and potentially increases the dynamic range of synaptic transmission well beyond what can be achieved by random positioning of the same number of synapses."Meaning spines that are clustered and receive inputs from the same neuron have more power to influence the cell than spines further apart. "Alternatively, clustered new spines may synapse with distinct (but presumably functionally related) presynaptic partners. In this case, they could potentially integrate inputs from different neurons nonlinearly and increase the circuit’s computational power. "Meaning that maybe the spines don't receive input from the same neuron, but are clustered so they can integrate signals across neurons more powerfully.And of course..."Distinguishing between these two possibilities would probably require circuit reconstruction by electron microscopy following in vivo imaging to reveal the identities of presynaptic partners of newly formed spines." More work is needed to figure out what is really going on. © TheCellularScaleFu M, Yu X, Lu J, & Zuo Y (2012). Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature, 483 (7387), 92-5 PMID: 22343892... Read more »

Fu M, Yu X, Lu J, & Zuo Y. (2012) Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature, 483(7387), 92-5. PMID: 22343892

November 29, 2012
06:36 PM
265 views

Growing 3D Cells

by TheCellularScale in The Cellular Scale

Neurons don't grow in a vacuum. They have white fibers, other neurons, blood vessels and all sorts of other obstacles to grow around.Some NeuroArt (source)A recent paper from France details the making of a 3D environment that can facilitate 'realistic' neural growth. Labour et al. (2012) created a collagen biomimetic matrix which contains neural growth factor (NGF). Labour et al., (2012) Figure 3These scanning electron microscope images show the porous fibril texture of the collagen matrix. Most of the paper is spent explaining the methods for making this biomimetic matrix, but they also actually grow some pseudo-neurons (PC-12 cells) on the matrix. They show that when cultured on top of this collagen surface, the cells extend neurons in three dimensions into the matrices and are affected by the NGF. (when there is no NGF, the neurites don't grow and the cells die.) This paper is mostly about the methods, but I like the new possibilities that growing 3D cells opens up. With these biomimetic collagen matrices, the factors that cause specific dendritic arborizations in three dimensions can be analyzed. The environment can be completely controlled and the neurons easily visualized during growth. The authors suggest using these matrices to study neurodegeneration as well.Another interesting thing this paper introduced me to is the 'graphical abstract.' I didn't know that that was a thing, but it seems like a good idea. However, trying to summarize an entire paper in one figure seems pretty difficult. Here is their attempt:Labour et al. (2012) graphical abstractI think it does actually get the feel of the paper across pretty well, though it's not really informative without the actual abstract next to it. © TheCellularScaleLabour MN, Banc A, Tourrette A, Cunin F, Verdier JM, Devoisselle JM, Marcilhac A, & Belamie E (2012). Thick collagen-based 3D matrices including growth factors to induce neurite outgrowth. Acta biomaterialia, 8 (9), 3302-12 PMID: 22617741... Read more »

November 25, 2012
05:42 PM
272 views

The ageless face of an Aes Sedai: Science Edition

by TheCellularScale in The Cellular Scale

How would the brain process a truly 'ageless' face? Moraine, an ageless Aes Sedai (source)I am sure this question has plagued many Wheel of Time fans, but only now has an experiment been designed to test it. Just 4 days ago, Homola et al. (2012) published a paper in PLoS ONE in which they have people guess ages of people in pictures and scan their brains. Homola et al. (2012) Figure 1A. (Which one looks most Aes Sedai to you?)The first interesting thing that they found was that the older the person in the picture (either a real picture of a real person, or a hybrid 'morphed' picture like the ones above), the harder it was to tell how old they were. This isn't really that surprising, as the range of ages that can 'look' a certain age gets wider over the years. Homola et al., (2012) Figure 2B.Here they plot the standard deviation in years for people's guesses as to the age. The authors showed videos of the faces morphing from one age to another to volunteers while they were in the fMRI machine.As a side note: they found that there was no difference between male and female volunteers. If they had I think a big deal would have been made about it. but since they didn't it's just a tiny sentence in a long paper. Ok, back to the processing of age. They threw out the results from people who were really really bad at rating age because they 'weren't motivating' and weren't really trying apparently. (This could be a bit of cherry picking or data massaging) Then they compared the areas of the brain that were active for people who were really really good at guess age, and people who were only average.Homola et al., (2012) Figure 4DThe basic finding was that the posterior angular gyrus area (pANG) on the left hemisphere was 5 times more active for the expert age guessers than it was for average. Conclusion: pANG is important for age-processing. This on its own is good to know, but not amazingly interesting. What I think is cool is the idea that the authors present as a follow up experiment in their discussion:"Even though our study highlights pANG as one key component for age processing, its precise role in this context is still speculative and needs further investigation. Our model, illustrated in Figure 7, gives rise to interesting hypotheses: One testable prediction would be that disruption of left pANG activity using transcranial magnetic stimulation (TMS), for example, should impair numerical age but not gender judgements, and that brain lesion-symptom mapping can eventually dissociate the two. " Homola et al., (2012)So now we know, the Aes Sedai must have some magic that transcranially impairs pANG in everyone around them so they can't guess their age. That is how to stay truly ageless.© TheCellularScaleHomola GA, Jbabdi S, Beckmann CF, & Bartsch AJ (2012). A Brain Network Processing the Age of Faces PLoS One DOI: 10.1371... Read more »

