Nature Neuroscience: Want to drink Coke after eating fried chicken? The Zhejiang University team found that a high-fat diet promotes the proliferation and activation of microglia, leading to inflammation of specific brain areas and greatly increasing appetite for sugars

*For medical professionals only

In today's era of thin beauty, the singularity cake, as a fat man wearing 3XL clothes, has already set up countless weight loss flags, but has repeatedly lost under the temptation of milk tea/ice cream/doughnut, knowing that these sweets are not conducive to health, but the concubines just can't control their mouths!!!

Scientists call this "compulsive sugar-seeking behavior," and in nature it is manifested as animals choosing to seek or ingest high-energy foods
despite knowing that adverse outcomes or dangers are likely.

So why do fat people have this compulsive behavior?

Yudong Zhou/Yi Shen's team from the Department of Brain Science and Brain Medicine of Zhejiang University School of Medicine published a major research on
the neural mechanism of compulsive behavior in Nature and Neuroscience.

They found that high-fat diet (HFD) mice were not afraid of the dangers of electric shock and stubbornly behaved more frequently
than mice on normal diets.

This is mainly due to the fact that HFD promotes the proliferation and activation of microglia in the brain, leading to inflammation of the anterior parathalamic nucleus (aPVT), which in turn makes the central nervous system of the brain abnormally excited
in foraging decisions when facing danger.

As a result, the metabolic inflammation of aPVT caused it to ignore the red flags, causing the mice to have a growing appetite and enter a vicious circle[1].

This study provides an important neurological mechanism
for HFD to promote compulsive sugar-foraging behavior.

Article cover

It is well known that both humans and animals prefer high-energy foods [2].


Scientists have found that excessive intake of HFD can lead to compulsive foraging behavior [3, 4].


However, the mechanism of its neuroadaptive response is unclear
.

So, the team compared the compulsive sugar-foraging behavior of HFD mice in a Skinner box (Figure 1
).

In this box, mice are first trained to earn sugar water rewards by pressing the lever, establishing an "operant conditioned reflex" that records the number of
lever presses every 30 min.

Subsequently, a "phobic conditioned reflex" is established by using a suggestive flashing light with a foot shock – each time the mouse presses the lever is pressed there is a 50% chance of flashing conditioned stimulation, and every 5 flashing conditional stimulation is accompanied by 1 foot shock
.

Figure 1.

After 1 week of training, the research team found that the flashing conditional stimulation made normal diet mice afraid to press the lever, however, in the HFD group, the stimulation only moderate the number of lever presses in the mice (Figure 2).

Figure 2.

In the presence of flashing conditional stimulation, HFD mice explored levers and trays for longer than mice in the normal diet group (Figure 3A), and they had sugar-foraging behavior after almost every lever press (Figure 3B).

After 1 week of training, the HFD group had been successfully induced to compulsive sugar-foraging behavior and their weight increased rapidly, while the HFD mice performed the same in the sugar-free water test as
the mice in the normal diet group.

This obsessive-compulsive sugar-foraging behavior in HFD mice suggests that a daily overfatty diet will cause animals to be more inclined to take risks for higher energy food rewards
.

Figure 3.

Next, the research team explored the neural mechanisms
of HFD-induced compulsive foraging behavior.

After compulsive glucosom-seeking behavior testing, they found that the aPVT region of mice in the HFD group was significantly activated (c-fos) (Figures 4A, 4B), which primarily regulates foraging behavior [5-7].


Moreover, more than 70% of activated cells in aPVT (c-fos positive) are also accompanied by CaMKIIα positive (Figure 4C
).

Figure 4.
A: Neural activation in the aPVT region of mice (positive for c-fos); B: Proportion of nerve activation in area; C: CaMKIIα-positive cells in proportion of c-fos-positive cells

Subsequently, they found that whether it was a normal diet mouse or an HFD group of mice, simply pressing the lever did not cause changes
in the^CaA2+ signal in the aPVT CaMKIIα-positive nerve.

However, when a lever press is accompanied by a flashing light conditioned stimulation, a violent^Ca2+ transfer signal occurs, and the^Ca2+ transfer signal of mice in the HFD group is significantly stronger than that in the normal diet group (Figure 5
).

More interestingly, regardless of whether the flashing conditional stimulation was accompanied by a foot shock, the shape of the^Ca2+ transfer signal in aPVT was not significantly altered
.

The above results show that in the compulsive sugar-foraging behavior of HFD mice, the CaMKIIα-positive nerve in aPVT only has a specific response
to the flashing conditional stimulus.

Figure 5.
APVT CaMKIIα-positive neural Ca2⁺ signal intensity under different conditions in each group

To confirm that CaMKIIα-positive nerve activation in aPVT is involved in regulating obsessive-compulsive foraging behavior, the research team used optogenetic techniques to activate the aPVT CaMKIIα-positive nerve in normal diet mice, and found that the number of lever compressions in mice (ChR2-on) where aPVT CaMKIIα-positive nerves were activated was significantly higher than in mice in the unactivated group (ChR2-off) (Figure 6A).

Conversely, after using CNO specifically inhibited the aPVT CaMKIIα-positive nerve of HFD mice, the number of lever presses under flashing conditional stimulation was significantly lower than that of unsuppressed mice (Figure 6B).


These results suggest that the activity of aPVT CaMKIIα-positive nerves is the main driver of compulsive sugar-foraging behavior in mice
.

Figure 6.
aPVT CaMKII α the number of times a mouse presses a lever on a positive nerve in an activated or inhibited state

So, how does HFD activate the CaMKIIα-positive nerve in aPVT?

They first found that HFD causes a significant increase in the number of Iba-1-positive microglia in aPVT, indicating that HFD induces inflammation
in aPVT.

And, these Iba-1-positive microglia are in extensive contact
with c-fos-positive CaMKIIα-positive nerves.

Subsequently, they used PLX3397 or anti-CSF-1 antibodies to inhibit the proliferation of microglia, and found that the excitability of c-fos-positive neurons in aPVT in HFD mice was inhibited, and the compulsive sugar-seeking behavior was also inhibited
.

These results show that the inflammation caused by the proliferation of small glial cells induced by HFD in aPVT is the main cause
of compulsive feeding in mice.

All in all, foraging due to aPVT inflammation of the brain regulates the abnormal activity of nerve cells and plays a key role
in compulsive foraging behavior.

From the perspective of biological evolution, in the case of food shortages, the adaptive response of aPVT induced by HFD is very important for the survival of animals; However, in today's human society, developed countries and some developing countries have a general surplus of food, the human brain still retains the hunger years of the desire for high-calorie food, the body will be forced foraging behavior "hijacked" and lead to obesity
.

It can be seen that reducing the high-fat diet is definitely the first principle to stop the weight from "snowballing"!

Resources:

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, et al.
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 Nat Neurosci, 2022.
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The author of this article Chen Weiwei

Editor-in-charge Daisi Rain