Ooh, I knew you couldn’t get enough of our squishier, yet rougher cousins and their nervous systems.
So, I told you about the amazing growth of a new nervous system. I told my dad about it over TG dinner, and he asked about potential in regeneration. I said: Whattayaknow, that’s what the other part of that same paper I worked on was about! The second paper looked at the process of neural tissue regeneration in echinoderms… specifically sea cucumbers!!!
So, how do these researchers think it is that echinoderms can regenerate, and why can’t we do the same? Basically, they have no myelin, and their glial cells are simple enough ththey are capable of dedifferentiating. The reason you can’t do this is because your ancestors apparently felt the need for their cells to be special. I mean, our glial cells are all highly specialized, and once a cell has been specialized, or set into an oligopotent progenitor cells, it cannot reverse back to pluripotency.
The sea cucumbers body induces neurodegeneration, killing cells within about 1.5 mm of the wound. Soon, glial cells near the margins dedifferentiate and grow new scaffolding providing a pathway for the growth of new axons. Ultimately, the damage is almost perfectly repaired. When we suffer neural damage, regeneration and migration of axons tend to be interrupted by glial scarring, especially by myelinating cells.
I don’t really know how to tie this one together, so I’ll give you this. My takeaway from this is that, if you wonder why you can’t completely repair damaged nerve tracts, and you feel jealous of the echinoderms who can, just remember that you have myelin and they don’t. Myelin is really good. It lets you think and process at an efficient speed.
So, I know the Great and Powerful Oz PZ likes his cephalopods. And I know cephalopods are really cool, because they can be very intelligent using an apparently simpler nervous system than we vertebrates have. But I think my fellow vertebrates are ignoring our crazy cousins here. I’m speaking of course about the echinoderms, which are (among the bilateria) very closely related to us. We are ignoring the amazing phenomenon that is our fellow deuterostome clade. What is so amazing about these creatures with so few sensory organs, let alone anything approaching sentience?
They are pentaradial, man, that’s what!
No joke, that’s really cool. They start off life with a body plan of bilateral symmetry, like any other balaterian, but by the time they are adults, they’ve switched to a body plan of five-fold radial symmetry. Their nervous systems consist primarily of five radial nerves extending from a nerve ring around the oral region. That is a crazy switch. If you’re curious, here is what some researchers in Japan did to investigate this, using sea cucumbers. I found this so cool, I wrote a 1500 word paper on the topic. Also, the paper counted as the take home exam PZ gave us. Continue reading →
Here’s a recent JBC article I wrote about for my biochemistry course. It’s about Parkinson’s Disease (PD). I’ll give you some background here. PD is a neurodegenerative disease involving dopaminergic neurons. What does that mean? Well, dopaminergic neurons produce the neurotransmitter dopamine, which is involved in mood, reward, and inhibiting or stopping motion. People with PD are deficient in dopamine, and so they experience tremors.
There is extensive evidence of damage to a dopaminergic region called the substantia nigra. One sign is that protein buildups (proteosomes), known as Lewy Bodies, have been found bound to the membranes of surviving neurons. The major protein involved in this is called α-synuclein, or α-syn. Another common observation in PD brains is that almost 90% of the α-syn is phosphorylated at serine residue 129 (Ser-129) whereas only about 5% is phosphorylated (Ser(P)-129 α-syn) in a healthy brain.
What Visanji and colleagues thought was that perhaps the phosphorylation is involved in binding to the synaptic membrane, which in turn affects its structure and function. Other hypotheses they had were that phosphorylation was an intermediate in binding to the membrane.
Well, here’s some evidence of what’s not happening. In cell-free assays (utilizing synaptosomes extracted from mice and α-syn filled cytosol extractions), they determined that α-syn can be found both in the cytosol and in the membrane. They also found that phosphorylation had no apparent effect on binding. Also, in binding and dissociation, they found that some of the phosphorylated proteins are lost (not dephosphorylated, lost). They concluded that phosphorylation is probably not an intermediate step, and that the protein can be in either cytosolic or membrane portions.
What next? Well they wanted to know what would happen with endogenously expressed proteins when you played with phosphorylation. So, they went to tinker with the genes of mice. They got knockout mice that did not express murine α-syn, but did express one of three human forms of the protein. Then they used vectors to overexpress or not express a phosphorylating enzyme (kinase) in neural progenitor cells. Well, they still got data saying that its effect was essentially crap-all in terms of membrane binding.
