Within our own studies, we’ve shown that BDNF can rescue alcohol’s impairing effects on the mammalian circadian clock; presenting animals with light during the nighttime produces delays in sleep/wake rhythms thereafter. Alcohol attenuates this delaying, but BDNF co-administered with alcohol rescues this delaying response.

Certainly, by now, some pharmaceutical company is investigating BDNF as a novel, more efficacious therapeutic for all drug addiction, not just alcoholism……..just a thought……. for sale for a million dollars……….

Ghazaleh Sadri-Vakili,1 Vidhya Kumaresan,2 Heath D. Schmidt,3 Katie R. Famous,2 Prianka Chawla,2 Fair M. Vassoler,3, & Ryan P. Overland,1 Eva Xia,1 Caroline E. Bass,4 Ernest F. Terwilliger,5 R. Christopher Pierce,3 and Jang-Ho J. Cha1 (2010). Cocaine-Induced Chromatin Remodeling Increases
Brain-Derived Neurotrophic Factor Transcription in
the Rat Medial Prefrontal Cortex, Which Alters the
Reinforcing Efficacy of Cocaine Journal of Neuroscience : 10.1523/JNEUROSCI.2328-10.2010

Jerome Jeanblanc,1 Dao-Yao He,1 Sebastien Carnicella,1 Viktor Kharazia,1 Patricia H. Janak,1,2,3,4* and Dorit Ron1,2,3,4 (2009). Endogenous BDNF in the Dorsolateral Striatum Gates
Alcohol Drinking Journal of Neuroscience DOI: 10.1523/JNEUROSCI.2243-09.2009

Rebecca A. Prosser1,*, Charles A. Mangrum1, and J. David Glass2 (2008). ACUTE ETHANOL MODULATES GLUTAMATERGIC AND
SEROTONERGIC PHASE SHIFTS OF THE MOUSE CIRCADIAN
CLOCK IN VITRO Neuroscience

In this study, human subjects were asked to keep a routine bed/risetime schedule which was verified through actigraphs. Actigraphs are watches that sleep study subjects commonly wear during the course of a study to measure their day and night time activity. It is also an easy way for the sleep researchers to ensure subject compliance to the mandatory bed/risetimes. In this study, a hair follicle was taken every 3 hr over a period of 48 hr to characterize the circadian expression of clock genes which regulate the endogenous (circadian) rhythm in the SCN. As shown below, four subjects activity records nicely complement circadian expression of clock genes.

What happens if you advance bed and risetimes, however? You see a shift in the circadian expression of clock genes too!!! This was accomplished by having the subject go to bed an hour earlier every day for 5 days.

And what would these circadian gene expression profiles look like in a rotating shift worker? That is, someone who every week has to drastically change their bed and risetime schedule and lifestyle from going to bed at 10PM and waking up at 6 AM to going to bed at 4 AM and waking up at 1 PM? Here, circadian gene expression appears to not be shifted as much as it is attenuated within only three weeks!!!

This attenuation of rhythmic gene expression, which you may know from my research and others, can actually increase predispositions to drug abuse and psychiatric disorders. Individuals with single nucleotide polymorphisms of PER and CLOCK genes, which also attenuate rhythmic clock gene expression, have high reports of alcohol use and depression. Alcohol use is already high among shift workers, because many of them use it to fall asleep in order to alleviate insomnia associated with shift work. A combination of shift work and a history of alcohol use for mitigating work-related sleep disturbance may be the tipping point of full-blown alcoholism.

I hate to not end this post so morbidly, so let me mention how this research will benefit public health. By knowing the preferred circadian phase of an individual, that is, whether their body operates as a lark, owl, or neither, employers may be able to better assign work shifts that will guarantee more productivity, less on-the-job accidents, improve company morale, and possibly, curb a work-induced downward spiral of alcoholism. This is, of course, the scientist speculating about the world as she sees it through her rosy-colored glasses……
Akashi M, Soma H, Yamamoto T, Tsugitomi A, Yamashita S, Yamamoto T, Nishida E, Yasuda A, Liao JK, & Node K (2010). Noninvasive method for assessing the human circadian clock using hair follicle cells. Proceedings of the National Academy of Sciences of the United States of America PMID: 20798039

As many of you know, glutamate binds to the NMDA receptor, stimulating calcium influxes into the neuron and activating molecular machinery (protein kinases, phosphatases, second messenger systems, transcription, translation), and eventually, causing a cell to respond differently, a hormone to release differently, and an animal to act differently. NMDA receptors and their subunits mediate the integration of light within the circadian timing system in order to maintain or shift its phase, amplitude, or period (of the endogenous rhythm).

Abnormalities of the NMDA receptor are also linked to alcoholism; during chronic alcohol use, the density of NMDA receptors increases to compensate for the fact that ethanol (the active ingredient in alcohol) is blocking glutamate signaling at these receptors. When someone stops abusing alcohol, the density of NMDA receptors don’t decrease, which unfortunately, leads to severe physiological withdrawal and eventually alcohol dependence. This occurs because these individuals are biologically encouraged to consume more alcohol to alleviate the glutamate-induced side effects only to feel even worse and worse and worse and worse. Hence, a vicious cycle of alcohol abuse and abstinence ensues.

