Archive for the 'Physiology' category
The Backyard Brains folks are at it again.
Presentation 22.17SU/YY91 will be on display Saturday 1:00 p.m. – Sunday 5:00 p.m. with their presentation time scheduled for Sunday. It is entitled:
The blue light special: a portable, low-cost optogenetics kit for the classroom
The abstract reads:
Optogenetics is an innovative technology for studying brain circuits, but to date the lay public has had little exposure to its potential and limited access to low-cost tools to do experiments. What if you have an interest in cutting-edge neuroscience but you aren’t near a university? What if you prefer to do science in your garage, in a truck-bed, or on a plane on a boat? What if you are a high school biology teacher who wants to keep your students abreast of the most current neurotechnology but the latest millage did not pass? We can help you! We have designed a low-cost, easy-to-build, and portable electrophysiology rig for simple optogenetics demonstrations. The rig consists of a extracellular amplifier (our SpikerBox), a 3D-printed 3-axis micromanipulator, an off-the-shelf monocular 30X microscope, a high intensity blue LED (light-emitting diode), and an LED control circuit that can be precisely controlled with a tailor-made iPhone application or simple tone generator. We have successfully used our first clunky prototype to record blue light-evoked electromyograms from channelrhodopsin-2 expressing Drosophila larvae. We plan to spend the summer refining our prototype (making it more stable, improving control of light emission) and genetic tools. We plan to begin demonstrations in high school classrooms by Fall 2011. We also have other low-cost neurotechnology inventions to show you, so come by our poster to participate in real-time peer review!
Right? RIGHT? You know you think this is cool. Go see their presentation folks, they always amuse, entertain and educate.
Athletes, particularly those that engage in the sustained-activity aerobic sports such as running, cycling and Nordic skiiing, are occasionally to be found describing their chosen physical activity as addictive. Some of them talk about symptoms of anxiety and depression and discomfort when not permitted to engage in their usual level of activity due to injury or other life circumstances. These can sound suspiciously like syndromes associated with addictive drugs, to those of us who are familiar with the type and aware that drug "withdrawal" is not limited to the dramatic symptoms associated with withdrawal from a substantial intravenous heroin addiction.
Is this real, though? Is there something neurobiologically similar to drug addiction about what can happen to the brain in the course of a sustained aerobic exercise habit? To answer these questions it helps, of course, to have an animal model, preferably one that has a lot of similarity to our drug-abuse models.
Eikelboom and Lattanzio published two papers in 2003 that proposed a possible model of exercise-dependence using activity wheels in rats. You will be familiar with the notion that hamsters, rats and mice will run on a treadwheel under single-housed conditions from your local pet store. Drop by one on your way home today if you don't know what I mean. There is also an older behavioral literature that shows that wheel access can act as a reinforcer in laboratory rats- they will press a lever to get a brief interval of wheel running. Manipulating the length of time they can run on the wheel acts, to a first approximation, like manipulating the number of food pellets delivered in a traditional setup.
But just because something is chosen voluntarily and acts as a reinforcer does not necessarily mean that it can model compulsive, repetitive behavioral patterns. It does not necessarily mean that it will tap into the disruption of brain reward pathways and mechanisms that is the hallmark of substance dependency. For this we need a little more evidence, starting with behavior and moving into neurobiology as the evidence mounts.
The background for the Lattanzio and Eikelboom work is the Ahmed and Koob 1998 paper which has become hugely influential in substance abuse models. The short version was that instead of permitting rats an hour of access to intravenous cocaine each day, they permitted the animals 6 hours of access per day. They observed that the 6-hr (termed "Long Access") group took more cocaine than animals run in the traditional 1-hour sessions, perhaps unsurprisingly given the increased opportunity. More importantly, as the sessions of longer access continued, the rats took an ever increasing amount including in the first hour of access. Not only that, but the Long Access group took more cocaine in the very first 10 minutes of the session. This seminal paper has been followed by a lot of additional evidence that this change in the Long Access group is brought about by lasting disruptions of common reward mechanisms.
[Sidebar: You will recall from my posts trying to work out the conditional probability of dependence, that I am not a fan of simple, drug-feels-good models of drug reinforcement; even though they have a place. The short version of my thinking is that we already know from the human epidemiology that a large fraction of the individuals who find that drugs make them feel good do not go on to develop dependence, addiction or what we might term a drug problem. Animal models that move on from the simple feels-good stage of drug taking resonate more strongly with me.]
Lattanzio and Eikelboom set out to provide rats with longer and shorter access to wheel running and see if there was behavioral evidence of the sort of "escalation" that was reported by Ahmed and Koob.
In the first paper the authors compared wheel running in rats who had 24/7 access to the wheel to rats who had only a two hours of access for 24 days. As depicted in the first figure, wheel activity gradually increased in the 24/7 group across the three weeks of study. This is pretty consistent with my reading of the circadian literature and has some interesting implications with respect to the development of aerobic fitness. Activity in the 2-hour group remained stable.
So far so good. They also show that the 24/7 animals ran more in a comparable 2-hr interval, reminiscent of the key first-hour comparison in the drug self-administration paradigm.
Or, they sort of show that.