Honestly, I don’t have time to go through all the stuff they did essentially gave a “nothin’ goin’ on here” result.
BUT WAIT! This isn’t the end for the Ser(P)-129 α-syn Story! There is some significant stuff happening!
There are two mutations of α-syn implicated in hereditary forms of PD. A30P an A53T missense mutations are the two forms that were tested. The third was the wild-type (non-mutant) protein.
Well, what happens when we accutely, or temporarily, phosphorylate the proteins NOT using kinases? Well, the researchers used epoxomycin, which is normally a proteasome inhibitor. Well, in the presence of this chemical, wild type proteins were not effected. The mutants, however, binded to the membrane like crazy.
The researchers suggested that phosphorylation could also be involved in protein-protein interactions. This means that once they’ve stuck to the membrane, the phosphorylation could be making other proteins stick to them, resulting in these big Lewy Bodies messing up the synapse. The missense mutations make the resulting proteins more likely to bind and form these damages, thus they result in the hereditary forms of PD.
I found this pretty interesting, and I especially liked the way they ruled out a crap-ton (that’s a metric measurement btw) of other possibilities before going into what actually gave significant results. This is really good science: “here’s what’s probably happening, and here’s a bunch of stuff that’s almost definitely not happening.”
Sorry for all the words.
Literature:
Visanji, N.P., Wislet-Gendebien, S., Oschipok, L.W., Zhang, G., Aubert, I., Fraser, P.E. and Tandon, A. (2011). Effect of Ser-129 Phosphorylation on Interaction of α-Synuclein with Synaptic and Cellular Membranes. Journal of Biological Chemistry 286, 35863-35873.
PS: I’ll try to do something else here soon that isn’t just summarizing a primary research paper, or that isn’t so molecule-focused. I just have molecules on the mind.
Did anyone try using probiotics to reduce stress? Did it work? Yes? No? Well, I have another suggestion.
Try having sex.
Now, I know some of you will probably think this seems obvious. Don’t we usually feel really good after sex? I am going to ask, however, that we ignore the notion of the post-coital glow, runner’s high, or whatever it is you get after copulation. Let’s cool those jets and look at two studies involving the anxiolytic effects of oxytocin in rat mating.
First, let’s give a preface that is kind of given by both of these studies. Oxytocin is involved in a lot of good stuff psychologically. Oxytocin has been shown to reduce stressful behavior in animals, and medical researchers are even working on using it to treat anxiety in humans. It is also involved in prosocial behaviors. Basically, this is a peptide involved in being trusting, friendly, cuddly and calm or open.
Now, let’s look at how the males do with sex. Waldherr and Neumann demonstrated that mating with a receptive female led male mice to exhibit less stress behavior and more risk-taking associated behavior (2007). They ran a number of different tests. They found that males who were mated to females explored with open arms and exhibited more risk taking behaviors even 6 hours later. They also monitored the periventricular nucleus of conscious rats exposed to receptive (primed) and non-receptive (non-primed) females. They were able to set up a partition allowing visual, auditory and olfactory, but not physical contact between the male and female. What they found was elevated oxytocin release in males presented with receptive females. When the researchers injected the males with an oxytocin receptor antagonist (a chemical that blocks oxytocin) the rats ceased to exhibit the open behavior, demonstrating that it was, in fact, the oxytocin that had had the anxiolytic effect.
Nyuyki and colleagues looked at oxytocin and mating in female mice (2011). What they found was that females needed to control or pace the situation in order to have positive effects (the major one being oxytocin release) from sexual encounters. What they did was place primed or unprimed females in one of two situations with a male. There was a non-paced arena and a paced one in which a partition allowed the smaller female to hide from the male. The behavioral tests they ran were quite similar to the previous test. The results indicated that steroidally primed females, in a paced sexual environment were able to achieve the anxiolytic release of oxytocin. However, those placed in non-paced situations quickly lost the effect of priming, and did not achieve the oxytocin levels the paced females did. Basically, the female mouse needed to be ready to get the beneficial effects of sex.
These studies suggest that, at least in rats, sex leads to a stress-relieving rush of oxytocin from the periventricular nucleus in both sexes. However, for the female to get the proper effect, the copulation must be done on her terms, at her pace.
Now I’m wondering if this may be related to that feeling of ennui some guys get post-climax. Perhaps I’ll look into that for next week…
… either that or chocolate.
