In contrast to land mammals, dolphins developed the ability to sleep with only one part of their brains at a time. While half of their brains rests – and dreams – the other half remains awake and alert. This finding explains how dolphins can keep a constant lookout for their pod mates and predators, like sharks. Dolphins regularly alternate the active side of the brain. If they stopped whole brain activity and slept like humans do, they would probably become easy prey or even drown.

In a clever experiment, researchers tested how “mindful” dolphins are with just half their brain. Because dolphins use echolocation to map the world, the investigators set up a portable floating pen outfitted with eight modules, each consisting of an underwater sound projector and microphone. During echolocation, an animal produces a sound and listens to returning echoes to gain information about its environment. So when a dolphin scanned any of the eight modules using echolocation, they were able to respond to the signal with sound-mimicking echoes of signals from remote surfaces. Essentially, these modules could behave as “phantom targets.”

Trained to respond to these signals for a year, in the experiment the dolphins could eventually successfully use echolocation with extremely high accuracy and no sign of deteriorating performance for up to 15 days straight! The researchers stopped the experiments at that point. but they suggested dolphins could continue much longer staying alert and doing tasks, perhaps indefinitely. Isn’t it amazing that the dolphins showed no sign of losing their sharpness as the days wore on?

“These majestic beasts are true unwavering sentinels of the sea,” said Branstetter, according to Live Science.

Future research will include monitoring the dolphin’s brains for electrical activity via electroencephalogram, or EEG.

“Research with freely moving humans who wear portable EEG equipment has been conducted; training a dolphin to wear a similar portable EEG backpack that is capable of withstanding and functioning in an ocean environment presents much greater challenges,” Branstetter said. “However, these hurdles are not insurmountable. Also, we are interested in investigating if dolphins can perform more complex cognitive tasks without rest, like problem solving or understanding an artificial language,” Branstetter added.

If the ability to keep half the brain turned on while the other is getting a good rest is an evolutionary adaptation to protect against predators, it makes me wonder why humans didn’t also developing this ability? On the other hand, nothing is more fun than getting a good night’s sleep and bending the laws of gravity in your dreams! So for us humans it is: Keep calm and sleep on!

The study was published in PLoS One. 

“Section through the cerebral cortex of a mouse, stem cells can be seen glowing in green, mature nerve cells in red; cell nuclei for both types of cell are shown in blue.” Source: IMBA

Your brain is a complex, highly organized organ. Each mammalian brain is made of approximately 10-15 billion nerve cells, called neurons. And each brain is built of thousands of different types of neurons, called neuronal subtypes. Neurons have the amazing ability to gather and transmit electrochemical signals, the more neurons the faster signals can be transmitted; think of them like the gates and wires in a computer. It has been known that neurons arise from a small set of progenitor cells that divide in a spatially and temporally controlled manner to generate a fully functional adult cortex.  However what drives daughter cells of these progenitors to different fates is poorly understood.

So the more nerve cells a brain is able to make, the smarter an organism should be. Turns out that humans are really good at it! Stem cells in the human brain produce far more nerve cells than corresponding cells in mice. Jürgen Knoblich and his research team at the Vienna Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) found out what mechanisms are responsible, and why the orientation of the cells plays a role.

It is understood that although the genes of mice and humans are more than a 90% alike, the cerebral cortex of a mouse has around eight million neurons while in humans there are more than 10-15 billion. Nerve cells are produced in the brain of the embryo from stem cells that continuously divide. Each dividing stem cell gives rise to a nerve cell and another stem cell.  So how could it be that humans have more neurons – and a much larger brain – than mice? The Knoblich laboratory suggests that it has to do with controlling the direction of cell division.

Generally spoken each stem cell can divide in different spatial planes (or directions); the daughter cells are then either ‘up and down’ or ‘left and right.’ According to current understanding the direction of division of stem cells defines whether new nerve cells, or only new stem cells, are produced. This is called a positional effect.

The IMBA scientists bred mice in which the direction of division of the stem cells can be controlled. This regulation is possible by using the protein ‘Inscuteable,’ which works like a switch for the direction of division: cells divide horizontally with Inscuteable but vertically without the protein.

