The frugal brain

Long-term memory is costly. To encode a memory, the brain needs to synthesize many proteins that ultimately lead to changes in synaptic strength, which is thought to be the molecular mechanism behind memory storage.

So what happens under nutrient starvation?  Does memory storage fail?

Plaçais, P. -Y. & Preat, T. To favor survival under food shortage, the brain disables costly memory. Science 339, 440–442 (2013)

Fruit flies can be trained to learn an association between sugar and an odor (appetitive memory) or an association between a shock and an odor (aversive memory). These little buggers are interesting in that they can form aversive long-term memory in two distinct ways, depending how they’re trained: the first, called anaesthetic-resistant memory (ARM), is formed during “cramming sessions”, in which they don’t get any breaks. This type of memory does not require new protein synthesis. The second, often referred to simply as LTM, needs protein synthesis, and can be formed after multiple training sessions with little breaks in between. LTM can actually repress ARM – during the little breaks, a pair of dopaminergic neurons oscillates to drive the formation of LTM and directly inhibit ARM.

The authors wanted to see how fruit fly brains dealt with memory under starvation. They used two types of mutant flies: the crammer and tequila flies, both of which cannot form LTM but can form ARM (gotta love fruit fly geneticist!).

Using a spaced training protocol (which should allow LTM formation), the authors found that when crammer and tequila were full, they were unable to link an odor to a shock 24 hours after training. However, when they were starved before training, the mutant flies could remember just as well as normal (wild-type) flies. So starvation seems to be activating some sort of mechanism that allows the mutant flies to remember.  Recall that neither mutant flies can form LTM. Since they do retain memory after starvation, are they forming ARM? To address this, the authors used drugs to specifically inhibit LTM and ARM, and showed that indeed, LTM is formed when flies are full, while ARM is formed when they are starved.

How is this change happening? As mentioned before, during rest periods in LTM-forming spaced training sessions, two dopaminergic neurons (MV1 and MP1) show oscillatory behavior that shuts down ARM. The activity of these neurons can be monitored by the amount and pattern of calcium release.  The authors found that starved flies indeed showed less oscillation between the two neurons.

So are MV1 and MP1 gatekeepers to LTM formation? Amazingly, the authors showed that in starved flies, artificially driving oscillation between the two neurons was enough to form LTM! This means that the brain voluntarily shuts down LTM formation in favor of ARM when nutrients are scarce. Why does this happen?

As mentioned above, LTM requires protein synthesis, and is much more energy demanding than ARM.  Under the stress of starvation, spending energy on LTM when ARM is an available option may further compromise energy balance. Indeed, the authors found that when LTM formation is artificially induced in starved flies, they die prematurely, which a life span ~70% of flies that were not driven to form LTM.

These experiments show that the brain is frugal: under nutrient starvation, it cuts down on its own energy expenditure to allow survival of the organism. It is interesting to speculate to what extent this finding translates to mammals. It is well known that starvation can interfere with memory formation by activation of cortisol receptors. Decreased blood sugar levels impair memory retrieval - patients with anorexia nervosa often show multiple-faceted memory deficits. It would be interesting to see if the mammalian brain has some sort of “counter measure” to retain its function in face of starvation.

PS. On a more personal note, I am currently on a ketogenic diet, often used clinically to treat intractable seizures. The diet requires an 80/15/5% energy split to come from fat, protein and carbohydrates, respectively. Hence the diet drastically reduces glycogen levels and forces the brain to use ketones in place of glucose as its major source of energy. In a sense it is a “starvation diet” without lowering overall calorie count. I’m doing an n=1 unblinded experiment to see if this metabolic switch alters memory, attention and normal brain function.

Plaçais PY, & Preat T (2013). To favor survival under food shortage, the brain disables costly memory. Science (New York, N.Y.), 339 (6118), 440-2 PMID: 23349289

Image: http://www.gregadunn.com/