In this study, the researchers applied a glycine agonist (D-serine) to the NR1 and NR3 NMDA receptor subunits resting on an intact optic nerve and characterized calcium activity using a “high-resolution calcium-imaging technique.” They found that glycine stimulated calcium release in NR1/NR3 subunits within myelin. What does that mean? It means that glycine agonists acting at NMDA receptors can control the speed of a neuronal message (that’s what myelin is for). Additionally, the researchers uncovered that the NR3 subunit was absolutely necessary for a glycine-induced calcium influx to occur because glycine-induced calcium influxes did not occur in animals without NR3 subunits (i.e. they were knocked-out). Even more interesting, treating the NR1/NR3 subunits with a glutamate antagonist did not stimulate calcium influxes in BOTH wild-type and knocked-out mice.

Certainly, characterizing the properties of these NMDA receptor subunits and what effects various neurotransmitters have on these receptors could yield more efficacious treatments currently available for the treatment of alcoholism such as naltexone and acamprosate. These novel NR1 and NR3 subunit treatments may even solve some of the limitations of naltrexone and acamprosate, such as a greater efficacy in Asian populations and reduced efficacy (i.e. tolerance) with continual use, respectively. Will there be a glycine-binding drug in the near future? Hopefully.
Juan C. Pin˜a-Crespo,1,2* Maria Talantova,2* Ileana Micu,5* Bradley States,2 H.-S. Vincent Chen,2,4 Shichun Tu,2, Nobuki Nakanishi,2 Gary Tong,2,3 Dongxian Zhang,2 Stephen F. Heinemann,1,3 Gerald W. Zamponi,6 Peter K. Stys,5, & and Stuart A. Lipton2,3 (2010). Excitatory Glycine Responses of CNS Myelin Mediated by
NR1/NR3 “NMDA” Receptor Subunits Journal of Neuroscience (34), 11501-11505 : DOI:10.1523/JNEUROSCI.1593-10.2010

But what if these headache and nausea complaints are also arising from chronic sleep deprivation? It has been well-documented that computers and smart technology devices greatly impair our ability to fall asleep easily at night by 1) suppressing melatonin release which allows us to fall and stay asleep; 2) eliciting stress by reminding us of what we have to do in the morning; and 3) convincing us that one more interactive game is more important. Additionally, common side effects of sleep deprivation include headaches, nausea, and difficulty concentrating. We also know that many school start times don’t comply with an adolescents biologically-preferred bed and rise times. So I’m pretty convinced that sleep deprivation is the culprit. here.

And if we have learned from South Park, this is what potentially could happen if the Internet is mysteriously deactivated.

In addition to not being impressed by the simplistic research methodologies and conclusions  (it very well could be an undergraduate project), I was also shocked that this study didn’t elucidate more of the neurobiological mechanisms of this circadian response, instead of confirming what was done previously. During the 60s, 70s, or 80s, when the field of circadian rhythms was pioneered, the founding fathers and mothers of circadia (Aschoff, Menaker, Hastings, Gillette, and Moore) sought to classify an abundance of circadian phenomena (behavioral and physiological) in a variety of mammalian, reptilian, amphibian, and invertebrate species. Many are documented in the circadian Bible (Biological Rhythms: Handbook of Neurobiology). Secondly, this study failed to discuss how the circadian regulation of anti-diuretic hormone (ADH) could easily drive this urinary rhythm. Though I somewhat sympathize, since everyone is fleeing from the SCN and flocking towards the idea of extra-SCN, circadian oscillators that lie centrally in the nervous system and peripherally in the organs. However, that doesn’t excuse the fact that ADH could have been measured or at least some other physiological marker evident of circadian urination could have been measured, especially given the impact factor of the journal in which the study was published. We already know in humans that ADH is upregulated at night (except when we drink), but what are the circadian-controlled mechanisms???
Gerald M. Herrera1,2, Andrea L. Meredith3* (2010). Diurnal Variation in Urodynamics of Rat
PLoS ONE : 10.1371/journal.pone.0012298

To focus on this particular study, Harvardian researchers have uncovered that sleep spindles protect people in noisy sleeping environments. To support this, they did baseline sleep recordings in individuals and found either a high or low density of sleep spindles. Following three days of exposure to a quiet (the country) or to a noisy (the city) environment induced, of course, by a sound machine, they found that those individuals who slept more soundly across the night in the noisy environment, as electrophysiologically determined through less nighttime arousals, had much greater densities of sleep spindles!

I immediately thought of sleep machines. I always assumed that sleep machines producing the sounds of the rainforest and beach were consumer lunacy, but perhaps this is the best way, after all, to ensure a good night’s sleep, though through an entirely different mechanism; your training your brain to spindle more and not training your stress systems to be soothed by the mating calls of tree frogs and crashing of waves.

Dang-Vu TT, McKinney SM, Buxton OM, Solet JM, & Ellenbogen JM (2010). Spontaneous brain rhythms predict sleep stability in the face of noise. Current biology : CB, 20 (15) PMID: 20692606

What were the results? As anticipated, the ADHD-like mice showed reduced responsiveness to the psychostimulants as shown here. The opposite was true for wild-types. The drugs also increased protein phosphorylation, which is one of the underlying mediators of the ADHD paradox.