Nyuyki KD, Waldherr M, Baeuml S, Neumann ID (2011) Yes, I Am Ready Now: Differential Effects of Paced versus Unpaced Mating on Anxiety and Central Oxytocin Release in Female Rats. PLoS ONE 6(8): e23599. doi:10.1371/journal.pone.0023599
Waldherr M, Neumann ID (2007) Centrally released oxytocin mediates mating-induced anxiolysis in male rats. PNAS 104(42): 16681-16684.
I am definitely expecting a classmate to blog about this also. Did anyone catch Curioity: Can You Live Forever with Adam Savage the other night? Pretty cool as far as speculative science goes, right? My answer to that is yes. Now, can we make the MythBuster immortal? Maybe we can, but there is one part of this that aroused my desire to go MythBusting.
The hypothetical future Adam says at one point that at 500 years, the hippocampus, a large mass in the brain involved in memory, ran out of space. His solution: Build an artificial hippocampus. Also, multiple bodies. Way far out, right?
Wait! Let’s put the Kurzweil-esque thinking aside. What was this about the hippocampus (which literally means “seahorse”)? I remember hearing in psychology courses that the hippocampus was involved in memory, but that it probably was not the location of memory storage.
Myth: (1) The Hippocampus is the brain’s natural storage center, and (2) it is possible to increase memory storage capacity by making an artificial extension of the brain.
Let’s first take a look at this myth via Wikipedia.
Role in memory
See also: Amnesia
Psychologists and neuroscientists generally agree that the hippocampus has an important role in the formation of new memories about experienced events (episodic or autobiographical memory).[16][20] Part of this role is hippocampal involvement in the detection of novel events, places and stimuli.[21] Some researchers view the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalized—these would include, for example, memory forfacts in addition to episodic memory).[15]
Due to bilateral symmetry the brain has a hippocampus in both cerebral hemispheres, so every normal brain has two of them. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the other hemisphere, the brain can retain near-normal memory functioning.[22] Severe damage to the hippocampus in both hemispheres results in profound difficulties in forming new memories (anterograde amnesia), and often also affects memories formed before the damage (retrograde amnesia). Although the retrograde effect normally extends some years before the brain damage, in some cases older memories remain—this sparing of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain.
Interesting. So far, it seems that the hippocampus is more of an encoding structure. But, a good MythBuster does not stop at Wikipedia. So let’s look at some recent primary research!
In 2009, Leonardo Restivo and colleagues wanted to see what structural changes happened in the hippocampus and anterior cingulate cortex. What they did was condition contextual fear in mice, except that they also had a control group of non-conditioned or pseudoconditioned mice. Next, they tested some of the mice 24 hours later (recent memory recall), tested some mice 36 days later (remote memory recall), and left some mice untested (another control measure). After this, they put the mice to sleep, cut out their brains and put the brains in a Golgi-Cox staining solution to look at neural growth.
Now that the scientists had these beautifully stained mouse brains, it was time to look at the structure. They made slides and checked for dendritic spine growth, a sign of neural plasticity. What they found was that in mice tested for recent memory recall there was more structural change going on in the CA1 region of the hippocampus, but in mice tested for remote memory, there was a high dendritic spine density in the anterior cingulate cortex (aCC) (Restivo et al., 2009, Fig 2).
In both recent and remote tested mice, as well as untested, there was a higher density of dendritic spines than in pseudoconditioned and naive mice. (Plasticity in behaviorally untested mice means that this stuff is going on without needing recall.) Pseudoconditioned mice also had higher spine density than naive mice.
They also tested what would happen when they formed hippocampal lesions. It turned out that lesions formed soon after conditioning hindered recall, and when slides were made of the brain, but significantly more spines were seen than in control mice on dendrites of aCC cells. However, when lesions were caused later (day 24) recall was not as severely hindered, and more spines were seen on aCC pyramidal cells than in the mice who had early lesions. (Restivo et al., 2009, Fig 5).
What does this all mean? Well, it suggests that the hippocampus has an important but limited role in memory formation and storage. We can see things going on (spines being formed) in the hippocampus when memory is being formed, and those spines are still somewhat present in tests for remote memory. However, when testing later after conditioning, more new connections are seen in the anterior cingulate cortex. We also have the evidence from lesions, showing that damage to the hippocampus does not much of an effect on remote memory. Therefore, we can probably conclude that the hippocampus is not a storage center, but rather a memory processing center.
