Sorry I haven’t been here in a while! Yesterday I gave my senior seminar—a 45 minute literature review presentation in front of my peers, all the faculty in the discipline, and my parents—so I’ve been a bit preoccupied with that during the last few weeks. I’m DONE and I think it went well. I slept in this morning and missed PZ’s class (sorry, PZ!), but I was really wiped and, dammit, I deserved it.

Anyway, today I’m writing about electroconvulsive therapy (ECT), or, in the vernacular, electroshock. Try to wipe your mind of what you think you know about ECT from movies. The media has not been kind in its representation of this therapy, and the therapy itself is not what it was fifty years ago.

ECT is the stimulation of a grand mal seizure in a patient by electricity applied through electrodes placed on the scalp. The patient is unconscious, having received a short-acting anesthetic, and his or her muscles do not convulse because a muscle relaxant is also administered.

ECT is still an important therapy in use today. As many as one in five patients experiencing major depressive disorder are classified as having treatment-resistant depression (estimates vary because criteria for this classification are not consistent). Pharmacological and psychotheraputic treatments are not effective for these individuals, but ECT can often help. However, in spite of its well-known effectiveness and its long history of use, we still do not understand how ECT manifests its antidepressant effects in the brain. We do, however, have some  hypotheses.

One is that ECT alters the neurotransmitter levels in the brain. The concentration of GABA has been shown to increase following ECT. As well, the monamine neurotransmitters—serotonin, dopamine, and norepinephrine—have been shown to be affected by ECT. The 5-HT1A serotonin receptor is sensitized by ECT, and both dopamine levels and dopamine receptors are affected by ECT. Repeated ECT treatments enhance dopamine binding to receptors.

Interestingly, ECT has been demonstrated to have neurogenic effects. One study in animals found increased neurotrophic factors and cell proliferation in the subgranular zone in the dentate gyrus of the hippocampus.

These don’t seem to be articulated hypotheses, you say. It’s true, they aren’t. This is basically a list of things we’ve shown that ECT does in the brain. We need some more data, and then we may be able to put this information together in a meaningful hypothesis on how ECT does it antidepressant thang in the brain.

The brain is really complicated. REALLY complicated. We don’t understand more than a small fraction of its workings. We also don’t really understand depression. We know that people who have depression seem to have lower levels of serotonin, dopamine, and norepinephrine, but that’s not even close to the whole story. So, given our poor comprehension of this thing called The Brain (seems it ought to be capitalized, mighty as it is), it’s not at all surprising that we don’t understand ECT.

Merkl, A.; Heuser, I.; Bajbouj, M., Antidepressant electroconvulsive therapy: Mechanism of action, recent advances and limitations. Experimental Neurology 2009, 219 (1), 20-26.

We don’t usually think about our cells moving, at least not of their own accord. WE move, not our cells, right? My leg moves because I tell it to, and my diaphragm contracts, drawing air into my lungs, because my brainstem tells it to—it doesn’t just contract on its own.

But some of our cells DO move. I’m talking, here, (I’ll bet you guessed it) about neurons.

In very early development, a process called delamination occurs. Neuroblasts—cells that will differentiate into neurons or glia—grow bigger than the surrounding cells and kind of squeeze out of epithelium.

Okay, see? The big circle made of little boxes (cells) with dots (nuclei) in them is a grastrula stage embryo. The pink cells are about to delaminate, and the red, round cells already have. It occurs in several waves, which is why the bottom diagram of the embryo shows both cells that are going to delaminate and cells that already have. (Aren’t pictures great?)

There’s more of this freaky cell moving crap going on in the cortical tissue in the brain. The cortex develops in layers. New cells are “born” through cell division in the most interior layer (the ventricular zone), and they migrate up toward the surface layers. The younger cells get to kind of crawl up these older cells, the radial glia, to reach the upper layers. Cool right? Yep, it’s picture time again:

….And I guess that’s all for now because I still have about 10 pages of that really long chapter to read before class tomorrow morning.

To recap: Synesthesia = pretty cool. Things that most of us experience in a single modality (e.g. aurally), synesthetes (people who have synesthesia) experience in one or more additional modality. For example, on hearing a particular tone, a synesthete might also see a color. There are many different types of synesthesia. Awesome, right?

Note that synesthesia is automatic and involuntary, and it strongly runs in families. However, the genes implicated in synesthesia have not yet been isolated.

There seem to be two main hypotheses right now on how synesthesia might arise in the brain. Both have their proponents and naysayers. I’m going to briefly walk you through the two hypotheses and the evidence for each.

