The Ash Twins Blog

The hottest topic and holiest grail in neuroscience research is trying to understand population coding, how groups of cells in the nervous system interact to process and store information. Neuroscientists think about this phenomenon all the time and have designed methods and theories to study it, but unfortunately we don’t have the data we need. It’s a technical nightmare to record the activity of neurons, and it’s possible to record from at most dozens or a hundred cells given current technology. Trying to measure the activity of all million or hundred-billion or so of them (depending on your model system), much less knowing their precise connectivity, will be impossible in the near future.

An interesting alternative model system for studying population coding is social insects. One can conceptualize an ant hill or bee hive as a brain in which each individual is a neuron or fundamental computational subunit. How does computation emerge out of the relatively simple interactions of ensembles of individual insects?

The great advantage here over studying neurons is that a single-layered honeycomb can be placed between 2 glass panels, every bee can be individually labeled with fluorescent dyes, and  all of the interactions of all of the subunits can be captured, imaged simultaneously over time with a video camera.

To study simple hive-mind computations, the behavior of all of the insects can be monitored in response to environmental insults or challenges, and the interactions which lead to adaptation can be measured. How memories are represented across the bee population can be assayed by training the hive with operant conditioning methods (e.g. associating an odor with food locations). Lesion-like studies could be performed by sacrificing individual bees which locate food and perform the targeting dance. A host of society level computations like division-of-labor, resource management, and reproduction likely are due to interesting dynamic interactions between individual insects.

I just started reading Bee Democracy to learn more.

I went to New Orleans last week, and after a few days on Bourbon street it became clear to me that the hangover is a scourge on society. I thought it would be good to try to cure the hangover.

Pathophysiology of the Hangover

Reading the literature, I learned that the pathophysiology of hangover is mostly unknown. Some believe that accumulation of acetaldehyde (the major metabolite of ethanol) could be the culprit, since artificially increasing acetaldehyde levels artificially leads to many of the bad symptoms of hangover, like flushing, nausea, and headache (disulfiram inhibits the enzyme that breaks down acetaldehyde and is actually a treatment for alcoholism – it makes drinking really terrible). Acetaldehyde levels are very low by the time that hangover symptoms start, though, so its probably not the cause.

Although important, dehydration has been mostly invalidated as the major cause of hangovers, since drinking a lot of water won’t abolish them, measures of dehydration are often normal in hung-over people, and dehydration by itself causes symptoms much different from hangovers.

A recent paper in PLoS-One (Maxwell et al 2010) lends credence to the idea that acetate, another breakdown product of ethanol, could cause hangover symptoms. They first gave rats chronic headache by injecting an inflammatory substance inside their skulls. Then, to induce headaches they hit the rats on the head with different forces and looked to see how uncomfortable it made them. Getting the rats drunk made the induced headache less painful, but then during the hangover, the headache was much worse. Increasing acetate levels (but not acetaldehyde levels) increased and lengthened hangover headache severity. Co-administering caffeine (a well-known hangover remedy, as well as an inhibitor of adenosine [a neurotransmitter which is increased by acetate]) blocked the negative effects of acetate.

Congeners, the random chemicals in alcoholic drinks other than ethanol, are another potential hangover cause; Drinks with a lot of congeners, like red wine and whiskey, have been shown to cause more painful hangovers than vodka. Also lending credence to this idea is the fact that drugs which bind congeners in the gut and prevent them from entering the blood stream (over-the-counter herbal mixtures like Chaser or RU-21) have demonstrated impressive effectiveness, at least anecdotally. Still, vodka can give you a giant hangover, so this doesn’t explain everything.

Ethanol consumption also disrupts normal sleep patterns, so sleep deprivation also probably causes some hangover symptoms. Not surprisingly, caffeine (as mentioned above) is one of the best tonics for a hangover.

There appears to be an immune or inflammatory component to the hangover, because the most effective treatment are non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen (advil), or naproxen (midol), which inhibit synthesis of the immune mediating prostaglandins.

Finally, I can say that although this hasn’t been attempted in clinical trials, I can say from personal experience that last week I cured one of the worst hangovers of my life with a single 10 mg dose of Adderall, the ADHD medicine. It’s reasonable to me that depletion of modulatory neurotransmitters norepinephrine and/or dopamine, or dysregulation of the neuron groups that regulate their release, could occur as a result of ethanol’s central effects. This definitely warrants further investigation.