Myth: “Hippocampus specifically a Memory Storage Center”: This part is BUSTED.
Myth: “Creating an External Hard Drive for your Brain”: This part is PLAUSIBLE and is also a whole other subject.
Cited
Restivo L, Vetere G, Bontempi B, Ammassari-Teule M. The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex. J. Neurosci. 29(25): 8206-8214.
… Ooh! Lolcats! … Wait, I’m sorry, what was I talking about?
Ah, yes, the class-required blog. I must apologize. Things have been busy, and that brings me into conflict with my scatterbrain. And it almost literally is a scatterbrain. You see: I have ADHD.
“ADHD?! What a load of crap. That’s some bogus stuff made up by doctors and pharmaceutical companies.”
Quite wrong you are, awkward strawman argument. ADHD is real and well documented and researched. Here, for example, is a link to a recent article (or its abstract if you don’t have a subscription) that supports my use of the word “scatterbrain”. This shows evidence that there is some interference coming from altered patterns of very low frequency (VLF) activity in the ADHD brain (as measured in wave functions on an EEG). Basically, my resting-state brain functions don’t attenuate, or decrease power, when I go into a goal-oriented mode, and this is what is thought to lead to the interference.
I suppose this is just one way in which my brain is different from others. It’s a complex organ, each of ours is unique, and it tends to do things we don’t want it to do sometimes, or it doesn’t do them how we want them to. Imagine you are a computer yelling at yourself “Dammit, Windows! Where did you put that file? Open task manager. No, not Firefox.” That is how it is some days. We all have issues with our internal processor, and this is just a little glitch with which I have to deal.
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Literature
Helps SK, Broyd JB, James CJ, Karl A, Chen W, Sonuga-Barke EJS. Altered spontaneous low frequency brain activity in Attention Deficit/Hyperactivity Disorder. Brain Research. 2010, 1322: 134-143.
Here’s something to help you appreciate the little things. Bacteria. I saw this little blurb in the Proceedings of the National Academy of Sciences, and I thought it was pretty neat. Also, I have that weird feeling like I’ve heard information like this somewhere before. Unfortunately, I could not get too many details, as its telling me UMM does not have the proper subscription.
Researchers were recently looking at Lactobacillus rhamnosus in mice. Yes, Lactobacillus. You know it. It’s that genus of bacteria you find in yogurt, some cheeses, and probiotics. It lives inside you, and you enjoy a mutualistic relationship with it. Well, it turns out you might be getting a better deal from this prokaryote than you thought.
Mice given lots of bacteria displayed less stress behavior than those who received none. They also showed physiological differences. The happy mice, as I shall joyfully call them, had higher levels of GABA-B, which apparently has an inverse relationship with depression, and lower levels of GABA-A, high concentrations of which are associated with stress or anxiety. The vagus nerve, which carries information from the GI tract to the brain, has been implicated and this phenomenon. In fact, disconnection of the vagus nerve prevented the bacteria from having this behavioral effect on the mice.
It really makes me curious as to whether this same kind of phenomenon works in humans. Well, I’m hungry. I’m thinking Dannon.
I have a couple interesting articles about another possible cause of MS. In fact, one of these articles is what initially got me interested in proteolipid proteins’ role in MS for my senior seminar.
Here is the background story to the process. Myelin sheaths around the axons in vertebrates (ie humans) make nerve impulses go faster. These sheaths are achieved by fatty glial cells wrapping around the axon, or shaft, of the neuron. One type of myelinating glial cell is called an oligodendrocyte. It sends out a number of processes, each of which flattens out and wraps itself around an axon to form a segment of the myelin sheath. The tight wrapping is thought to be maintained by adhesion of several transmembrane proteins, including myelin basic protein (MBP) and proteolipid protein (PLP). PLP has been shown to have long chain fatty acids, namely palmitic acid side-chains.
I’ll admit that I cannot quite determine from the articles I’ve found, but I think these fatty acid chains act as a sort anchor for the proteins inside the membrane (I admit I’m making a leap here, I will look into this). These fatty acids are attached via thioesters on the cysteine residues. For those who aren’t up to speed on organic or biochemistry, cysteine is an amino acid with a thiol, or -S-H, side chain, and a thioester is an ester with a sulfur atom in place of oxygen between carbons. Loss of these fatty acids has been linked to decompaction of the rolled sheets (or lamellae) of the myelin sheet (Bizzozero et al, 2001). Decompaction of these sheets has been implicated in turn, with slowing velocity of nerve impulses (Gutierrez et al, 1995).