The first is the cross-activation hypothesis, which was proposed by Hubbard and colleagues (2005). Hubbard et al. were studying grapheme-color synesthesia—in which letters and numbers (graphemes) are perceived to have particular colors—using functional magnetic resonance imaging (fMRI). fMRI monitors changes in blood flow in different areas of the brain. More blood flow to an area = more activity in that area of the brain. Hubbard and colleagues found that when grapheme-color syesthetes were presented with a grapheme, V4, a part of their brains involved in color processing, was active as well as the adjacent visual word form area (VWFA). Non-synesthete control subjects did not have activity in their V4 areas when shown graphemes—they only had activity in their VFWAs.

See? The VWFA is in green, and V4 is red.

Hubbard et al. thought that this difference in activity in the brains of synesthetes could be due to cross-activation. In other words, activation of one sensory pathway directly causes activation in another sensory pathway. This could occur due a lack of normal neural pruning between the pathways in early development. If there was a mutation that caused neural pruning to occur abnormally, this could also account for the heritability of synesthesia. Hubbard and Ramachandran (2005) cite a study in macaque monkeys showing that in the V4 brain region and the region of the VWFA were neurally connected in prenatal macaques but not in adult macaques. A connection study like this one would be the best way to test the cross-activation hypothesis, but such a study cannot be done on humans because it is…um…invasive, to say the least.

Another fMRI study on word-color synesthesia found activation of the V4 and V8 (another color processing region) only in the synesthetes in response to a hearing a spoken word (Nunn et al. 2002). The authors felt their results supported the cross-activation hypothesis.

The second hypothesis is known as disinhibition feedback, and it was proposed by Grossenbacher and Lovelace (2001). This hypothesis suggests that synesthesia is caused by disinhibited feedback from a so-called multisensory nexus in the brain, where signals from multiple pathways are fed forward to other brain areas. In most people, these signals are sufficiently inhibited such that they do not experience synesthesia.

Grossenbacher and Lovelace thought that since synesthesia could be induced by drugs such as LSD, synesthesia should not require any abnormal brain architecture to occur, since non-synesthetes who experience synesthesia under the influence of LSD presumably lack the atypical brain architecture.

Another piece of evidence that may support disinhibition feedback is the case of a man who his vision at the age of forty (cited in Hubbard and Ramachandran 2005). After two years, he reported that tactile stimuli elicited for him the impression of seeing movement. A more intense tactile stimulus was needed to give the impression of seeing movement when the man held his hands in front of his face, suggesting that his synesthesia was related to a kind of top-down sensory processing. The two-year delay between the man’s loss of his vision and the development of his synesthesia, however, does suggest some kind of neural rewiring.

When considering these hypotheses, it’s important to keep in mind that we don’t know that congenital synesthesia and drug-induced synesthesia arise through the same mechanisms. Congenital and drug-induced synesthesia have very different characters, and it does not necessarily make sense to claim they have similar origins in the brain. We also don’t know that the many different types of congenital synesthesias have the same neural mechanisms.

I personally think that the cross-activation hypothesis seems stronger, more logical, has more evidence in its favor. But you know, I’m just an undergrad, and not particularly (or at all) qualified to spout an opinion on the topic.

But you never know. Maybe in fifty years we’ll have learned that neither cross-activation nor disinhibited feedback are responsible for synesthesia, and neurobiologists will look back on these hypotheses and giggle in the same way we now giggle about Freud and his theories on penis envy.

Grossenbacher, P. G.; Lovelace, C. T., Mechanisms of synesthesia: cognitive and physiological constraints. Trends in Cognitive Sciences 2001, 5 (1), 36-41.

Hubbard, E. M.; Ramachandran, V. S., Neurocognitive Mechanisms of Synesthesia. Neuron 2005, 48 (3), 509-520.

Hubbard, E. M.; Arman, A. C.; Ramachandran, V. S.; Boynton, G. M., Individual Differences among Grapheme-Color Synesthetes: Brain-Behavior Correlations. Neuron 2005, 45 (6), 975-985.

Nunn, J. A.; Gregory, L. J.; Brammer, M.; Williams, S. C. R.; Parslow, D. M.; Morgan, M. J.; Morris, R. G.; Bullmore, E. T.; Baron-Cohen, S.; Gray, J. A., Functional magnetic resonance imaging of synesthesia: activation of V4/V8 by spoken words. Nat Neurosci 2002, 5 (4), 371-375.

This week, ladies and gentlemen, I will be discussing synesthesia. Synesthesia comes from the Greek for “together sensation”, and it refers to the neurological condition in which the activation of one sensory (or cognitive) pathway causes a person to automatically and involuntarily experience a second sensation.