Homola GA, Jbabdi S, Beckmann CF, & Bartsch AJ. (2012) A Brain Network Processing the Age of Faces. PLoS One . DOI: 10.1371

November 16, 2012
03:42 PM
312 views

How to Build a Neuron: step 3

by TheCellularScale in The Cellular Scale

Steps 1 and 2 of neuron-building, as well as an important set of shortcuts can be found in the How to Build a Neuron index. Step 3 is deciding which simulation software or programming language you want to use. Simulated Neuron in Genesis (source)The big two are Genesis and Neuron. They are pretty similar in a lot of ways, but Genesis runs in Linux and Neuron runs in windows. However, you can run Genesis in windows if you install the Linux environment Cygwin.Both programs can read in morphological data, but they use different syntax and coding procedures. There are other types of neural simulators as well, and an ongoing problem in the field of computational neuroscience is compatibility between programs. If someone has done the work to make a beautiful Purkinje cell in Genesis like the one above, it will take a lot of time and effort to translate that neuron into a different simulator such as Neuron. Gleeson et al., (2010) explains this problem and presents a possible solution in the form of the "Neuron Open Markup Language" or NeuroML. "Computer modeling is becoming an increasingly valuable tool in the study of the complex interactions underlying the behavior of the brain. Software applications have been developed which make it easier to create models of neural networks as well as detailed models which replicate the electrical activity of individual neurons. The code formats used by each of these applications are generally incompatible however, making it difficult to exchange models and ideas between researchers....Creating a common, accessible model description format will expose more of the model details to the wider neuroscience community, thus increasing their quality and reliability, as for other Open Source software. NeuroML will also allow a greater “ecosystem” of tools to be developed for building, simulating and analyzing these complex neuronal systems." -Gleeson et al (2010) Author SummaryNeuroML is basically a "simulator-independent" neuronal description language. A neuron built with or converted to NeuroML should be able to run on Neuron, Genesis, and plenty of other platforms. Gleeson et al. validated NeuroML by using a simulated pyramidal neuron converted to NeuroML format and run with several different simulators.Gleeson et al., (2010) Figure 7Zooming in:Neuron, Genesis, Moose, Psics comparisonAll the simulators overlay so tightly that you can barely tell that they are separate lines.So when building you neuron, take care to follow the NeuroML format and then you and others can use it with any simulator you want. © TheCellularScaleGleeson P, Crook S, Cannon RC, Hines ML, Billings GO, Farinella M, Morse TM, Davison AP, Ray S, Bhalla US, Barnes SR, Dimitrova YD, & Silver RA (2010). NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail. PLoS computational biology, 6 (6) PMID: 20585541... Read more »

Gleeson P, Crook S, Cannon RC, Hines ML, Billings GO, Farinella M, Morse TM, Davison AP, Ray S, Bhalla US.... (2010) NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail. PLoS computational biology, 6(6). PMID: 20585541

