We can agree to disagree. Although I’m a huge, geeky fan of hers, I have to respectfully disagree with Apoorva’s post on Spoonful of Medicine about the Stanley Medical Research Institute’s $100 million gift to the Broad Institute (originally reported in the Boston Globe). The Broad Institute, which is arguably the be all and end all of genomics research, plans to compile genetic and clinical data from thousands of people in order to identify candidate genes that associate with psychiatric disorders, including schizophrenia and bipolar disorder. Apoorva said:

But these are extremely complex disorders, each involving multiple genes. What roles do those genes play in the disease? Without understanding how the different genes interact and what the impact is of the different variations, the data will be all but meaningless.

I would argue that the very complexity of these diseases is the reason that such large datasets (and the bioinformaticians to make sense of them) are necessary. A really good example is in this month’s Nature Genetics. The Autism Genome Project Consortium identified new gene candidates associated with autism from a dataset containing genetic information from nearly 8000 people. Have they poof! figured out what causes autism? No, but they have identified a place to start.

Finding a place to start is really the whole point. These are disorders for which there just isn’t a lot to go on. Apoorva’s concern about understanding the roles of candidate genes in health and disease is really putting the cart before the horse. The molecular interactions between disease-related genes and their roles in psychiatric disorders can only be deciphered once candidates are in hand. With this fantastic grant, maybe the Broad Institute will get that far. That would really be something.

In case you missed it, the New York Times profiled Joseph LeDoux’s rock band, which is appropriately named the Amygdaloids. The band’s fans may be even more impressive than its members, who are all neuroscientists. Nobel prize-winning mathematician John Nash (subject of A Beautiful Mind) describes the Amygdaloids music as “psychoanalytic”.

If you lose your marbles in zero gravity, your fellow astronauts are assigned to catch them. According to the LA Times, NASA has a detailed, if slightly barbaric plan for dealing with an astronaut’s psychotic or suicidal behavior while in space. To prevent a distraught astronaut from harming his colleagues, crewmates are instructed to physically restrain him with bungee cords and administer tranquilizers. Then what? The written plan does not elaborate, but a NASA spokesman quoted in the Times suggests that officials on the ship and on the ground would decide if the mission should be aborted. This report comes in the wake of astronaut Lisa Nowak’s arrest in Orlando for attempted kidnapping.

Although I have no issue with NASA’s concern for the safety of its astronauts in an understandably delicate situation, I am a little uncomfortable with the brutality of its plan. Yes, a suicidal or psychotic astronaut could endanger the lives of his crewmates, and the seriousness of the situation is unquestionable. However, I wonder about the criteria fellow astronauts would use to evaluate a troubled crewmate. Will astronauts be educated about signs of deteriorating mental health, or will they be trusted to ‘know it when they see it’?

Coincidentally, a bill before the US Senate will make it easier for Americans to seek treatment for mental health. The Mental Health Parity Act of 2007 would require health insurance companies to cover treatments for psychiatric and neurological disorders, including substance abuse, comparably to other health disorders.

If you were happy with the level of NIH funding in 2006, you’re in luck! According to the 2008 budget proposed by US President George Bush on Monday, NIH funding will remain flat. Oh sure, the numbers sound good. On paper, the proposal includes a $232 million increase relative to 2006 (Congress has yet to pass 2007’s doozy of a budget). However, $200 million of that is already promised to the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria. The remaining $32 million increases NIH’s budget by 0.1% relative to 2006, far less than the 3.7% yearly inflation rate estimated by NIH. Although the budget includes allotments for new grants, no inflationary increases are planned to increase grant size. That means you, students and post docs with NRSAs: the proposal freezes student and post doc stipends at fiscal year 2007 levels.

The very special episode of Family Ties that guest starred Tom Hanks as Alex Keaton’s cough syrup-guzzling, alcoholic uncle scarred me for life. Tom Hanks will be happy to know that he has finally been outdone. News reports circulated this week that people are ingesting hand sanitizers to get drunk. Hand sanitizers contain nearly twice the amount of alcohol as vodka and are toxic because they contain isopropanol, not ethanol. So, hand sanitizers make poor beverages.

