A few months ago my stack of papers began to slide, and one from Nature Neuroscience ended up at the top of the pile.  That always makes me flinch a bit, because Nature Neuroscience is rather advanced. In most papers every other word is an abbreviation for some sort of obscure brain chemical or neurologic process which makes for a lot of blinking and re-reading. Fortunately, for the same reason, most Nature Neuroscience papers are very short.

Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

Endocannabinoids! I know! Those are our innate chemicals that stimulate the endocannabinoid receptors, which happen to also be stimulated by the merry-making chemical known as THC in marijuana. I am not, personally, a marijuana fan, having seen too many psychotic young people brought in by parents after a summer of six bowls a day, and also seeing a few too many older folks who could barely put a sentence together after four decades or more of heavy use. And of course the innumerable people with lack of motivation, weight gain, and rebound anxiety "but I just smoke one or two puffs a day, doctor." And I'm sorry, you really aren't as interesting as you think you are when you are high. It's just cold hard fact. It is especially uninteresting in the emergency room at 3 a.m. Trust me.

I don't suggest that marijuana is 100% evil or entirely uninteresting from a neuroscience point of view.  I do see the downside to it, however, quite frequently.

But back to our own natural and innate versions of the funny cigarettes... we have our little endocannabinoids (the most famous in neuroscience circles being anandamide and 2-arachidonoylglyceral (2-AG)) that stimulate our endocannabinoid receptors.  They serve a very useful purpose in the brain. In fact, there was a great hub-bub a few years back about a potential new weight loss drug, rimonabant. This drug blocked the cannabis receptors, leading to weight loss. (The appetite regulating hormone leptin will short-circuit the binding of endocannabinoids in the hypothalamus, decreasing appetite and resulting in weight loss (1))

I believe rimonabant was approved in Europe and may be in use there. However, it was never FDA approved in the US due to some unfortunate side effects such as anxiety, depression, insomnia, mood swings, and even aggression (2). The longer you were on rimonabant, the worse the side effects became. In fact, a doctor in Texas had his license suspended after prescribing himself rimonabant for weight loss, and then becoming erratic and aggressive at his place of work.

So what on earth is going on with those endocannabinoid receptors, and what does that have to do with omega 3s and mice? Back to the paper, which I have obviously been avoiding attempting to translate into understandability for a couple of paragraphs now. These researchers had two groups of mice, one born after a pregnancy of omega 3 supplementation (flax oil) and then continued on supplementation. The other group was fed a diet rich in peanut oil (mostly linoleic acid - omega 6) without omega 3s. Then the researchers used some very sophisticated machinery and lots of abbreviations to prove that "dietary PUFAs influence eCB-mediated synaptic plasticity... in PFC slices prepared from mice that had received an n-3 diet, tetanic stimulation induced a robust eCB-LTD of excitatory synapses onto layer V/VI pyramidal neurons in the PrPFC."

Roughly translated, our brain has off switches if we get too much stimulation in one area. For example, have a buddy poke you in the forehead between your eyes repeatedly. At first you won't be able to stop blinking when the finger comes close, but after a while, you can keep your eyes open. This is a process called "stimulus extinction" or "extinguishment."

There is a lot of evidence that problems such as psychosis and even depression develop because certain signals just keep going and going and going and getting through, without extinguishing. In the brain, a signal that goes on too strong for too long will result in a process called "long term depression" (LTD). Simply stated, a repeated signal ad nauseum or a signal that is too strong will result in the synapse being modulated to reduce the signal strength. This process is an important part of "synaptic plasticity." And it turns out this process is modulated in the mouse prefrontal cortex by the endocannabinoid system. And in mice raised on a lifelong diet deficient in omega 3 fatty acids, the long term depression did not occur in the prefrontal cortex. This means the omega 3 deficient mice had decreased neuronal plasticity. Their brains were, essentially, more brittle, less flexible in responding to different stimuli.

The researchers used excessive abbreviations to prove that it was the endocannabinoid systems affected in the mouse, not a myriad of other systems one might suspect in the brain.

There is an interesting wrinkle.  Polyunsaturated omega 6 fatty acids(PUFAs) happen to be the precursors to our own natural funny cigarette compounds, anandamide and 2-AG. It is possible that a high level of PUFAs result in an excess of natural funny cigarette compounds (OMG, that soybean oil ranch dressing was like, so totally amazing man) which then saturate and perhaps desensitize our endocannabinoid receptors. In this mouse paper groups of lifetime n-3 deficient and n-3 replete mice had equal circulating levels of natural endocannabinoids in their little mouse brains. In other papers, there were differences, suggesting that there may be compensatory mechanisms for endocannabinoid levels.

So, what are the effects of omega 3 deficiency on mouse behavior again? They are more depressed, are less motivated and explore their environments less. They scratch more, indicating anxiety. They also avoid open spaces and like to remain close to walls, also thought to be a sign of mouse anxiety. The researchers then gave the sad and nervous mice of control and omega 3 deficient groups some cannabinoid agonists (not puff the magic dragon, but another one hilariously called WIN), and the mice perked up and started hanging out in the middle of open space again, and presumably began planning trips to the minimart for twinkies and bugles. The omega 3 deficient mice were less responsive to WIN than the regular mice, consistent with the theory that cannabis receptor functioning was a bit shorted out in the omega 3 deficient mice.

There is a lot to like about this paper. It doesn't answer all questions, to be sure, but it brings up plausible links between industrial diets, depression, anxiety, and even possible connections to hypothalamic dysfunction, leptin, and obesity. It plugs some missing links in the overall picture of mood and appetite regulation. Excellent.

Photo credit

Thanks to Jamie for pointing out the paper, as always!

Copyright Emily Deans, M.D.

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