Your gut is talking, and your brain is listening
The fact that your digestive system communicates with your brain is nothing new. Your stomach tells your brain you’re full, your intestine might suggest it’s time to find a toilet soon. The gut has its own little brain, the enteric nervous system. Until recently, it was thought that the communication between the brain and the enteric nervous system was only indirect. The brain or the gut can secrete hormones and other signalling molecules, and these travel through the bloodstream to eventually have their effects.
Now, as reported in Science, Kaelberer et al show there is a far more direct route of communication. At least in the mouse, there is a direct nervous connection between the gut and the brain. The starting point was the observation that the signalling cells in the gut, the enteroendocrine cells, make peptides such as CCK and PYY which are normally released into the blood as hormones. However, these can also function as direct neurotransmitters at synapses.
Using a modified rabies virus, which only spreads through synaptic neuronal connections, they show these enteroendocrine cells do connect to a prominent nerve fibre called the vagus nerve, as well as the brainstem. The authors managed to recreate this system in a dish by culturing cells from the vagus nerve and this intestine, and not only showed that these wire up, but that the nerve cells respond to nutrients such as glucose. Through a series of experiments, they were able to confirm that it’s the enteroendocrine cells talking to the nerve cells causing this response.
Using optogenetics, a technique that allowed for cells to be turned on or off at will by exposing them to light, they show that activating or blocking the signalling from enteroendocrine cells modifies the firing rate of the vagus nerve. Doing this modifies the response to a glucose stimulus, and significantly affected the feeding behaviour of the mouse, showing this system has a real function. Far from just being an organ to absorb food, it seems more and more the case that the gut can have a real influence on our behaviour.
Microglia don’t like fat
Ok, I think we might be hitting peak microglia soon, they do seem to be involved in absolutely everything these days. This new study from Elisabeth Gould’s lab looks at the role of microglia in obesity. Something most people (including me!) might not have realised is that life-long obesity is associated with a decline in cognitive functioning, such as memory impairments.
In this study, mice were fed a high fat diet, leading to high levels of obesity (40 grams might not sound much, but it makes for a pretty chubby mouse….). These obese mice did perform worse on a number of cognitive tasks than the normal diet controls. Looking closely at the brains of these mice, they saw a decreased density of synaptic spines, or in other words, reduced numbers of connections between neurons.
As I’ve discussed before, one of the most prominent suggested non-immune functions of microglia is synaptic pruning, or the removal of weak neuronal connections. Could this process be going wrong here? Indeed, the authors saw increased activation of microglia in the obese animals, and more of them on or around synapses.
Genetically blocking microglial activation by knocking out the gene CXCR1 meant obese mice didn’t develop changes in neuronal connectivity or cognitive problems. Treating the mice with the anti-microglial drug minocyline, or inhibiting synaptic pruning with annexin-V for several weeks gave the same results, showing these deficits can be reversed.
So why would this be the case? It has been known for some time that chronic obesity can lead to low level inflammation. This can lead to higher levels of inflammatory proteins such as interleukin 6 and CRP. It is quite likely these inflammatory factors in the rest of the body turn on the microglia in the brain, which then in turn do neuronal damage. Would be a good hypothesis to test!
Hit the loop button to remember
As any student who has ever revised for an exam knows, repetition will help things stick. The brain knows this as well. There has been a lot of work in rodents where animals have been trained to run on a maze. This training is reflected by brain cells firing at specific places in a maze. When you record the activity of these cells when the animals sleep after the training, these exact same cells become active again, in the exact same order as if the animal was running on the maze again. If you disrupt these process, the animal won’t learn the maze as well. This phenomenon has also been seen in humans, brain areas that have been activated during a task also get activated in rest periods afterwards, and the hypothesis is that, as in rodents, this helps with consolidating memories.
In a cool study in Nature Communications, Shapiro et al present data that suggests this is in fact true. In the first session, volunteers were presented with a series of images of objects and asked to remember their specific features. Brain activity was measured by fMRI during the training and when subjects were tested on their memory of the objects. Afterwards, they were scanned while not seeing the subjects or being tested. Twelve hours later, this was repeated.
What they found was that interestingly, in the period after the testing, the brain activity patterns correlating to the objects that were remembered the worst were replayed by the brain the most. It is almost like the brain known which memories it needs more practice on. Evidently this practise works, as those memories which were replayed most often after session 1 were best remembered in the second session, 12 hours later.
However, this was only strongly the case in one situation; if the participants slept in between the sessions. If the two sessions were on the same day, there wasn’t anywhere near as strongly an effect of replay. So, all in all this would suggest there is a scientific reasoning for the old advise to keep revising and get a good night sleep before an exam.
Neurogenesis as a therapeutic mechanism? Hit the ground running
The formation of new neurons, or neurogenesis, in the adult brain is limited and restricted to certain areas such as the hippocampus – this is why losing neurons is such a big deal, most of the time, you can’t replace them. Hippocampal neurogenesis is required for a variety of memory processes and is disrupted in many diseases. There have been attempts to increase neurogenesis as a therapeutic strategy, mainly in depression, but so far this has not been successful.
Writing in Science earlier this month, Choi et al show an approach that might change this. Their study uses a transgenic mouse model of Alzheimer’s disease (how valid these models are is a good question, but that is a different debate). These animals start showing learning and memory problems as they age. The authors show that just increasing hippocampal neurogenesis with drugs either did not improve the performance of the animals in memory tasks, or showed at most a modest improvement, depending on the sex of the animals and the specific task.
However, if the treatment was combined with exercise, which is also known the stimulate neurogenesis, there was a much more robust increase in performance. On the other hand, exercise alone did not cause an improvement either, only the combination did. In the reverse experiment, they showed that blocking neurogenesis worsened task performance.
So why is this combination effective when the individual treatments aren’t? It is known that exercise increase the levels of BNDF, a factor which supports the survival of neurons. The authors showed that increasing BNDF levels mimicked the actions of exercise. Although they do not directly show it, the idea is that you require the beneficial effects of exercise, through increased BDNF levels to help the new neurons survive and give a functional improvement.
As good as that seems, the increases in test performance are still modest, and getting this to work in humans would be a challenge. Nevertheless, interesting data.
Stay tuned for more posts here on Neuroscience Ramblings, and in the mean time, follow me on Twitter: @DrNielsHaan
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