November 11, 2012
08:51 PM
265 views

Cut your brain some SLACK

by TheCellularScale in The Cellular Scale

Action potentials are the main means of communication between neurons, and their exact timing can be really important. But the specific timing of action potentials is really important in the auditory system, because the auditory system encodes (among other things) information about sound wave frequency. Sound waves (source)I've previously written about auditory processing with regards to the wonder that is the chicken brain, but today we will focus on timing-specificity in the mammalian brainstem. Specifically, some weird channels in the Medial Nucleus of the Trapezoid Body (the MNTB). Mammalian Auditory Brainstem (source)At the Society for Neuroscience meeting, I learned about the sodium-activated potassium channels which help the electric fish fire super-fast super-large action potentials. I was suprised to learn that sodium-activated potassium channels are located in many parts of the mammalian brain. A paper from the Kaczmarek lab at Yale explains that these sodium-activated potassium channel (SLICK and SLACK) are present in the mouse auditory brainstem and contribute to the 'temporal accuracy' of the MNTB neurons. Yang et al. (2007) record the action potentials from these neurons at a range of frequencies and show that the neuron can 'keep' up with the frequencies better when more sodium is present. Yang et al., 2007 Figure 9BIn the figure above, the 'flatter' the line, the better the 'temporal accuracy.' They also made a computational model of this neuron and ran simulations altering the sodium values and reversal potential. Yang et al., 2007 Figure 9DTheir model simulations are similar to their experimental recordings, in that more sodium results in more temporal accuary of the action potential. They confirmed that this was dues to a sodium-activated potassium channel by directly activating SLACK and seeing a similar improvement in temporal accuracy. The SLACK channel still blows my mind, but its role in helping the auditory system fire with the utmost precision actually makes a lot of sense. © TheCellularScaleYang B, Desai R, & Kaczmarek LK (2007). Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27 (10), 2617-27 PMID: 17344399... Read more »

Yang B, Desai R, & Kaczmarek LK. (2007) Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27(10), 2617-27. PMID: 17344399

November 4, 2012
08:38 PM
414 views

Ketamine for depression via neurogenesis?

by TheCellularScale in The Cellular Scale

A lot of fuss has been made recently about the street drug "Special K" (ketamine). It's basically an anesthetic used in labs and veterinary offices to tranquilize mice, rats, cats, and (famously) horses, but recently its been lauded as a newer faster anti-depressant. Ketamine: from the dealer or from the doctor? (image source)The possibility that it might have near immediate anti-depressant effects on humans has been around for a little while, but the concept is picking up steam as new research finds mechanisms for how it might actually work in depressed patients. (I briefly mention one new study in an SfN neuroblogging post. )An emerging theory is that depression is not so much a chemical imbalance as it is a loss of neurons. Thus the cure for depression is not restoring the balance of serotonin or dopamine, but restoring the growth of new neurons. Some suggest that this is how classic anti-depressants (like Zoloft) work, by fixing the neuron atrophy problem. This could also explain why these anti-depressants take so long to work, though I have expressed skepticism about this hypothesis. So the question is: Does ketamine cause the growth of new neurons, help in their maturation, or prevent neuronal atrophy? Ketamine is an NMDA receptor antagonist, so it inhibits synaptic transmission. It doesn't inhibit all synaptic transmission like deadly poisons do (tetrodotoxin for example), but enough of it to change something in the brain. Knowing something about NMDA receptors, it was still hard for me to conceive of a connection between blocking them and neuronal growth.A nice review by Duman and Li (2012) spells it out for me, explaining new research that links ketamine with the growth of new synapses. Duman and Li 2012 figure 3The idea is that ketamine blocks the NMDA receptors on the GABAergic (inhibitory) neurons, so there is less inhibition and more glutamate. When there is more glutamate, there is more BDNF (brain derived neurotrophic factor). BDNF helps synapsse grow by triggering a cascade of events (via mTOR) which causes more AMPA receptors to be inserted into the synapse, making the synapse stronger, more stable, and more mature. The authors cite their previous Li et al., 2010 Science paper explaining that when they block mTOR with the drug rapamycin, the effects of ketamine on new spine growth disappear and its anti-depressant effects disappear. However, this is a study in rats and assessing the depressed state of a rat is as tricky as assessing a rat's post-traumatic stress. As shiny and interesting as this is, I am not quite sold on it. I don't see how the NMDA antagonist is going to inhibit the inhibitory neurons more than the excitatory neurons, and I would love to see research showing how ketamine causes glutamate accumulation. And as far as actually using it as a treatment for depression, there are some serious side-effects. Ketamine is a hallucinagenic street drug which can cause a schizophrenia-like state. Therefore, it seems unlikely that ketamine itself will ever be prescribed as an anti-depressant, but new research could reveal (or synthesize) other molecules that activate mTOR directly or somehow bypass the hallucinogenic aspect of ketamine. For more, see some skeptical and critical analyses of human ketamine studies. © TheCellularScaleDuman RS, & Li N (2012). A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367 (1601), 2475-84 PMID: 22826346Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, & Duman RS (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, N.Y.), 329 (5994), 959-64 PMID: 20724638... Read more »