Estimates vary, but there seems to be a rough consensus in the literature that around 1 in 20 people experience some form of synesthesia. One of the most common types of synesthesia is grapheme-color synesthesia, in which individual letters and numbers (graphemes) have particular colors. Some people report that a given grapheme will have an overlay of a certain color, while others say that they just “know” the grapheme has a particular color (Hubbard 2005).

Other types include sound-color synesthesia, in which various environmental sounds trigger colors, and spatial-sequence synesthesia, in which numbers, months of the year, and dates are associated with particular locations in space. There seems to be an association between synesthesia and mnenonism, the ability to remember long lists of data. For example, Daniel Tammet, the savant with Asperger’s syndrome who holds the European record for reciting digits of pi (22,514 digits in 5 hours and 9 minutes), is a synesthete who says he experiences each positive integer up to 10,000 as having a unique shape, color, and texture.

Many artists and musicians are synesthetes. Wassily Kansindsky was a sound, color, touch, and smell synesthete.

I don’t know about you, but I think that explains a lot!

How does synesthesia happen in the brain? Well, that’s the topic I choose to write about for my neurobiology essay exam for Monday, so I’ll get back to you likely early next week with the highlights of my readings on the hypotheses and research that are out there. Stay tuned!

Hubbard, E. M.; Ramachandran, V. S., Neurocognitive mechanisms of synesthesia. Neuron 2005, 48 (3), 509-520.

According to Dr. David Eagleman, an author and neuroscientist who visited campus last week, the human brain has about 10,000,000,000 neurons, and on average, each neuron has around 10,000 connections to other neurons. And 10,000,000,000 neurons multiplied by 10,000 connections per neuron is roughly 10^14 connections in the human brain. Which is to say, the human brain is an incredibly complex beast and we barely even understand it well enough to figure out what questions to ask, to discover what techniques we will need to develop in order to study it.

From my Brainbow post a couple of weeks ago, you know of one technique that can be used to examine neural connectivity. But all this complexity beggars the question: how does this happen? How do neurons “know” where to go to make all of these precise connections?

This is a problem referred to as neuron pathfinding, and it is the subject of a great deal of research. Developing neuron axons have growth cones at the ends of their growing tips. Growth cones have many long, thin, finger-like projections called fillipodia. The filipodia move around and probe the chemical environment of the growth cone.

Certain chemical cues in the cell’s environment are attractants for particular neural growth cones; others are repellants. Not all chemical cues induce the same response in different neurons. Some growth cones also utilize certain cells in their environment to direct their growth. The neurons appear to use these cells as landmarks or guideposts, so I will refer to them as guidepost cells.

PZ mentioned a paper that examined the mechanism of the interaction between the neuron growth cone and the guidepost cells in lecture last week. It sounded interesting to me (yeah, I’m such a nerd :-P ) so I looked it up.

This paper used transmission electron microscopy to examine slices of interacting growth cone filopodia and guidepost cells in grasshopper embryos. For the neuron the researchers focused on, six of its twenty-eight filopodia were contacting the surface of the guidepost cell, and seven filopodia were found actually inserted from 0.1 to 7 micrometers into the guidepost cell. Insertion of the filopodia appears to induce formation of coated pits in the surface of the guidepost cell around the inserted filopodia. Researchers also found that while other neuron growth cones may approach the cell, but their filopodia do not get inserted in the guidepost cell. The authors thought this was evidence that the insertion of the filopodia was an active process on both the part of the filopodia and the guidepost cell rather than just a passive engulfing due to the advancing filopodia. They also suggest that the insertion of the filapodia into the guidepost cell may be used for molecular communication between the neuron and the guidepost cell.

And, just for giggles, here is one of the TEM photos taken in this study, showing a filopodium (“f”) penetrating a guidepost cell almost to the guidepost cell’s nucleus, conveniently marked by the authors with an “N”.

Figure 2A from Bastani and Goodman, 1984.

Aaand that’s all for now folks.

Bastiani, M. J.; Goodman, C. S., Neuronal growth cones: specific interactions mediated by filopodial insertion and induction of coated vesicles. Proc Natl Acad Sci, USA 1984, 81 (6), 1849-1853.

(The photos above I took diving in Belize in June 2005.)

Sponges are really simple animals. They don’t have nervous systems. AT ALL. Well, if you’re like me, you’re wondering how the hell that works. Granted, pretty much all sponges do is sit on the ocean floor and filter stuff out of the water. However, some species are capable of movement (at prodigious speeds of 1-4 mm per day), and most can close their ostia and oscula (or, the water intake pores in the body and the central opening of the body where water exits after being filtered by the sponge, respectively).