Aside from the observation that this research re-confirms the widely known ADHD paradox, it is a great example of a basic neuroscience principle; what happens when you have too much of a neurotransmitter. In this case, the dopamine systems compensate for dopamine overexpression in the synapse by downregulating receptors and molecular machinery, so when a response is finally elicited by dopamine binding to its receptor, it’s less dramatic. Recently, I’ve also read an article stating that ADHD meds are an effective hedonic substitute for alcoholism. Taking it makes alcohol dependent mice drink less. Though, obviously, while this is interesting, ADHD medications as a hedonic substitute in alcoholics is certainly not the resolution; “treating” one addiction by encouraging another. Exercise is a healthy hedonic substitute though.

Most importantly, this research article should be posted in many pediatric offices around the US because as you may know, America has a problem with of over-diagnosing ADHD. Kids can’t be kids anymore. Perhaps a slip of ADHD medications is the answer to making an accurate and unbiased diagnosis of ADHD, but of course, there’s plenty of ethical issues with that. But is this the only way?

Francesco Napolitano,1* Alessandra Bonito-Oliva,1* Mauro Federici,2* Manolo Carta,3 Francesco Errico,1, Salvatore Magara,1 Giuseppina Martella,4 Robert Nistico`,2,5 Diego Centonze,2,4 Antonio Pisani,2,4 Howard H. Gu,6, & Nicola B. Mercuri,2,4 and Alessandro Usiello1,7 (2010). Role of Aberrant Striatal DopamineD1 Receptor/cAMP/Protein
Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect
of Amphetamine Journal of Neuroscience, 30 (33), 11043-11056 : 10.1523/JNEUROSCI.1682-10.2010

A handful of paleontologists have hypothesized that our exponentially shrinking brain (currently 1350 cubic centimeters, previously 1500 cubic centimeters, that being about a tennis ball size difference) manifests from our transition from territorial societies that necessitate aggression to get ahead and survive to more social societies that necessitate charisma to get ahead and survive. Evidence for this derives from other mammalian species that have also transitioned from territorial to social lifestyles, including the wolf and its modern canine relative. Aggression selects for bigger brains, much like more muscle requires more somatosensory cortical space, which was also reported in the article. Comparing us with our Cro-Magnon or even early homo sapiens ancestors, it’s true that we are less stalky, squared-jawed, and muscular than they (though given the rising prevalence of obesity, the anatomical observation that we are smaller than our ancestors is not really valid). In addition, if we compare our Cro-Magnon ancestors, which are the premiere Leonardan, Michelangelan, Picassan, Cezannen, and Machiavellian creative geniuses and social butterflies, we see a tremendous difference in brain size between them and our even more primitive, wallflower ancestors.

I couldn’t access the article (in the September 2010 issue), but this related lecture is equally as informative (and equally as time-fitting….it’s only 8 minutes)

What does it all mean?

As we know, many autistic individuals have phenomenal photographic memories and/or multilinguistic. It’s no surprise that increased cortical volume in specific areas of the brain (the temporal cortex) complement these impressive talents. Also, while watching Temple Grandin the other day, I noticed that she was astutely attentive to complicated objects and patterns, such as pulley systems and busy wallpapers, and would subsequently, calculate angular and architectural dimensions of the objects or form convoluted patterns from the wallpapers in her head. Most people do not possess this magnitude of attentiveness. She also was terrified of entering automatic doors because she equated them with the guillotine used to decapitate cows on her aunt’s farm, and therefore, found it too risky to enter a store with an automatic door. This autistic-stereotypic behavior of Temple Grandin nicely complements the present findings, as the potentiated cortical volume found in the anterior cingulate cortex and orbitofrontal cortex of ASD individuals regulates attention and risk-taking, respectively.

To compare control subjects with ASD individuals, it’s also no surprise that the control group had more representative cortical matter in the frontal association and parietal regions. Though autistic individuals have genius-like talents, including a photographic memory and multilinguism, most have an IQ around 80, limited speech, and poor social intelligence. Though I’m certainly not an expert in autistic research, perhaps it is reduced cortical volumes in these frontal association and parietal regions involved with complex cognition (reading social cues and problem solving) that contribute to the vast cognitive and social differences of autistic individuals. I refrain from using handicap here, because as Temple Grandin said routinely throughout the movie, “I’m different, but no less.”

Christine Ecker,1 Andre Marquand,2 Janaina Mourão-Miranda,3,4 Patrick Johnston,1 Eileen M. Daly,1, Michael J. Brammer,2 Stefanos Maltezos,1 Clodagh M. Murphy,1 Dene Robertson,1 Steven C. Williams,3, & and Declan G. M. Murphy1 (30). Describing the Brain in Autism in FiveDimensions—Magnetic
Resonance Imaging-Assisted Diagnosis of Autism Spectrum
Disorder Using a Multiparameter Classification Approach Journal of Neuroscience (32) : 10.1523/JNEUROSCI.5413-09.2010