Duman RS, & Li N. (2012) A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1601), 2475-84. PMID: 22826346

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, & Duman RS. (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, N.Y.), 329(5994), 959-64. PMID: 20724638

October 28, 2012
05:15 PM
309 views

Dopamine and GABA working together

by TheCellularScale in The Cellular Scale

Until recently, the neurotransmitters of the brain have thought to be generally separate. That is, if a neuron is inhibitory, it releases GABA, and if it is neuromodulatory, it releases something else, dopamine perhaps. But two new papers show that specific neurons release both GABA and Dopamine. I briefly mention these new findings here. Dopamine and GABA together forever (source)First a subset of cells that were mainly thought to be GABAergic turn out to release dopamine as well. In 2010, Ibanez-Sandoval et al. found that there are interneurons in the striatum that stain positive for Tyrosine Hydroxylase. Tyrosine Hydroxylase is a precursor molecule needed for the creation of dopamine, and is a telltale sign of a neuron that can make and release dopamine. The authors found that these neurons release GABA and inhibit nearby cells. In this paper they did not confirm that the cells actually release dopamine, just that they have the machinery for it. This is weird for a few reasons. 1. Why would the striatum need dopamine in its interneurons? The main source of dopamine to this brain region is the substantia nigra pars compacta, and it pretty well covers the entire striatum with dopamine when it wants to. 2. Why would a cell release dopamine and GABA at the same time? Second the canonical dopaminergic neurons of the substantia nigra turn out to release GABA as well. In 2012, Tritsch et al., found that when stimulated with light, the dopaminergic neurons of the substantia nigra cause inhibitory responses in the cells in the striatum.The authors did extensive control experiments to make sure that they were indeed seeing GABA release from dopaminergic axons. They used carbon fiber amperometry to measure dopamine, and confirmed that dopamine was being released, and they blocked GABA receptors to make sure that it was GABA that was causing the inhibitory response. Finally they tested whether these cells were directly releasing GABA or perhaps stimulating other cells that released GABA. They did this by adding TTX, a sodium channel blocker, to prevent action potentials. In this condition, they could still evoke neurotransmitter release by light-based activation of these axons, confirming that these neurons directly release both dopamine and GABA. So what's with this mash up?Within two years it's been shown that GABA cells might release dopamine and dopamine cells do release GABA. Why? Neither paper speculates much on why GABA and dopamine might be co-released, or what the consequences of such a partnership might be.© TheCellularScaleIbáñez-Sandoval O, Tecuapetla F, Unal B, Shah F, Koós T, & Tepper JM (2010). Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (20), 6999-7016 PMID: 20484642Tritsch NX, Ding JB, & Sabatini BL (2012). Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature, 490 (7419), 262-6 PMID: 23034651... Read more »

Ibáñez-Sandoval O, Tecuapetla F, Unal B, Shah F, Koós T, & Tepper JM. (2010) Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30(20), 6999-7016. PMID: 20484642

Tritsch NX, Ding JB, & Sabatini BL. (2012) Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature, 490(7419), 262-6. PMID: 23034651

October 23, 2012
11:26 AM
401 views

Can you turn a rat gay?

