Can't control what you eat?

Authors: Richard Simerly & Ralph DiLeone Artificial activation of neurons in the cerebellar region reduces food intake in mice
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This finding may help people with appetite disorders
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Food cravings are one of the strongest driving forces in nature, and pathways that inhibit food intake are essential in order to maintain energy balance
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In calorie-plentiful conditions, our food intake is influenced by a combination of internal states (for example, how hungry we feel) and environmental factors (for example, the aroma or visual appeal of the food)
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When we see or smell good food when we are hungry, we initiate a series of actions and ultimately eat the food
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If we feel full or have no appetite, we may end the meal by pushing the plate away
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Writing in Nature [1], Low et al.
showed that neurons in the cerebellar brain region play a key role in regulating satiety and meal cessation
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Unhealthy eating habits occur when the delicate balance between the urge to eat and the signals that counteract that urge is disrupted
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For example, patients with Prader-Willi syndrome (PWS, a genetic disorder characterized by persistent hunger) are prone to obesity [2]
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Low and colleagues used functional magnetic resonance imaging (fMRI, a technique that visualizes local metabolic changes in the brain to characterize neural activity) to track the brain's response to images of food in both PWS patients and controls
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The authors observed differences in fMRI responses to food images between PWS patients and control subjects in a small region at the base of the cerebellum called the deep cerebellar nucleus (DCN)
.

The authors next used a cell-labeling approach in mice to identify neurons in the outer (lateral) DCN that were activated by feeding
.

Artificial activation of the mice's lateral DCN neurons (using a technique called chemogenetics) resulted in a significant reduction in food intake
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Notably, while feeding frequency and feeding speed were not affected, both feeding volume and feeding duration were reduced, suggesting that these lateral DCN neurons are involved in the process of feeding termination
.

In addition, artificial activation of lateral DCN neurons affected food intake independent of whether the mice were hungry, and did not appear to be related to whether the food was tasty
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The authors then used high-resolution gene expression profiling techniques to identify molecular signatures of these "food-activated" lateral DCN neurons, including the expression of marker genes that distinguish them from other lateral DCN neurons
.

When the mice received food cues, a technique called calcium imaging visualized the activity of cells expressing one of these marker genes
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The results showed that a class of excitatory neurons in the lateral DCN, namely glutamatergic neurons, were activated when food was presented, confirming that the activation of these neurons inhibited feeding behavior in mice
.

The neural circuits that regulate feeding behavior are usually divided into neural circuits that regulate feeding based on "demand" or starvation state, and neural circuits that affect feeding based on "desire" or based on reward [3,4]
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Although the distinction between these behaviors and circuits is not absolute, a brain region known as the hypothalamus may be the central region that mediates responses to the hunger state, and signaling from the neurotransmitter molecule dopamine is involved in the rewarding properties of eating
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Most studies on how the brain controls food intake have focused on the hypothalamus or a closely related brain region [5-7]
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It has long been known that the cerebellum has bidirectional neuronal connections to the hypothalamus
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Low and colleagues showed that while artificial activation of AgRP protein-expressing neurons in the hypothalamus increased food intake, this response was overridden by concurrent activation of lateral DCN neurons
.

Although this finding suggests that the activity of lateral DCN neurons affects the activity of AgRP-expressing cells, direct neural connections have not been demonstrated
.

It is of course also possible that both lateral DCN neurons and AgRP-expressing neurons project to downstream targets to inhibit feeding
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Dopamine is involved in the regulation of various motivated behaviors
.

Here, we found that basal levels of dopamine increased in the ventral striatum (a region of the brain that processes reward) after artificial activation of lateral DCN neurons (Figure 1), suggesting that these neurons may act by affecting the activation of dopamine-releasing neurons.
activity to regulate food intake
.

Activation of lateral DCN neurons also attenuates the rapid, transient (phasic) release of dopamine in the ventral striatum, which typically occurs in response to food or food cues [9,10] and correlates with the value of food reward
.

The researchers used chemogenetic activation of lateral DCN neurons to reduce the activity of dopamine-releasing neurons in mice, thereby reducing basal dopamine levels in the ventral striatum to those of controls
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This manipulation restored the phasic increase in food dopamine levels in these mice, and the authors propose that lateral DCN activation may reduce the reward value of food by increasing background dopamine levels in the ventral striatum
.