When they selected the same two-hour interval of the day in which the 2-hr group was exposed to the wheel, the 24-hr animals ran less. A lot less. Because. they. ran. the. 2-hr. group. in. the. light. cycle. Rats are nocturnal and more active in the dark. So when the authors (cherry) picked the most-active 2-hr interval in the 24/7 access group, then yes, it looked like an escalation across the days of training.
Frustrating. A hint of an escalation type of effect with longer access to the wheel but confounded by an inexplicable choice to run the short-access group in the light part of the cycle. Luckily, the authors did not leave off at this one study.
The second paper is more interesting because they run both the longer and shorter sessions in the dark, when rats are most active. In addition they are pitting 1 hr access against only 4 hours of wheel access, instead of a full 24 hrs. So it makes it a little more comparable to the typical drug self-administration experiment. These results are again consistent with escalation of wheel running. In Figure 2B they show that the 4-hour group's wheel running in the first two hours of access increased substantially more with sequential training sessions in comparison with the 1-hour group's running.
These papers are, to my eye, a good first attempt at a model. This is not the answer to whether exercise is addictive or becomes a compulsive behavior similar to drug self-administration. However it shows that we can now go on to ask additional questions which might answer the question. Are the brains of the longer-access rats changing in the same way that the long-access to cocaine rats' brains change? Are they in a state of reward deficit (disrupted allostasis in the Ahmed/Koob handwaving) that generalizes across reinforcers?
If evidence develops for this, we can only then move on to the larger issues. Does a substantial history of exercise leave individuals at risk for reward-related disorders when they stop exercising? Are they at increased liability for compulsive eating or drug abuse? If so, what is the threshold? Etc. Really, there is a lot of fascinating research ahead on this topic.
I have a few current questions about the exercise physiology angle because I know there is a blogger or two around and about that might have some information. Are the physiological changes brought about by wheel running in laboratory rats similar to those we might expect from a human in aerobic conditioning training? The circadian literature shows pretty consistently, to my eye, that daily running in rats given 24/7 access to wheels increases over a several week interval to reach a sustained plateau of daily activity. This suggests that there are perhaps cardiovascular and muscular adaptations at play, in a word "fitness". But then again the sort of exercise that results in human conditioning is sort of aversive at the start, isn't it? We force ourselves to do it because we want to be fit or to race or whatever. We don't do it because every step of the 6 mi run is pure bliss right off the couch, right? So why would rats voluntarily run themselves into this sort of conditioning effect?
Those of us who are looking at this from a perspective of reward mechanisms will eventually need to show that wheel "escalation" is not just a result of a conditioning effect which permits the rats to run for longer distances. Or for that matter a motor skill effect which permits them to tread the wheel bars more efficiently.
Disclaimer: See the Disclaimer page for the usual about my conflicts when it comes to drug abuse research topics. Also, I am professionally acquainted with some of the authors of the work under discussion in this post.
Ahmed SH, & Koob GF (1998). Transition from moderate to excessive drug intake: change in hedonic set point. Science (New York, N.Y.), 282 (5387), 298-300 PMID: 9765157
Lattanzio SB, & Eikelboom R (2003). Wheel access duration in rats: I. Effects on feeding and running. Behavioral neuroscience, 117 (3), 496-504 PMID: 12802878
Eikelboom R, & Lattanzio SB (2003). Wheel access duration in rats: II. Day-night and within-session changes. Behavioral neuroscience, 117 (4), 825-32 PMID: 12931966
sourceA report in Popular Science (authored by Jeremy Hsu) points to a recent paper published in Academic Emergency Medicine. In this, Dawes and colleagues report on an investigation on the effects of TASER on sheep intoxicated with methamphetamine (MA). I was alerted to this by Damn Good Technician who wanted a little bit of context for what would seem to be a WTF? kind of study.
The study was conducted in Dorset sheep who were anesthetized, and administered 0, 0.5, 1.0 or 1.5 mg/kg of methamphetamine HCl (curiously from dissolved Desoxyn, the approved pharmaceutical product) in an IV infusion. The drug treatment was a between subjects factor (N=4 per group) and animals were monitored for "continuous blood pressure, heart rhythm (one-lead), pulse oximetry, and capnography... Arterial blood sampling was performed at baseline, 30 minutes after the administration of the methamphetamine, and after each exposure from a TASER X26".
To answer the question of why?, and for appropriate background on the science try a PubMed search for "cardiac TASER". I note a study in which 5 sec of TASER didn't cause cardiac damage or symptoms in law enforcement trainees and another showing minimal cardiac effects on law enforcement volunteers after vigorous exercise. Also of interest are the case studies of atrial fibrillation in a previously healthy adolescent and recovery of a teen in TASER induced asystole. These, a mini-review by the Dawes group and other searched papers should give you some context and support from the feeling you might have from half-remembered MSM reports over the years that TASER is suspected of being somewhat less than "safe".
What I'm not finding right away is very much about the drug intoxicated suspect who might be TASER'd by law enforcement. Remember this guy? My best estimate was that he was acutely intoxicated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") although that might be one of my blog interests talking. You might also wish to consider some papers found by searching PubMed for "methamphetamine cardiac toxicity", "methamphetamine vetricular fibrillation" and "methamphetamine heart attack".
Together this background would seem to identify a situation crying out for additional study.