by TheCellularScale in The Cellular Scale

What does it take to 'turn a rat gay'? This question may have crossed your mind, but a group in Mexico actually did the experiments to test it. A weak first attempt (source)Triana-Del Rio et al., 2011 used a co-habitation conditioning paradigm to see if they could condition a male rat to prefer a male partner.The basic paradigm was to house the 'experimental rat' to the 'stimulus rat' (who was scented with almond) for a full day every 4 days. Under these conditions, the experimental rat did not show any preference for the almond-scented stimulus rat later on. However, if the experimental rat was injected with quinpirole, which stimulates dopamine D2 receptors, he did develop a preference for the almond-scented rat. This preference was not sexual in nature. Preference was measured by time spent together, and these guys just wanted to hang out.Triana-Del Rio et al., 2011 (figure 1)The authors then did a separate experiment where instead of using 'sexually naive' rats as the stimulus rats, they used 'sexually expert' rats. They created these Cassanovas by riling them up with very 'receptive' female rats at least 10 separate times. They refer to this as 'sexual training.' When the sexually expert rats were used as stimulus rats, the experimental rats developed a sexual preference when injected with quinpirole. These experimental rats strongly preferred their almond-scented partners as measured by time spent together, mounting, and 'genital investigation.' So what does this mean? First of all, even the most drastic change was not permanent, partner preference dissipated after 45 days. And as I mentioned in my SfN summary, this protocol did not have the same effect in female rats. I do not think that the researchers here 'turned a rat gay.' While they did succeed in biasing the preference of the experimental rat for the guy he was housed with, they certainly didn't change the rats sexual preference in a deep or universal way. There is no evidence that the experimental rat preferred males in general over females, just that he really likes the one guy he was hanging out with. So this study does not really tell us anything about the biological basis of homosexuality, and it certainly does not tell us how to make a gay bomb. The most interesting implication for this study is in the activity of the D2 dopamine receptor, which may be involved in pair-bonding. I would be interested to see what some ex vivo cellular studies revealed about this treatment. Does quinpirole application cause a change in the number or location of the D2 dopamine receptors or the activity of the neuron?© TheCellularScaleTriana-Del Rio R, Montero-Domínguez F, Cibrian-Llanderal T, Tecamachaltzi-Silvaran MB, Garcia LI, Manzo J, Hernandez ME, & Coria-Avila GA (2011). Same-sex cohabitation under the effects of quinpirole induces a conditioned socio-sexual partner preference in males, but not in female rats. Pharmacology, biochemistry, and behavior, 99 (4), 604-13 PMID: 21704064 ... Read more »

October 16, 2012
06:05 PM
328 views

SfN Neuroblogging 2012: Implicit and Explicit Gender Bias

by TheCellularScale in The Cellular Scale

Today I am going to talk about just one thing rather than poster highlights from the whole day. As always, all the SfN Neuroblogging posts can be found here. Other posts on gender and neurosexism can be found here. Today was the annual "Celebration of Women in Neuroscience Luncheon." This is one of the highlights of SfN for me each year. There is always a fantastic speaker (Phyllis Wise this year) and the lunch is delicious. Phyllis Wise brought up the 'exact same resume study' in her speech and it got me thinking. The 'exact same resume' study is where researchers construct a fake person and write up their resume, and then submit it in application for various jobs. However, sometimes they put a woman's name at the top and sometimes they put a man's name at the top. The study found that the male names received more and higher paying job offers and were judged to be more qualified. And it wasn't just that men thought women less capable. The females who judged the resumes were just as biased as the males who judged resumes. This is pretty depressing. I mean this isn't the middle ages, or even the Victorian era, aren't we past this bias? But that's exactly the problem. We think we are past this bias. Even though people (both women and men) don't think they have a bias, they actually do. Even you. Just like you probably think you are smarter than average, or a better driver than average, you also probably think that you are less biased than average. That. is. the. problem. People have an implicit bias towards thinking men are smarter, better and more capable even when faced with the exact same description of the person. And they don't acknowledge this bias. How can you combat or fix a bias that people don't even think they have? A gender blind resume process could be implemented in the initial application process for a jobs. But as soon as the applicant arrives for an interview, the gender bias would rear its ugly head. Should faculty or hiring committees develop an explicit bias towards women in their hiring and salary negotiation process? I do not know the answer to this question. I can't think of a better way to combat implicit bias than with explicit bias, but it's hard to argue that implementing an explicit bias is 'fair' (It is a bias after all). It would especially seem unfair to those who don't think that they are implicitly biased (which we have established is basically everyone). But is there a fair way to handle this problem?© TheCellularScaleMoss-Racusin CA, Dovidio JF, Brescoll VL, Graham MJ, & Handelsman J (2012). Science faculty's subtle gender biases favor male students. Proceedings of the National Academy of Sciences of the United States of America, 109 (41), 16474-9 PMID: 22988126... Read more »

Moss-Racusin CA, Dovidio JF, Brescoll VL, Graham MJ, & Handelsman J. (2012) Science faculty's subtle gender biases favor male students. Proceedings of the National Academy of Sciences of the United States of America, 109(41), 16474-9. PMID: 22988126

October 3, 2012
09:31 PM
395 views

Bomb Dogs or Bomb Cells?