Hold the phone—animals with no nerves and no muscles can move? Apparently. It seems that movement in most sponges occurs via continuous movement of cells within the sponge, which rearrange its anatomy through space. Weird.

Sponges do have everything that would theoretically be needed for a nervous system: synapses, pathfinding mechanisms, excitation…. (Source: PZ’s neuro lecture on 9/19/11)

Exaptation: stuff that evolved for one purpose is co-opted for another purpose. A common example is feathers, which may have originally evolved for thermal regulation but were then used for display and for flight. Exaptation is an important idea used to help explain how complex biological structures and systems came to be. Sponges are pretty old, probably having evolved in the early to mid Cambrian period. The phylogenetic descendants of sponges are ctenophores (comb jellies) and cnidarians (corals, anemones, etc), which do have sensory organs and primitive nervous systems. They didn’t magically create their nervous systems whole-cloth, though; instead, the basic features of nervous systems that were already present in the sponges were adapted to new purposes.

***

Sorry, not a very exiting post this week. I’m not feeling 100%, and I was thinking about exaptation from a biology senior seminar I went to this week on infrared-sensing organs in snakes.  Stay tuned though, next week should be better, although I haven’t the faintest what I’m going to write about.

Everyone knows cephalopods are tricky bastards. The coleoid cephalopods, anyway (squid, cuttlefish, and octopuses). I haven’t read any stories about tricky nautiluses, but if you find one, I’d love to hear about it.

Anyway. The coleoid cephalopods. They are sneaky predators. Octopuses apparently have been found to steal crabs out of fishermen’s crab pots. Some apparently use tools—veined octopuses have been documented gathering discarded coconut shells and constructing shelters from them (Finn 2009). (They took video of this, which you might be able to see here. You also might not, I’m not sure if you need subscription access, which I have through the U of M…sorry.)

Figure 1b from Finn 2009. Squee!

Sorry, I got a bit excited and distracted there. Back to the tricky bastards business. Octopuses in aquariums have been known to escape through tiny cracks, pull down lights, and open jars with twist-off lids. Humboldt squid might possibly coordinate to catch prey (I read this several places but could not find a reputable source for this tibdit.) Cephalopods are also good spatial and navigational learners. Claims have been made that octopuses have observational learning abilities as well (i.e. monkey see, monkey do) but these are disputed.

In any case, cephalopods seem to be pretty smart. Cephalopod intelligence is an interesting topic because cephalopods are invertebrates, lacking a spinal cord. They have large, complex neural systems with fairly large brains. Which are wrapped around their esophaguses. Seriously.

See? By the way, I found that here. Because citations are important. You’re welcome.

Cephalopods have these giant nerve cells with axons about 1 mm thick that are responsible for their extremely rapid escape response. Stimulation of these neurons results in contraction of a series of muscles causing water to be forced out of the animal, moving it backwards.

Cephalopods also have chromophores, which are basically pigment sacs under the skin that allow their skin to change color. (So cool!) The chromophores are strongly linked to the animal’s visual input, since the color-changing thing is used for protective camoflage and signaling when predators, prey, mates, or rivals are around. So cephalopods also have this complicated neural system for processing all visual input and controlling the chromophores.

Then there’s the whole learning and memory thing, which was what I was going to talk about originally… (Some days, the ADD wins, okay?) The physical stuff behind the learning and memory is very complicated and not very well understood. Simpler systems are easier to research, and these are not simple systems. From what has been found so far, however, it is apparent that cephalopods have two distinct systems for visual learning and memory and for tactile learning and memory…and that’s about all I’ve got for you.

This is so not a satisfying entry! I wanted to address the question “why are cephalopods so smart?” And I kind of did, but I couldn’t answer it beyond “they have big, complex neural systems.” This is partially because we simply do not understand how brains work in very much detail and partially because it’s a really complicated topic. I mean, look! There’s a 560 page textbook just on coleoid cephalopod neurobiology. Oh well. Points for trying?

Finn, J. K.; Tregenza, T.; Norman, M. D., Defensive tool use in a coconut-carrying octopus. Current Biology 2009, 19 (23), R1069-R1070.

Williamson, R.; Chrachri, A., Cephalopod neural networks. Neurosignals 2004, 13, 87-98.

So I was reading the September volume of National Geographic (c’mon, you know you have a pink squishy place in your heart for good ol’ NatGeo)… when I came upon this article about rescuing elephants orphaned by poaching for ivory or bush meat in Kenya. Orphaned elephants need help to survive because, according to the article, they are completely dependent on their mothers’ milk for the first two years of life and partially dependent on it until the age of four.

