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Fasting Fruit Flies: Improved Focus and Brain Power

Fasting Fruit Flies: Improved Focus and Brain Power

Fasting: solely religious or also beneficial for focus and brain power?

Recently, Japanese scientists observed fruit fly behavior, taking another step in answering this diet-related question. These insects do not solely fly around rotten fruit, they are also frequently-used animal models to study brain function. The research described below links fasting and hunger to formation of long-term memory.

Procedure: Choosing the odor

To test the link between long-term memory (LTM) and fasting, most fruit flies (scientifically named: Drosophila melanogaster) fast before a single training, feed themselves and undergo a LTM-test (picture left, I&II). To validate the effect of fasting, control fruit flies undergo spaced training (multiple trainings), fast continuously and/or do not fast at all (picture left, III&IV).

During this training, groups of 100 fruit flies (experimental groups and control groups) were put inside two tubes (for one minute sequentially), both containing a stinky odor: 3-octanol (OCT, mushroom-like and buttery smell) or 4-methylcyclohexanol (MCH, benzene-like smell) (picture right). One of these odor-tubes delivers a non-lethal but disturbing electrical shock of 60V (CS+, odor 1, left picture right) for 1,5 seconds, the other odor-tube does not deliver a shock (CS-, odor 2, middle picture right).

fruitfly, brain, ltm, memory, fasting, benificial24 hours later, the olfactory-trained fruit flies enter an elevator (deep purple square, right picture right) that sends them to the T-maze, choosing for the CS+ odor or the CS- odor at the T-junction of the maze (right picture right). The performance of the fruit fly groups is determined by the amount of fruit flies who choose odor 2. To exclude the possibility that the specific odor itself is decisive, both odors were used as odor 1 and odor 2 during the investigation.

Fasting-dependent long-term memory formation

A single aversive training is enough to cause substantial formation of fasting-dependent long-term memory (fLTM) in fruit flies. More specifically, if fruit flies fast 9-16 hours before a single training (moderate fasting) and they feed themselves between training and test, they show a higher LTM than flies that fast continuously or do not fast at all. In other words: fasting before training is helpful for LTM-formation, but fasting before training AND between training and test is not. Interestingly, this aversive fLTM formation is very similar to the conclusions of earlier research on fLTM formation after appetitive training. In an appetitive test, fruit flies are trained to choose the odor linked to a sweet reward (instead of avoiding the odor linked to an electrical shock punishment in the aversive test).

Fasting and the relevance of hunger

These results show that a combination of moderate fasting and only a single training (aversive or appetitive) is enough to cause substantial LTM in fruit flies. So what is the link with hunger? Fasting triggers hunger and this hunger could trigger fruit flies to be more alert during training (focus) and learn more effectively (brain power) than their non-fasting counterparts. In natural environments, hungry fruit flies could use an increased learning ability to discover new ways to get food. Nevertheless, long fasting is not helpful (even after multiple trainings) and after 50 hours of fasting, flies die from starvation. The actual relevance of the increased LTM for hungry flies is still subject of investigation.

The molecular backgroundruitfly, brain, ltm, memory, fasting, benificial

Formation of fLTM depends on the expression and activity of CRTC proteins in neurons of the so-called Mushroom Bodies, a prominent structure in the insect brain that is involved in learning (green structure in fruit fly picture). If CRTC is continuously active, CRTC induces fLTM formation without fasting activities. In natural circumstances, CRTC is activated by the reduced presence of insulin on the cell. Insulin is highly present after a meal and it allows glucose (a prominent nutrient) to enter the cell. This mechanism underlines the importance of CRTC during fasting. In moderately fasting fruit flies, CRTC-activity increases before training (during fasting), but they also profit from this activity during the test (after the 24 feeding period). In this and other fruit fly research, genetically modified fruit flies were necessary to show the relevance of specific molecules, in this case high CRTC and low insulin.

Because CRTC is the central protein in Mushroom Bodies, it drives the hunger-induced LTM in fruit flies. If this molecule is highly present and active in Mushroom Bodies, it binds and activates a protein called CREB, which is needed for LTM (picture above). CBP is another activator protein of CREB, however, multiple trainings are necessary for the formation of CBP-dependent LTM. Active CREB  binds to CREB-binding sites on the DNA in neurons, contributing to the synthesis of many proteins related to hunger-management and memory.

What do fruit flies have to do with us?

LTM-formation of fruit flies is a well-developed field of research which is more than 40 years old. It evolved from a purely behavioral field to a molecular-behavioral field. This fruit fly research is a relevant, quick and cheap predecessor (300 USD and six weeks for gene modification) of similar rodent research (thousands of USD and many months for gene modification). Subsequent rodent studies highly influence research on LTM-formation in humans (no gene modification allowed, unless as gene therapy).

If LTM-formation in human subjects is improved after moderate fasting (one or a couple of days), policy makers and food experts should make moderate fasting more attractive for citizens. However, from fruit fly research to human reality can take more than 10 years. In the meantime, if one prefers to perform an activity that approaches the fruit fly experiment: Fast for one or two days and venture this odor-rich game with non-fasting competitors.

References:
Hirano Y, Masuda T, Naganos S, Matsuno M, Ueno K, Miyashita T, Horiuchi J, & Saitoe M (2013). Fasting launches CRTC to facilitate long-term memory formation in Drosophila. Science (New York, N.Y.), 339 (6118), 443-6 PMID: 23349290
Hirano Y, & Saitoe M (2013). Hunger and memory; CRTC coordinates long-term memory with the physiological state, hunger. Communicative & integrative biology, 6 (5) PMID: 24265850
Altarejos JY, & Montminy M (2011). CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature reviews. Molecular cell biology, 12 (3), 141-51 PMID: 21346730
Dubnau J (2012). Neuroscience. Ode to the mushroom bodies. Science (New York, N.Y.), 335 (6069), 664-5 PMID: 22323806
Krashes MJ, & Waddell S (2008). Rapid consolidation to a radish and protein synthesis-dependent long-term memory after single-session appetitive olfactory conditioning in Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28 (12), 3103-13 PMID: 18354013
Quinn, W., Harris, W., & Benzer, S. (1974). Conditioned Behavior in Drosophila melanogaster Proceedings of the National Academy of Sciences, 71 (3), 708-712 DOI: 10.1073/pnas.71.3.708
Pandey UB, & Nichols CD (2011). Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological reviews, 63 (2), 411-36 PMID: 21415126
Mushroom body QA

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