by TheCellularScale in The Cellular Scale

It's about to get really neuro-heavy here at The Cellular Scale because of the impending Society for Neuroscience annual conference. So before that onslaught of neuroinformation, lets step back and talk about two of my other favorite things: smell and beer. Dogs are good at Smelling Things... (I took this picture)But could beer yeast eventually be better at it? In 2007, researchers genetically engineered Saccharomyces cerevisiae (beer yeast) to express a rat olfactory receptor. But not just any old fully functioning olfactory receptor. Radhika et al. (2007) made a lovely franken-protein by using bits of dna from all over the place. They basically end up with a dna sequence coding for a receptor that expresses GFP (green fluorescence protein) when it is 'triggered.' The key here is that this 'trigger' could be easily changed. They first demonstrate that they can replace the trigger part of this receptor, making it sensitive to the scent of vanillin or cintronellal. While yeast that can turn green in response to the relaxing scent of vanilla might make for great advances in home decorating, the authors actually wanted to make a yeast strain that would fluoresce in response to the scent of bombs.Specifically, they wanted the yeast to respond to DNT, a mimic of TNT. To do this, they had to conduct a large assay on a 'library of cDNA inserts.' That basically means they had to switch in different 'triggers' for the receptor based on known strings of olfactory receptor dna and test each one to see if it responded to DNT. Lucky for them, they happened to find one. Radhika et al., 2007 Figure 4A: yeast glows in response to DNTAnd voila! a strain of bomb-sniffing yeast!While I don't think we'll be replacing bomb-sniffing dogs with petri dishes of glowing yeast any time soon, this is a significant step toward cellular level bomb-detection. More importantly, this study developed a new way to screen dna. They have created a versatile receptor 'cassette' into which they can place a string of dna and test which ligands or odors 'trigger' that section of the protein.© TheCellularScaleRadhika V, Proikas-Cezanne T, Jayaraman M, Onesime D, Ha JH, & Dhanasekaran DN (2007). Chemical sensing of DNT by engineered olfactory yeast strain. Nature chemical biology, 3 (6), 325-30 PMID: 17486045... Read more »

Radhika V, Proikas-Cezanne T, Jayaraman M, Onesime D, Ha JH, & Dhanasekaran DN. (2007) Chemical sensing of DNT by engineered olfactory yeast strain. Nature chemical biology, 3(6), 325-30. PMID: 17486045

September 30, 2012
03:50 PM
317 views

Almost Creating a Fake Memory Trace

by TheCellularScale in The Cellular Scale

Mouse Memories (source)Last post, we talked about the fallibility of flashbulb memories. Today we're going to discuss a new paper in which scientists claim to have created a fake memory in a mouse. Garner et al., (2012) use the same kind of genetic trickery that Han et al. (2009) used to erase memories from cells. They genetically modified mice to express a foreign receptor that mice don't normally express. These kinds of receptors are called DREADDs which stands for "Designer Receptor Exclusively Activated by a Designer Drug." A DREADD can activate the cell, inactivate the cell, or even kill the cell. (Han et al., added a receptor that killed the the cells, but Garner et al. add a receptor than activates the cells.) But, here's the real genetic trickery, the DREADD is promoted only in the cells that are active at a certain time. When something happens, the cells that are active during the event will express the DREADD. So later, when the designer drug is applied, only the cells which were active during the event will respond. Using this DREADD system, Garner et al. try to trick mice into thinking that they were shocked in one room, when really they were shocked in another room. They call this a 'generating a synthetic memory trace' and this is how they do it:Garner et al., 2012 Figure 2AFirst of all the kind of memory the authors are synthesizing is the association between a room (or context) and an electric shock. If you put a mouse in a room and then give it an electric shock, the next time it is in that same room it will 'remember' that that room is scary and will show a freezing behavior. The measurement of how good this memory is is simply counting the percent of the time that the mouse spends freezing in the room. They have two rooms, context A (Ctx A) and context B (Ctx B). First they take the mouse and put it in context A (but don't give it an electric shock). This activates a certain subset of neurons and so the DREADD will get expressed in those neurons. Let's call them the "Context A neurons." Then they stop the creation of new DREADDs by adding in doxycyclin, which turns off the DREADD gene expression. This makes it so (in theory) the only cells that have DREADDs are the "Context A neurons." Then they put the mouse in context B, but at the same time they apply the "designer drug" to activate the DREADDs. Since the DREADDs are (supposedly) only in the "Context A neurons," the neurons that the drug activates should trick the mouse into thinking it is actually in context A, when really it is in context B. Then they apply the shock to the mouse. To see if they have 'generated a synthetic memory trace' the authors test whether the mouse freezes in context A (where it thinks it was shocked) or context B (where it was actually shocked). Garner et al., 2012 Figure 2B&CUnfortunately the authors don't find something simple. First of all, they find that the mice with the DREADDs (the filled black circles above) almost always freeze less than the normal control mice (grey triangles), and they don't really explain why that might be. Second of all, they find that the application of the designer drug (+CNO) increases freezing for the DREADD mice in both context A and context B. The mouse didn't learn that Context A is where it got shocked. Instead it learned that Context B with the "Context A neurons" is where it got shocked. It's like the "Context A neurons" become part of context B. The authors call this a 'hybrid memory trace' where the mouse learns to associate a combination of the "Context A neurons" and the actual context B environment with the shock. So what if just adding this drug is enough to create a hybrid memory? The authors did a nice control experiment to test this. They did the exact same protocol, but put the mouse in context B every single time (never in context A). That way the neurons expressing the DREADD are the "Context B neurons" and should basically be the same set of neurons that are active anyway when the mouse is shocked in Context B. In this case, the mouse froze a lot to context B without the drug, and it froze the same amount to context B with the drug. The drug caused no enhancement when it was activating the "Context B neurons." This is strong evidence that the hybrid memory trace has to involve the activation of a new set of neurons.This is a experimental design, but I think that the authors oversold their result a little bit in the title "Generation of a Synthetic Memory Trace." They didn't create a totally fake memory, they created a hybrid memory by adding in new neurons to the 'context' that the animal associated with the shock. There is no evidence that the mouse thought it was in context A or even that having a context A is important. If they had just stimulated a random, but new, set of neurons in context B and then stimulated that same random set of neurons when testing the mouse for freezing behavior, they might have seen the same results.© TheCellularScaleGarner AR, Rowland DC, Hwang SY, Baumgaertel K, Roth BL, Kentros C, & Mayford M (2012). Generation of a synthetic memory trace. Science (New York, N.Y.), 335 (6075), 1513-6 PMID: 22442487... Read more »