Hangover Neuroscience

The neurophysiology of the hangover is a wide-open field. No one has even put a person into an fMRI or EEG before and after getting drunk! To me, since there aren’t any metabolites that have been shown to convincingly correlate with hangovers, and given that the hangover is primarily a subjective phenomenon, it’s likely that there is a prominent central nervous system component to the disorder.

First step: Self-test of current therapeutic options

Before going to Taaka with a grant proposal, I’m going to test the current symptomatic treatments on myself and assay their effectiveness. Based on my reading of the literature, I designed what I think is an optimal treatment regimen:

1. Take 2 Chaser tablets with the first drink – this will block congener absorption for 2-3 hours
2. Take an extended-release acetaminophen (tylenol) right before bed. This is mainly used for arthritis, and because of its long half-life should be able to provide some analgesic effects even in the morning. If you were drinking often, this would be a bad drug to use because ethanol and acetaminophen together cause liver toxicity. But once every week or 2 will be fine – the liver can actually regenerate itself even if you resect most of it.
3. Take Equate (generic excedrin), a combination of acetaminophen-aspirin-caffeine, in the morning. This gives you two different kinds of analgesic (aspirin, which is an NSAID, and acetaminophen which is similar but whose precise mechanism is unknown), plus caffeine, which helps by both normalizing sleep deprivation and blocking the effects of acetate.
4. A strong latte.
5. Adderall (if I can get some)

I’ll try these treatments in different combinations as well as all-together to see what works best, and to decide if curing the hangover is worth a 5-year investment.

I started a new band, Cutie Pie and Baby, with my lab mate Jiyoung Park.It’s a Korean-Texan pop alternative giant pumpkin filled with gold. Elliott plays the drums when he’s around.

Check us out at cutiepieandbaby.com.

Elevated RhoA/Rho-kinase activity in the aged rat penis: mechanism for age-associated erectile dysfunction. Jin, Liu, Lagoda et al FASEB 2006

Epidemiologic studies have shown that aging accounts significantly for the prevalence of erectile dysfunction (ED). The pathophysiology of ED during aging and its underlying molecular mechanisms are largely unknown. We hypothesized that increased RhoA/Rho-kinase signaling is a major factor in the pathogenesis of age-associated ED and the mechanism involves increased penile smooth muscle contractility through inhibition of myosin light chain phosphatase. Male Fischer 344 young (4 month old) and aged (20-22 month old) rats underwent erectile function testing in vivo by measuring intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) upon electrical stimulation of the cavernous nerve. The data demonstrated that erectile function was significantly lower in aged rats than that in young rats at all voltages tested (P<0.05).

Western blot analysis results showed that there were no significant changes in protein expressions of RhoA, Rho-kinase-alpha and -beta isoforms, and myosin light chain phosphatase target subunit (MYPT1); however, membrane-bound RhoA and phosphorylated MYPT1 were increased in aged rat penes by 95 +/- 15 and 56 +/- 8% (P<0.05), respectively, indicating enhanced RhoA and Rho-kinase activity. Inhibition of Rho-kinase with Y27632 maximally increased ICP/MAP to 0.72 +/- 0.05 in aged rats vs. 0.47 +/- 0.06 in young rats (P<0.05).

Gene transfer of adeno-associated virus (AAV) encoding dominant negative RhoA (T19NRhoA) to penes of aged and young rats for 7 days markedly improved erectile function in aged rats when compared with that in young rats (P<0.05). These observations were also supported by Rho-kinase activity assay results showing that basal Rho-kinase activity in aged rat penes receiving AAV vehicle treatment was twofold greater than that in young rat penes receiving AAV vehicle treatment, while it was reduced to a level similar to that in young rat penes after gene therapy of T19NRhoA (P<0.05). Taken together, these data suggest that impaired erectile function during the aging process involves increased RhoA/Rho-kinase signaling, and this pathway may be exploited for the treatment of age-associated ED.