Figure 1 | A group of neurons in the cerebellum regulates the reward value of food
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Low et al.
[1] investigated the effect of artificial activation of a group of neurons in the cerebellum on feeding behavior in mice
.

a, Rapid, transient (immediate phase) increases in levels of the neurotransmitter molecule dopamine in another brain region called the ventral striatum, reflecting the rewarding value of food
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b, Artificial activation of a group of neurons in the deep lateral cerebellar nuclei (DCN-LAT) using chemogenetic methods increases background levels of dopamine in mice
.

This elevated background level leads to a decrease in the phasic release of dopamine
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Mice with lateral DCN neuron activation ate less food than control mice—mainly because their single meal durations were shorter than those in the control group
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The relationship between dopamine signaling and food intake is complex, as both high and low levels of dopamine are associated with increased feeding behavior [11,12]
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Furthermore, dopamine neurons encode various types of information related to sensory input, motivation, and learning [13]
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The paper's work can be viewed through the lens of a broader model of dopamine function that emphasizes the role of dopamine signaling in balancing energy conservation and expenditure by regulating whether or not to "utilize" rewards in the existing environment, Or use energy to "explore" and seek more valuable environments to achieve [14]
.

Specifically, the findings of Low and colleagues are consistent with the decreased feeding (representing decreased exploration) observed in mice with higher-than-normal background levels of dopamine [11]
.

The authors suggest that the cerebellum may act as a "brake" on neural networks that promote food intake
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Although the work of Low et al.
did not propose a pharmacological approach to treating patients with PWS, their findings suggest that determining whether lateral DCN neurons can be targeted by such approaches or gene therapy based on our understanding of the genetic basis of PWS, would help [15]
.

Known for its role in coordinating and calibrating movements, the cerebellum is an efficient predictor of the "error" between movement and actual movement, as well as the effect of behavior on subsequent sensory input [16,17]
.

It has also been suggested that the cerebellum filters so-called mutual inductive information—sensory information that encodes internal states [18]
.

Although the specific sensory pathways that influence the activity of lateral DCN neurons remain unidentified, and it is unclear which cell types in the reward circuit are affected by lateral DCN neurons, the results reported by Low and colleagues extend our understanding of the role of the cerebellum as a maintenance Knowledge of sensory and motor signal integrators required for motor balance
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Lateral DCN neurons were found to modulate hypothalamic and dopamine pathway activity, suggesting that the cerebellum may perform a similar balancing act of stopping meals -- with dramatic effects on how much we eat
.