Studies of the mice with Inscuteable showed that nerve cells are actually generated in both vertical and horizontal divisions (and not only in one); however the cells were far more parallel to the cell surface. So a mouse with more Inscuteable protein has more horizontal divisions, and so overall more nerve cells. A lack of Inscuteable has the opposite effect. This mechanism could be responsible for the tremendous proliferation of nerve cells in the human brain!

But how does a human brain manage to generate the correct numbers of neurons?

Higher organisms like humans reproduce nerve cells through a ‘detour,’ meaning horizontal division initially creating a stem cell and an intermediate progenitor. This cell has lost its stem cell properties but can still divide, on average once in mice, so that two nerve cells are generated per horizontal stem cell division. This indirect neurogenesis is also controlled by the Inscuteable protein.

Indirect neurogenesis seems to be the key to larger and more intelligent brains. If we compare mice to organisms with less developed brains we can see that they are lacking this kind of fast neurogenesis and have accordingly fewer nerve cells. Therefore indirect neurogenesis is a very important in terms of evolution. In humans intermediate progenitors are already much more complex and divide more frequently than in the mouse; therefore compared with mice, humans have a plethora of nerve cells.

The researchers also tried to determine  whether the mice without the Inscuteable protein are dumber than their counterparts due to fewer nerve cells, or whether an artificially induced overproduction of the protein could lead to more intelligent animals, but couldn’t prove either hypothesis, yet.

So does the Inscuteable protein make man human? “Far more interesting however is the role played by Inscuteable in humans” says Jürgen Knoblich. “It probably also regulates the number of neurons in our own bodies by activating indirect neurogenesis, the evolution of the protein and its function may have contributed to the enormous enlargement of the human brain.”

This hypothesis is supported by the finding that the division pattern of the intermediate progenitors closely correlates with the level of intelligence. This specific pattern only appears in primates, including humans, so without Inscuteable we would certainly not be what we are.

References:

Mouse Inscuteable Induces Apical-Basal Spindle Orientation to Facilitate Intermediate Progenitor Generation in the Developing Neocortex  Maria Pia Postiglione, Christoph Jüschke, Yunli Xie, Gerald A. Haas, Christoforos Charalambous, Juergen A. Knoblich Neuron – 20 October 2011 (Vol. 72, Issue 2, pp. 269-284)

Alu is an example of a so-called “jumping gene” – a transposable DNA sequence that “reproduces” by copying itself and inserting into new locations throughout the genome. Alu elements are classified as SINEs, or Short INterspersed Elements. All Alus are approximately 300 bp in length and derive their name from a single recognition site for the restriction enzyme AluI located near the middle of the Alu element. Alus are also classified as retrotransposons, because they need a special enzyme (a reverse transcriptase) to produce mobile copies. However Alus are “defective transposons” as they depend on the enzymes of other transposons for mobility, like the best characterized retrotransposon family called L1, a Long INterspersed Element (LINE).

Once an Alu inserts at a chromosome locus, it can copy itself for transposition, but there is no evidence that it is ever excised or lost from a chromosome locus. So, each Alu insertion gets fixed through evolutionary time. Like genes, Alu insertions are inherited in a Mendelian fashion from parents to children.

First discovered in corn about 60 years ago by Nobel laureate Barbara McClintock of Cold Spring Harbor Laboratory, jumping genes are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution by creating new mutations and gene combinations.

Until this recent study, L1 retrotransposition was assumed to take place during early development mainly in germ cells (ovaries and testes) and rarely in somatic tissues (non-sex cells). Now researchers from the Roslin Institute near Edinburgh, Scotland, have capaciously mapped retrotransposon insertion sites in the genomes of normal human brain cells.

The researchers used state-of-the-art DNA sequencing technology to identify retrotransposons in brain tissue samples taken at postmortem from three individuals who were healthy when alive and had no neurological disease, nor signs of abnormality in their brain tissue. Focusing on two regions—the hippocampus and caudate nucleus (that is also involved in memory)—they identified nearly 25,000 different sites for the three main retrotransposon families: L1, Alu and SVA.

The numbers are impressive: their analyses identified a total of 7,743 insertions of L1s in the hippocampus and caudate nucleus, areas that were known to show cell division after embryogenesis. They also found nearly 14,000 insertion sites for the Alu family, which has not been encountered before in the brain.

Interestingly each sample showed its own set of unique retrotransposition events, which meant each one had an individual mutagenesis background. According to the study, retrotransposons more likely to be integrated in genes that were expressed in the brain, perhaps because these genes are more susceptible, as their DNA is packaged in a more accessible way.