Garner AR, Rowland DC, Hwang SY, Baumgaertel K, Roth BL, Kentros C, & Mayford M. (2012) Generation of a synthetic memory trace. Science (New York, N.Y.), 335(6075), 1513-6. PMID: 22442487

September 26, 2012
11:53 PM
302 views

you can't trust your brain: memory

by TheCellularScale in The Cellular Scale

"Flashbulb" memories are those vivid memories of specific salient events. The 'everyone remembers exactly where they were when...' sort of events. In the USA, and depending on how old you are, you might remember the assassination of JFK, or Martin Luther King Jr. in this way. In this century, most Americans remember exactly where they were when they heard about the 9/11 attacks on the world trade center and pentagon."Never Forget" (source)It's widely acknowledged these days that the brain is not really a safe place to store information. Memories of events change over time. But for a while the "flashbulb" memory was thought to be immune from the memory-altering properties of time. Think about your own memories of 9/11 or another highly meaningful event. I bet you are pretty certain about the details. I, for example, was in my second year of college and I know exactly who told me that the first tower was hit, exactly where I was standing on the quad, and exactly what class I was going to.......or do I? A study in 2003 tested the consistency of flashbulb memories over time and compared the details to 'control memories' of everyday events. They specifically recorded memories from people during the day after the 9/11 attacks, and then recorded memories of the same events from subsets of those same people 1 week, 6 weeks, and 32 weeks later. They found that the flashbulb memories did have different properties when compared to control memories, but that consistency was not one of them. Talarico and Rubin 2003, Figure 1aTalarico and Rubin show that the flashbulb memories and the everyday memories had the same time-dependent decay (that x axis is in days), demonstrating that the flashbulb memory did not have some special property that protected it from corruption. However, they did find that the level of confidence in the memory was higher for flashbulb memories than for everyday memories. People thought (incorrectly) that their memories of the 9/11 attacks were more accurate than their other memories. So again we learn the lesson that we cannot trust ourselves. In the authors words:"The true 'mystery,' then, is not why flashbulb memories are so accurate for so long,... but why people are so confident in the accuracy of their flashbulb memories." Talarico and Rubin (2003)But I think the most interesting finding in this paper was that the flashbulb memories of 9/11 were more likely to be recalled 'through ones own eyes' than the everyday memories. Everyday memories were seen 'through ones own eyes' at the beginning and a at 1 week, but at 6 and 32 weeks the everyday memories were more likely to be seen 'from an outside observer perspective.' The flashbulb memories, on the other hand, were seen 'through ones own eyes' at all time points. Indeed, when I think of my own 9/11 memory, I still see it through my own eyes.The authors don't go into why that might be or what it might mean, so we are left to wonder.© TheCellularScaleTalarico JM, & Rubin DC (2003). Confidence, not consistency, characterizes flashbulb memories. Psychological science, 14 (5), 455-61 PMID: 12930476... Read more »