Perhaps those in search of a quick high should instead open their wallets and inhale. According to Science Daily, 100% of Euro notes tested near Dublin contained traces of cocaine. Approximately 62% of the Euro notes contained in excess of 2 and 5% contained more than 200 nanograms per note, suggesting these bills might have been used during drug inhalation or transactions. Relative to 5 and 10 Euro notes, 20 and 50 Euro notes tended to have more cocaine residue. Previous studies in the U. S. showed that 65% of dollar bills held traces of cocaine. Researchers believe that cocaine adsorbs to bank notes and rubs off on other bills. Are most people, let alone bankers, therefore sensitized to small amounts of cocaine?

How about LSD? Hallucinogens, like LSD, act at 5-HT2a receptors, as do non-hallucinogens, including lisuride, which is used to treat Parkinson disease. How do 5-HT2a receptors differentially respond to different types of ligand? Gonzalez-Maeso et al. report that hallucinogens activate different cell signaling pathways than do non-hallucinogens in an article published yesterday in Neuron. Both LSD and lisuride act at 5-HT2a receptors to activate phospholipase C-beta via Gq/11 proteins. The authors showed that LSD, but not lisuride, increased the expression of the early growth response-2 (egr-2) gene. A phospholipase C-beta inhibitor, a Src inhibitor and pertussis toxin all blocked LSD-induced increases in egr-2. Therefore, the authors concluded that unlike non-hallucinogens, LSD acts at 5-HT2a receptors to activate pertussis toxin-sensitive Gi/o proteins and Src, which may mediate its hallucinogenic effects.

Nicorette be damned! Quitting smoking is easy…if you’ve had a stroke. Naqvi et al. report that stroke-induced damage to the insula associates with smoking cessation in today’s issue of Science.

The insula lies in the pocket separating the temporal lobe from the parietal lobe and is thought to provide emotional context for sensory information. Sixteen of nineteen smokers who suffered strokes that affected the insula quit smoking immediately. Smokers who sustained damage to the insula were more likely to quit than smokers who had sustained damage to other brain regions. Although several of the patients with insular damage also sustained damage to the putamen, which is part of the striatum thought to be involved in learning drug use behaviors, no other brain region associated with smoking cessation in the stroke patients.

Do smokers with insular damage lose pleasure in smoking? After smoking cessation, none of the patients with insular damage reported losing pleasure in eating or drinking, suggesting that they had not lost motivation or the ability to experience pleasure. Do these patients lose other habits? Unfortunately, the authors did not address this possibility.

These findings suggest that the insula is important in experiencing the need to smoke and is therefore a target for smoking cessation therapy. Considering the insula’s proximity to language centers, surgical lesion of the insula is certainly not advisable. However, targeted pharmacological therapy might some day help smokers quit. According to the authors, the efficacy of smoking cessation programs might be determined by imaging insular activation.

Despite my best efforts to stop it, my most productive planning always occurs in the last five minutes of a yoga class. Relax my mind? I don’t think so! What goes on in the brain when we let our minds wander? Mason et al. report that a network of brain structures is active during daydreaming in a recent article in Science.

The authors had people do repetitive (i. e. boring) tasks, like memorizing and rehearsing the same short list of words forward and backward, for 30 minutes each day. The subjects reported that their minds wandered more during this task than when they were given a new task to do. On the fifth day, the subjects did the same task in an MRI machine. The authors identified regions of the brain that were active during this literally mind-numbing activity relative to those that were active when participants worked on a novel task. Then they correlated the activity of these brain regions to the participants’ daydream frequencies. BOLD signal in the medial prefrontal cortex, cingulate, precuneus, right superior frontal gyrus and the left and right insula associated with daydreaming. In addition to daydreaming, the authors believe that these brain regions might be important in ‘housekeeping’ functions or might cause people to be aware of their daydreams.

Why do we daydream? I’ll look that up once I stop thinking about a beach vacation…

Several sources, including news@nature and the Washington Post, reported today that relative to the early 1990s, the average blood level of folate in women is declining. Folate deficiency is associated with neural tube defects during fetal development. So women of child-bearing age are encouraged to take folate supplements even if they are not pregnant or actively trying to get pregnant. Incidence of neural tube defects has declined by approximately 25%, presumably because we are all taking folate.