The part that I found particularly interesting was about the behavior and complex social bonding of elephants. Elephants apparently show what could be interpreted as signs of grief after a death. One field biologist quoted in the article described elephants trying to lift the body of another elephant and cover it with brush; she also observed a mother standing by the body of her stillborn baby for three days. Elephants may also return to to bodies of their deceased for months and sometimes years after the death. (I was somewhat skeptical about this, but after doing some cursory journal searching on the web, I find that these behaviors are fairly well documented.)

The article went on to discuss some further more “human” elephant behaviors, which a brief foray into elephant brains (aha! there’s that neuro stuff!). NatGeo suggests that perhaps the reason elephants have these behaviors that we can easily anthropomorphize is that they have very human-like brains, with large hippocampuses (hippocampi??) and spindle neurons.

Huh? What is this spindle neuron thing you speak of, you say? Well, Wikipedia says they are also known as von Economo neurons (VENs). They have a particular morphology and are typically found in the anterior cingulate cortexes and the frono-insular cortexes of humans, great apes, some cetaceans,  and the African and Asian elephants. Research suggests that spindle neurons may be implicated in various human disorders such as autism, Alzheimer’s disease, and other neuropsychiatric disorders. Hmm, very interesting…

Two papers about spindle neurons suggest they are important in quickly relaying social information in the brain. Allman et al. propose that spindle neurons play a role in rapid, intuitive assessment of complex social situations. These papers, which I’m feeling too lazy to really describe in detail, are extremely interesting, fairly readable, and not very long, so if you’re interested I highly suggest you look them up!

UPDATE: The National Geographic article is also online here, for those of you not lucky enough to have been given a magazine subscription for your birthday from your daddy :P Or, you know, financially solvent and able to purchase your own subscription, whatever.

Allman, J. M.; Watson, K. K.; Tetreault, N. A.; Hakeem, A. Y., Intuition and autism: a possible role for Von Economo neurons. Trends in Cognitive Sciences 2005, 9 (8), 367-373.

Hakeem, A. Y.; Sherwood, C. C.; Bonar, C. J.; Butti, C.; Hof, P. R.; Allman, J. M., Von Economo Neurons in the Elephant Brain. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 2009, 292 (2), 242-248.

Siebert, C., Orphans no more. National Geographic Sept 2011, pp 40-65.

Is it just me, or are papers that utilize fluorescent proteins actually extra badass? 

This particular work by Livet et al. was published in Nature in 2007 (for citation, see below). The idea was to come up with a method that allows you to produce connectivity maps in order to analyze neuronal network architecture. One possible way of doing this was proposed by Livet and colleagues. They cloned three or four different fluorescent protein genes into mice, which were expressed on the cell membranes. This only yields limited colors, however, so the researchers also used the Cre/lox recombination system. Cre is a DNA sequence specific recombinase, which splices the DNA at loxP sites.

Via strategic placement of lox sites,some of which were incompatible with one another, Livet et al. forced the Cre recombinase to “choose” one of several mutually exclusive excisions. Only one excision can occur because excision of one pair of identical lox sites removes one site of the second pair, preventing additional recombination. (Confusing, I know. See Figure 1a in their paper! Or below.)

So, via recombination of these fluorescent protein genes, each neuron expresses a different set of fluorescent proteins on its membrane. Okay, okay, not *each* neuron. Livet et al. found that combinatorial expression of three different fluorescent proteins yielded about 90 colors in neurons, which they think will allow mapping of neuronal circuits. They demonstrated this technique in neurons and glial cells.

Pretty cool right? PICTURE TIME:

Sorry, I couldn’t get a higher resolution one :( Additional, better pictures can be seen here.

Livet, J.; Weissman, T. A.; Kang, H.; Draft, R. W.; Lu, J.; Bennis, R. A.; Sanes, J. R.; Lichtman, J. W., Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 2007, 450 (7166), 56-62.

I have to make a blog on neuroscience for my neurobiology class, so, since I’m lazy, I’m just going to repurpose this one. So consider yourself warned: this will now be a weekly blog for the duration of the semester on whatever random neurobiological topics I find myself moved to write about.

In case you happen to be interested, this class is taught by Dr. Paul Myers, who is a developmental biologist with a relatively popular (in some circles, anyway :-P ) and pretty awesome blog called Pharyngula. Also, he and his commenters recently pissed off Glenn Beck, which makes me giggle, because Glenn Beck is a giant douche who probably shouldn’t speak. Ever.