So what is the consequence when retrotransposons preferentially jump within genes that play key roles in normal brain function? They cause normal gene expression to shut down, disrupting normal gene function. Affected genes include those genes encoding receptors for the neurotransmitter dopamine and membrane transporters. Others integrated in tumor-suppressor genes, which are deleted in several different types of brain cancer. Jumping genes were also found within genes encoding regulatory proteins linked to psychiatric illnesses, such as schizophrenia and Alzheimer’s disease. As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. Such alterations can have a valuable or harmful outcome, without doubt a powerful tool driving evolution.

The researchers also reported that jumping genes were more active in the hippocampus compared to the caudate nucleus. This is highly interesting, because the hippocampus is known to be critical for memory and learning, and is thought to be one of the few parts of the brain that continues to produce new cells throughout life. Are jumping genes therefore involved in how we learn? Researchers are now beginning to investigate whether jumping genes help us adapt processing information through learning.
So when do jumping genes actually get mobile?  It has to happen during the brain’s development because retrotransposition requires cell division. After early childhood this does not take place in the brain; new neurons are generated in the hippocampus from stem cells, through a process called neurogenesis.  Retrotransposons then take the opportunity to jump randomly (!) into parts of the chromosome that have been opened up for DNA replication.

Once thought to be rare, these neural integration events actually take place surprisingly often. The analyses in this latest study suggested that most brain cells undergo an average of 80 L1 integration events! This means each neuron is likely subjected to a unique combination of insertions, leading to a “genomic plasticity” within populations of cells.

This research completely overturns the belief that the genetic make-up of brain cells remains static throughout life. It indicates that neuronal networks are constantly changing with each new experience as novelty and challenge both trigger neurogenesis. It may finally result in differences in brain function among individuals, even in genetically identical twins.

Further reading:

Video link about Alu elements and Autism.

Nature papers about L1 transposition in human neurons and the impact of Alus on human evolution.

Researchers have known for a while that not only are glioblastoma multiforme cells highly resistant to chemotherapy, but they can also deftly migrate away from sites of radiation or surgery, setting up camp and regrowing in other parts of the brain. This means that brain cancer is notoriously difficult to treat and the prognosis is almost always grim.

Last year the New York Times described Hanahan and Weinberg’s Hallmarks of Cancer as follows:

“Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline. With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.”

This is a nice analogy, relating overgrowth of cells paired with lack of cell death (apoptosis) as the accelerator and brakes of a car.

However Amy Keating and colleagues at the University of Colorado Cancer Center focused on the car’s GPS system. They published data in Nature: Oncogene showing that when a receptor tyrosine kinase involved in cancer cell growth, Mer, is switched off, significantly less cancer cells migrate to neighboring tissue in cultured laboratory cells. Keating found that not only does Mer interfere with the molecular signaling pathway, but also the cytoskeletal organization (the structure of the cell).

In other words, the Mer switch interferes with the electrics of the GPS system as well as the steering wheel of the car.

This added to their previous finding that Mer could increase some brain cancer cells’ sensitivity to chemotherapy.

So Mer inhibition could be a “double whammy” approach to treating brain cancer: kill as many cancer cells as possible and stop those remaining from migrating.

So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors.  As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulates the utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3).  In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5).  Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease.  Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled,  Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD.  The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively.  The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels.  When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

1. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. PUBMED
2. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
3. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
4. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168. FREE FULL TEXT
5. Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
6. De Felice FG, Vieira MN, Bomfim TR; et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-1976. FREE FULL TEXT
7. Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
8. Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging. 2009;30(3):377-387. PUBMED

Researchers at the University of California Los Angeles and Ohio State University Comprehensive Cancer Center are investigating a new treatment for glioblastoma, the deadliest form of brain cancer. Their paper, out this week in Cancer Discovery, shows how blocking a mechanism involved in cell metabolism and triggered by a cancer gene can reduce brain tumors.

Glioblastoma affects about 18,500 Americans each year, with less than a third surviving. The brain tumors are very difficult to remove as the cancer cells invade surrounding brain tissue. To make matters worse, some people are genetically predisposed to resisting chemotherapy or radiotherapy.