Elliott and I are traveling in the Balkans (former Yugoslavia) this August. We went to Dubrovnik, Split, Hvar, and Zadar in Croatia last week. Today we went to Plitvice lakes, which is an incredible series of lakes in the mountains surrounded by rain forest (yeah, it was weird to see rain forests in Europe).

Then our hotel owner Damir drove us across the border to Bihač  in Bosnia. We had to stop for a few minutes at one point to wait for mine sweepers to finish checking a spot by the road. A bit later we drove through a deserted town which Damir told us was an old Serbian village – The townspeople had fled during the 1990s war (it’s very close to Croatia), and now most of them are afraid to come back because there are 12 unexplained Croatian deaths. We took a bus from Bihač to the medieval mountain castle town Jajce, seat of power of the ancient Bosnian kings. One wall of the house we are staying in is a thousand year old stone tower.

Interesting trivia – The medieval Bosnian kings didn’t like Christianity very much, so they converted the entire country to a primitive religion called Bogomil around 600 AD. When the Turks conquered Bosnia in the 1400s, the people didn’t care much about their old-fashioned religion, so thez were easily converted to Islam. Ergo, By the early 1900s, almost the entire country was made up of ethnically European Muslims. Even after being killed in vast numbers in WW1, then again in WW2, and in the mid 1990s, Bosnia and Hercegovina is still the only country in Europe with a Muslim majority.

Forgive the lack of links – it is really tough to make them on this shit keyboard. Wikipedia anything you’re interested in.

In the previous post, I mentioned that our studies in the mouse model for MECP2 duplication syndrome indicate that synapses are being formed and lost at a high, immature rate for the life of the animal, which is associated with the development of stereotyped repetitive behaviors and epileptic seizures.

Achieving a balance between cortical circuit stability and plasticity allows us to adapt to and learn from novel environmental experiences without forgetting useful information from the past. Children and adolescents have little experience to guide their actions, so new information is very important, and plasticity (learning) is favored over stability (memory). Conversely, the elderly have a wealth of past experiences, so incorporating new information into world models is less likely to be beneficial, and stability is favored over plasticity.

One theory for the pathophysiology of developmental brain disorders like Fragile X syndrome, Rett Syndrome, Angelman syndrome, and MECP2 duplication syndrome is that the link between genetic lesions and certain neuropsychiatric phenotypes is an imbalance between stability and plasticity. If the brain’s synapses are too stable, the brain will have trouble adapting to new experiences; Synaptic rigidity of this sort could lead to the permanent infantilism seen in Angelman syndrome, and has indeed been demonstrated Angelman syndrome mouse model. If the brain’s synapses are too labile, on the other hand, extant memories may be continually overturned by new experiences, or even worse synapses will continue to develop past their normal strengths, generating stereotypic behavior and epileptic circuitry. In either case, the cumulative refinement of neural circuitry that is important for brain development cannot occur.

Results in my lab suggest that MECP2 duplication syndrome is an example may be such a syndrome of too much plasticity. In juvenile mice, this bias toward synapse turnover allows relatively rapid acquisition of both adaptive (enhanced motor learning) and maladaptive (enhanced conditioned fear response) environmental adaptations. As the mice reach adulthood, they have sampled a broader range of world states, but the normal developmental deceleration of cortical plasticity which would shift the continuum to stability in cortical circuits does not occur. Instead, circuits oversaturate, leading to hyperexcitable ensembles which continue to self-strengthen by positive feedback. Activity in these dysfunctional cortical circuits produces compulsive, repetitive, stereotyped behaviors as well as runaway resonant excitation and epileptic seizures. Along these lines, it appears that patients steadily acquire developmental milestones until a critical point in which neurodevelopment stagnates and seizures ensue (Karas & Zoghbi, unpublished observations).

In my lab, we are studying the developmental brain disorder MECP2 duplication syndrome. It is caused by genomic duplication of the q28 region on the X chromosome, and common symptoms include severe intellectual disability and autism, progressing to severe epilepsy and early death. Genotype-phenotype analyses of patient samples suggest that the key dosage-sensitive gene in Xq28 duplication is the transcriptional regulator methyl-CpG binding protein 2 (MECP2), mutations of which have also been linked to Rett Syndrome, Angelman Syndrome, and autism. To study the neurobiology of this neurodevelopmental disorder, we use mice which have been engineered to overexpress MECP2 at twice normal levels. Analogous to humans with MECP2 duplication, these MECP2 duplication mice develop a progressive neurological phenotype with repetitive compulsive motor behaviors, abnormal social behavior and learning, anxiety, spasticity, and seizures.