Dr. Sultan Darvesh researches Butyrylcholinesterase (BChE), a coenzyme with Acetylcholinesterase (AChE) found throughout the central nervous system. This enzyme has an affinity for deacylating thioesters attached to long-chain fatty acids. Knowing this, Darvesh looked at slides of brains from people with MS and people without MS. He found that BChE was expressed prominently in MS affected areas of the brain in MS patients. In normal brains, it was mostly only found in cholinergic pathways (Darvesh et al, 2010).
Darvesh worked on an experiment with a biochemist to test the deacylating affinities of BChE (Pottie et al, 2010). They developed a way to synthesize thioesters between cysteines and fatty acids of different lengths. They then introduced BChE in vitro (in a dish or test tube). With it they introduced a chemical called DTNB, a sulfur-bonded dimer. When a thioester was deacylated, the DTNB would split and one of the molecules would form a sulfur bridge with the protein analogue, leaving behind a yellow colored nitro thiophenolate, which allowed them to track the reaction. What they found was that the longer the fatty acid chain, the higher the affinity of the BChE for deacylating it.
It isn’t clear yet whether this activity is what happens in vivo, but this certainly could shed light on new MS pathways and possibly lead to new treatments involving BChE regulation. I also find it very interesting to study this condition from a chemical perspective.
I found an article on PubMed from a few years ago. Researchers engineered Theiler’s murine encephalomyelitisvirus (TMEV) to bear peptide epitopes naturally occurring in Haemophilius influenzae that mimics a sequence in the proteolipid protein (PLP) in the membrane the myelin. They found that mice infected with this virus carrying the epitope developed more of an immune response (i.e. an autoimmune response) than mice that were simply injected with the mimic peptides by themselves. What they also found was that the viruses could, in the authors’ words, exacerbate a preexisting, non-progressive autoimmune condition. The autoimmune response they were investigating in particular was the inflammation of the myelin in the Central Nervous System.
I found this very interesting, since this falls under the topic on which I want to do my senior seminar. The importance of this article is that the proteolipid protein is an important transmembrane protein in myelin, the sheath around the neurons, and it is important to myelin structure. Damage to the proteolipid proteins have been implicated in degradation of myelin, leading to multiple sclerosis. Multiple sclerosis has been linked to autoimmune responses and to viral infection.
In the experiment, exposure to a PLP sequence and to the mimic protein both resulted in an increased expression of MS or demyelination symptoms (lack of tail tone, impaired righting, varying degrees of hind-limb paralysis, etc.). They also resulted in the expression of higher concentrations of antibodies specific to PLP. This study strengthens evidence for a possible pathway of viral induction of MS.
This week the professor handed us a review article from the Royal Society about using insects as models for determining the cost-benefit relationship involved in learning and memory. As it explains, there is much evidence supporting a link between hippocampus size and learning in larger, more complex animals. But causation is not clear, and determining the size and neural density of such large brains is very difficult, because they are so large. The mushroom body, a higher processing center in insect brains, only tends to have a few hundred thousand neurons. Research into the costs of learning has expanded in the past decade with a lot of help from insects.
The brain is an expensive organ, taking up a lot of energy. One cost mentioned is the energy cost of maintaining resting potential. So, if learning is correlated to brain size and neural density, it is not necessarily adaptive. However, some insects perform surprisingly complex cognitive tasks. This may mean that more connections between neurons is better and more efficient than using more neurons. There is also evidence that higher order processing units may have at least as good an effect as upping the size of an entire brain. If we can learn the energy costs and performance of different units of nervous systems, we can understand how their relationship effected their evolution.
There is also an analysis of two basic types of costs of learning. Constitutive costs are costs that an animal pays whether or not it uses the memory. This can be a structure in the brain or even simply a lengthened axon resulting from a learning experience. There are also induced costs of learning. which are paid during the act of learning. There is a lot of evidence backing up the induced costs of learning, which may mean behavioral costs or the costs of processing information in the brain. Some studies on Drosophila have suggested that only crucial, repeated information makes it into the more costly type of memory storage. As well as encoding memory, deleting memory may be very expensive.
These studies have show gaps in that performance in a particular task does not necessarily translate into fitness. There is still a lot more to explore in this field.
Neuro-Tick 