The researchers looked at the cellular mechanism that involves an over-active PI3K signaling pathway. This pathway is stimulated by a gene variant called EGFRvIII, which is present in nearly half of all glioblastomas. The gene variant also switches on a transcription regulator, increasing the activity of the low-density lipoprotein (LDL) receptor. This increases the uptake of LDL, providing more cholesterol for the brain tumor cells to feed on, grow and survive.

The number of LDL receptors was reduced in these experiments by activating an alternative receptor, the nuclear Liver X Receptor. This then caused the cholesterol to be transported back out of the tumor cells using an ABCA1 protein pump. Without the extra cholesterol, the greedy brain tumor cells eventually starve and die.

The good news is that this signaling pathway is not just confined to glioblastomas so this therapy may eventually be used to treat other forms of cancer.

So it’s yet another reason to cut out the eggs, cream and butter and have oatmeal for breakfast!

Guo D, Reinitz F, Youssef M, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discovery 2011; early online.

(For more on signaling pathways in cancer cells, check out “Pathways to Cancer” @ the Inside Cancer website.)

Researchers at the University of Wisconsin- Madison conducted tests with rats that were kept up past their normal bedtime. The rats were given objects to play with to keep them awake. During play, electrodes were implanted in their brains to measure brain activity. The results were interesting.

It seems that sleep does not involve the whole brain at once. It was once believed that a central control system determined when the brain would sleep and then later when it would wake. However, due to new research, this doesn’t seem to be the case. It seems that individual cells make the decision to sleep which eventually spreads throughout the rest of the brain.

The rats that were “wide awake” and playing with their toys weren’t “wide awake’ at all! Parts of their brain were snoozing- as the electrodes showed. This means that even though the rats weren’t showing their sleepiness and weren’t nodding off, their brains were not working to their full potential.

The electrodes measured activity in two parts of the brain: the motor cortex and parietal cortex. The rats were given an activity that required them to reach through a plexiglass wall and grasp a sugar cube. The rats that had a napping motor cortex (the part of the brain that controls movement) failed to grasp the sugar cube after many mistakes. The rats that had a napping parietal cortex, however (which was not needed for the task) was able to complete it without any mistakes.

As to how this would apply to the human mind, this could mean that the loss of sleep can be even more dangerous than previously thought. Someone could feel awake enough for tasks without realizing that essential parts of the brain are dozing. This can lead to slips of the tongue, driving mistakes, errors of judgment or other problems. It makes us rethink sleep derivation and how it’s really affecting us.

Just another reason why getting the recommended amount of sleep is important!

In a study published in Attention, Perception, & Psychophysics, a group of researchers have been examining a condition called “Inattentional deafness.” The group from University College London examined study participants’ ability to detect a sound while focusing intently on a task.

When subjects did a simple version of the computer based task, most recalled hearing a soft tone (that they were not expecting) in their headphones. A very difficult task caused most participants to become totally unaware of that same stimulus.

Although the study may fuel excuses the next time you are accused of not listening, it has more serious implications as well. While a frenetic pace of life puts a premium on people who can “multitask,” this study emphasizes that multitasking is not something the brain has limitless capacity for. Texting, having conversations, or just daydreaming while we are driving, are all instances of things that rob us of our ability to focus. Having any kind of inattentional deafness or blindness may does not necessarily have to cause the level of impairment that alcohol may bring, but may still cost precious seconds of reaction time that could mean the difference between avoiding an accident, or causing one.

Recently, a group from Naples reports that D-Aspartic acid functions as a neurotransmitter in both a mammal the rats (Rattus norvegicus), and a mollusk (Loligo vulgaris). D-Aspartic acid (D-Asp) has been known to scientists for well over a century. However, its role as a neurotransmitter was only now confirmed by the work presented by D’Aniello et.al.

The brain is usually thought of in its own category when considering our organs; deservedly so, since it seems to be the seat of our personal identity, our selves.  Still, the molecules we think of as neurotransmitters (GABA, glutamate, serotonin, etc.) we most often isolated from other parts of the body, and have roles in biology unconnected with neurotransmission.

Presence in the brain is of course not the qualifying factor for describing any particular molecule as a neurotransmitter. The D’Abuello et.al demonstrate not only the presence of D-Asp acid in high concentrations in synaptic vesicles, but also show that there are specific post-synaptic receptors for D-Asp which trigger signal-transduction of cAMP upon binding of the D-Asp ligand.