Talarico JM, & Rubin DC. (2003) Confidence, not consistency, characterizes flashbulb memories. Psychological science, 14(5), 455-61. PMID: 12930476

September 22, 2012
01:53 PM
282 views

LMAYQ: Eating

by TheCellularScale in The Cellular Scale

Eating Questions (source)Let Me Answer Your Questions, where I answer your important questions about things tangentially related to this blog. Today they are about eating. As always, these are real true 'search terms' that The Internet directed to my blog. 1."What physiological mechanisms makes food smell better when you are hungry?" I almost address this in You can't trust your receptors: Smell, where I explain how the brain can actually modulate the sensitivity of the smell receptors themselves.The real answer is that it is not exactly known, but it might have to do with grhelin. The hormone ghrelin is related to feeling hungry and a receptor for ghrelin is found in the olfactory (smell) pathways. One study actually tested whether ghrelin would affect a person's sense of smell. Tong et al., 2011 gave people an IV injection of ghrelin and then tested how 'strongly they sniffed' with a 'sniff magnitude test (SMT)'. The higher levels of ghrelin correlated with a higher 'sniffing magnitude'. However, the sniffing magnitude was increased to both food and non-food smells. This means that people didn't necessarily inhale deeply because they liked the delicious smell of banana, they were just engaging in 'exploratory sniffing'. In addition, the authors had the smellers rate how pleasent the smell was, and the ghrelin did not increase the pleasentness ratings. So the actual physiological reason for food smelling better when you are hungry is still a mystery research question.2. "best Madeleine recipe" Well, this isn't exactly a question, but I am pretty sure this particular googler did not find what they wanted on my post on literature references in science. So here you go. Though I have never made Madeleines, this one from Iamafoodblog.com looks delicious!Earl Grey Madeleines Recipe adapted from 101 Cookbooksyield: 7-8 large madeleines6 tablespoons butter1 egg3 tablespoons flour2.5 tablespoons sugar1/2 teaspoon loose leaf earl grey tea1/4 teaspoon vanillabutter to grease madeleine panPreheat oven to 350 F.Melt the butter in a small pot over medium heat. Add the tea and cool to room temperature. While the melted butter is cooling, grease the madeleine pan.Put the egg in the bowl of an electric mixer with a whisk attachment. Whip on high speed until thick – approximately 3 minutes. The egg should double or triple in volume. Continuing to mix on high speed, and slowly add the sugar in a steady stream. Whip for 2 minutes or until mixture is thick. With a spatula, gently mix in the vanilla.Sprinkle the flour on top of the egg batter, and gently fold in. Now fold in the butter mixture, stirring only enough to bring everything together. At this point, I like to refrigerate my batter for a bit. I find it helps with baking. Press saran wrap directly against the batter and refrigerate for at least 30 minutes.Spoon the batter into the flutes, filling each 2/3 -3/4 full. Bake the madeleines for 12 – 14 minutes, or until the edges of the madeleines are golden brown. Remove from oven and unmold immediately.3. "What does a mouse eat?"Peanut head (source)Mice eat lots of things. If you have a pet mouse, you should feed it normal pet-store mouse food because it is a complete mouse diet. But mice love new things, so you should give them oatmeal or peanuts or other seeds and grains as treats.In some labs, mice and rats get to eat froot loops when they find the reward cup at the end of a maze. © TheCellularScaleTong J, Mannea E, Aimé P, Pfluger PT, Yi CX, Castaneda TR, Davis HW, Ren X, Pixley S, Benoit S, Julliard K, Woods SC, Horvath TL, Sleeman MM, D'Alessio D, Obici S, Frank R, & Tschöp MH (2011). Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (15), 5841-6 PMID: 21490225... Read more »

Tong J, Mannea E, Aimé P, Pfluger PT, Yi CX, Castaneda TR, Davis HW, Ren X, Pixley S, Benoit S.... (2011) Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(15), 5841-6. PMID: 21490225

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