A convincing physiological link between the symptoms of MECP2 duplication syndrome and its underlying genetic lesion has yet to be established, but work in mouse models and neuronal culture indicates that deranged dendritic/synaptic structure and plasticity may be an important locus of disease. The MECP2 duplication mice have a dramatically increased density of excitatory synapses in the hippocampus which is most prominent at young ages. Overexpression of MECP2 in primary slice cultures (to make a primary slice culture – a brain is harvested, sliced into slabs, and placed in a petri dish with oxygen and nutrients. They can survive for weeks and months with appropriate care)  causes a range of structural abnormalities in dendritic arbors and dendritic spines (the small protrusions from dendrites at which most excitatory synapses form). Detailed neuropathology with postmortem MECP2 duplication syndrome patient samples has yet to be performed.

In our lab, we are studying the formation, development, and pruning of these dendritic spines in MECP2 duplication mice. We cross the MECP2-duplication mice to the thy1-GFP (Green Fluorescent Protein form jellyfish) transgenic mice, which have been engineered to express bright fluorescence in a small number of layer  pyramidal neurons. These glow-in-the-dark neurons allows us to image apical dendrite and dendritic spine morphology in intact animals over days, weeks, and months, using two-photon microscopy (basically, a laser scans through the brain tissue identifying points of fluorescence in 3 dimensions). We are imaging the synaptic development from presymptomatic (4 weeks) stages to severe symptomatic (40 weeks) stages.

Our key finding so far is that the process of dendritic spine turnover (formation and pruning of synapses over time) does not undergo the normal developmental deceleration with age, but rather stays abnormally high well into adulthood, and that this elevated spine turnover is correlated with a net decrease in dendritic spine densities.

Chen, Katuscak, and Ozdenoren have an unpublished working paper that would fit in perfectly at the Journal of Bioeconomics:

In this study, we investigate gender differences and menstrual cycle effects in first-price and second-price sealed-bid auctions with independent private values in a laboratory setting. We find that women bid significantly higher and earn significantly less than men do in the first-price auction, while we find no evidence of a gender difference in bidding in the second-price auction. At a biological level, we find a sine-like pattern of bidding in the first-price auction throughout the menstrual cycle, with higher bidding in the follicular phase and lower bidding in the luteal phase. Further analysis shows almost all of the variation is driven by contraceptive pill users.

SSRN link: http://papers.ssrn.com/sol3/papers.cfm?abstract_id=881748

Heaton, Journal of Law and Economics (2006):

Many sociological theories positing a deterrent effect of religion on crime are empirically examined using ordinary least-squares (OLS) regressions of crime measures on measures of religiosity. Most previous studies have found a negative effect of religion on crime using OLS, a result I am able to replicate using county-level data on religious membership and crime rates. If crime affects religious participation, however, OLS coefficients in this context suffer from endogeneity bias. Using historic religiosity as an instrument for current religious participation, I find a negligible effect of religion on crime and a negative effect of crime on religion. To further explore the relationship between religion and crime, I examine variation in crime incidence before and after Easter. Consistent with the IV results, I find no evidence of a decrease in crime following Easter.

Link: http://www.jstor.org/stable/10.1086/501087

From Chou et al, Journal of Law and Economics (2008):

In this paper we employ the 1979 Child-Young Adult National Longitudinal Survey of Youth and the 1997 National Longitudinal Survey of Youth to estimate the effects of television fast-food restaurant advertising on children and adolescents with respect to being overweight. A ban on these advertisements would reduce the number of overweight children ages 3-11 in a fixed population by 18 percent and would reduce the number of overweight adolescents ages 12-18 by 14 percent. The elimination of the tax deductibility of this type of advertising would produce smaller declines of between 5 and 7 percent in these outcomes but would impose lower costs on children and adults who consume fast food in moderation because positive information about restaurants that supply this type of food would not be completely banned from television.

Full text: http://democrats.edworkforce.house.gov/documents/111/pdf/publications/20100701hearingarticle3.pdf