So why are folate levels declining? It’s not clear, but officials from the U. S. Centers for Disease Control and Prevention have several ideas. Obese individuals metabolize folate differently than thin people and may need to consume more folate than their thin counterparts. Because obesity is on the rise, that may explain the decline in average folate levels. Alternatively, diet trends may be to blame. In the U. S., the Food and Drug Administration requires that enriched flour used in cereals and breads be fortified with folic acid. But in 2003, the Atkins diet craze encouraged us all to trade in our Cheerios for steaks. Now diet gurus are encouraging people to eat whole grains, which unlike their processed counterparts, are not supplemented with folic acid.

So, women should consume far more folate. That is, unless you remember this bizarre news item from last spring, reporting that each generation of obese pregnant mice fed folate and other methyl donors had increasingly heavier offspring.

What’s new in neuroscience? A physical scientist asked me this question at a holiday party last week. I’d already been thinking about the highs and lows (but mainly highs) of what I’ve seen in 2006, so I told him about my favorite group of papers to come out in the last few months.

The genes that make us human are expressed in the brain and may be involved in brain development. This is the basic gist of several recent papers that sit on the fence between evolutionary genetics and neuroscience. Pollard et al. (my favorite of the bunch) report that among all genes, the non-coding gene HAR1F has had the most accelerated changes in the human relative to other species. HAR1F is expressed in Cajal-Retzius cells, which are important in cortical development, and is developmentally regulated. Since the cortex is specifically enlarged in humans relative to other species, these data may suggest that HAR1F is important in the evolutionary expansion of the human brain.

Popesco et al. looked for genes with the biggest copy-number expansion in humans relative to other species. They report that humans have more copies of the MGC8902 gene than other species. Humans have approximately 50 copies, whereas chimps and macaques have 10 and 4 copies, respectively. MGC8902 encodes repeats of a protein domain called DUF1220, whose function is unknown. DUF1220 domains are only found in primates. In humans, DUF1220 is found in neurons in the hippocampus, cortex and cerebellum.

Finally, Prabhakar et al. report that non-coding genes with the most human-specific substitutions are disproportionately involved in neural cell adhesion.

Best wishes for a New Year filled with great neuroscience.

During the holiday season, Tyzio et al. give us one more reason to buy mom a really nice present. They report that maternal oxytocin, which induces uterine contractions during labor, protects the newborn brain from hypoxic/ischemic neuronal cell death in a recent article in Science.

GABA is the major inhibitory neurotransmitter in the adult brain, but it is the major excitatory neurotransmitter in the neonatal brain. The intracellular chloride concentration is elevated in neonatal relative to adult neurons at least in part because the transporter that shuttles chloride out of the cell is not yet expressed. Therefore the reversal potential, the membrane potential at which the concentration gradient driving an ion in one direction is balanced by the electrochemical gradient driving it in the other, is positive relative to the resting membrane potential, so the driving force for chloride is out of the cell, resulting in GABA-mediated depolarization. In the adult, the chloride exporter helps keep the intracellular chloride concentration low. The reversal potential for chloride is negative relative to the resting membrane potential, so the driving force for chloride is into the cell, resulting in GABA-mediated hyperpolarization.

In hippocampal slices from neonatal rats, the authors found that the number of neurons excited by GABA and the reversal potential for GABA neurons declined right around the time of birth, but rebounded shortly thereafter. During this period, the driving force for chloride ions changed from positive to negative, suggesting that GABA was inhibitory. Neurons grown in culture don’t experience this brief period of inhibition, so the authors proposed that a maternal factor might be the cause. Oxytocin reduced the number of hippocampal pyramidal cells excited by GABA and their intracellular chloride concentration relative to untreated cells. Pups from pregnant dams treated with an oxytocin receptor antagonist did not show GABA-mediated inhibition around the time of birth, suggesting that oxytocin is necessary for this short-lived effect.

So, why does GABA flip-flop? Birth can cause hypoxic conditions, which can lead to excitotoxic cell death. If the source for neuronal excitation is suddenly inhibitory, then the chances for cell death should decline. In the presence of an oxytocin receptor antagonist, hippocampal neurons from late embryonic rats were more vulnerable to anoxic depolarization relative to control neurons, suggesting that oxytocin is neuroprotective in the neonate.

What does this mean for babies born by Cesarean Section? I would think C-section avoids the anoxic conditions present in the birth canal. However, I wonder whether oxytocin analogs, like Pitocin and Syntocinon, that are used to induce labor affect fetal brain development or conversely offer extended protection for the neonatal brain.