References: 1.
Low, AYT et al.
Nature 600, 269–273 (2021).
2.
Angulo, MA, Butler, MG & Cataletto, ME J.
Endocrinol.
Invest.
38, 1249–1263 (2015).
3 .
Berthoud, H.
-R.
& Morrison, C.
Annu.
Rev.
Psychol.
59, 55–92 (2008).
4.
Castro, DC, Cole, SL & Berridge, KC Front.
Syst.
Neurosci.
9, 90 (2015).
5.
Williams, KW & Elmquist, JK Nature Neurosci.
15, 1350–1355 (2012).
6.
Sternson, SM & Eiselt, A.
-K.
Annu.
Rev.
Physiol.
79, 401–423 ( 2017).
7.
Andermann, ML & Lowell, BB Neuron 95, 757–778 (2017).
8.
Zhu, J.
-N.
, Yung, W.
-H.
, Chow, BK-C.
, Chan, Y .
-S.
& Wang, J.
-J.
Brain Res.
Rev.
52, 93–106 (2006).
9.
McCutcheon, JE, Beeler, JA & Roitman, MF Synapse 66, 346–351 (2012).
10 .
Robinson, JE et al.
eLife 8, e48983 (2019).
11.
Beeler, JA, Frazier, CRM & Zhuang, X.
Eur.
J.
Neurosci.
35,146–159 (2012).
12.
Wang, GJ et al.
Lancet 357, 354–357 (2001).
13.
Engelhard, B.
et al.
Nature 570, 509–513 (2019).
14.
Beeler, JA, Frazier, CRM & Zhuang, X.
Front.
Integr.
Neurosci.
6, 49 (2012).
15.
Chung, MS, Langouët, M.
, Chamberlain, SJ & Carmichael, GG Open Biol.
10, 200195 (2020).
16 .
Krakauer, JW & Mazzoni, P.
Curr.
Opin.
Neurobiol.
21, 636–644 (2011).
17.
Ohyama, T.
, Nores, WL, Murphy, M.
& Mauk, MD Trends Neurosci.
26, 222– 227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602–608 (2011).
The original article was published in Nature on November 17, 2021 under the title Cerebellar neurons that curb food consumption "News and Views" © naturedoi: 10.
1038/d41586-021-03383-9 Activating neurons to suppress inflammation is toxic: A "stay away" history of nerve agents Copyright notice: This article was translated by Springer Nature Shanghai Office13.
Engelhard, B.
et al.
Nature 570, 509–513 (2019).
14.
Beeler, JA, Frazier, CRM & Zhuang, X.
Front.
Integr.
Neurosci.
6, 49 (2012).
15.
Chung, MS, Langouët, M.
, Chamberlain, SJ & Carmichael, GG Open Biol.
10, 200195 (2020).
16.
Krakauer, JW & Mazzoni, P.
Curr.
Opin.
Neurobiol.
21, 636–644 (2011).
17 .
Ohyama, T.
, Nores, WL, Murphy, M.
& Mauk, MD Trends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602– 608 (2011).
The original article was published on the News and Views section of Nature on November 17, 2021 under the title Cerebellar neurons that curb food consumption © naturedoi: 10.
1038/d41586-021-03383-9 Click to read the original text to view the original English text Click on the text or image to read the related article "SpongeBob SquarePants" cells hide secrets of nervous system origin ·Natural Shanghai Office is responsible for translation13.
Engelhard, B.
et al.
Nature 570, 509–513 (2019).
14.
Beeler, JA, Frazier, CRM & Zhuang, X.
Front.
Integr.
Neurosci.
6, 49 (2012).
15.
Chung, MS, Langouët, M.
, Chamberlain, SJ & Carmichael, GG Open Biol.
10, 200195 (2020).
16.
Krakauer, JW & Mazzoni, P.
Curr.
Opin.
Neurobiol.
21, 636–644 (2011).
17 .
Ohyama, T.
, Nores, WL, Murphy, M.
& Mauk, MD Trends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602– 608 (2011).
The original article was published on the News and Views section of Nature on November 17, 2021 under the title Cerebellar neurons that curb food consumption © naturedoi: 10.
1038/d41586-021-03383-9 Click to read the original text to view the original English text Click on the text or image to read the related article "SpongeBob SquarePants" cells hide secrets of nervous system origin ·Natural Shanghai Office is responsible for translation6, 49 (2012).
15.
Chung, MS, Langouët, M.
, Chamberlain, SJ & Carmichael, GG Open Biol.
10, 200195 (2020).
16.
Krakauer, JW & Mazzoni, P.
Curr.
Opin.
Neurobiol 21, 636–644 (2011).
17.
Ohyama, T.
, Nores, WL, Murphy, M.
& Mauk, MD Trends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602–608 (2011).
Original article titled Cerebellar neurons that curb food consumption in the News & Opinion section of Nature on November 17, 2021 © naturedoi: 10.
1038/d41586- 021-03383-9Click to read the original text to view the English original text Click the text or picture to read the related article "SpongeBob SquarePants" cells hide the secret of the origin of the nervous system Electroacupuncture therapy suppresses inflammation by activating neurons Toxic: a nerve agent's "stay away" "History copyright notice: This article is translated by Springer Nature Shanghai Office6, 49 (2012).
15.
Chung, MS, Langouët, M.
, Chamberlain, SJ & Carmichael, GG Open Biol.
10, 200195 (2020).
16.
Krakauer, JW & Mazzoni, P.
Curr.
Opin.
Neurobiol 21, 636–644 (2011).
17.
Ohyama, T.
, Nores, WL, Murphy, M.
& Mauk, MD Trends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602–608 (2011).
Original article titled Cerebellar neurons that curb food consumption in the News & Opinion section of Nature on November 17, 2021 © naturedoi: 10.
1038/d41586- 021-03383-9Click to read the original text to view the English original text Click the text or picture to read the related article "SpongeBob SquarePants" cells hide the secret of the origin of the nervous system Electroacupuncture therapy suppresses inflammation by activating neurons Toxic: a nerve agent's "stay away" "History copyright notice: This article is translated by Springer Nature Shanghai OfficeTrends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602–608 (2011).
The original article was published in 2021 under the title Cerebellar neurons that curb food consumption On November 17, 2019 in the News and Views section of Nature © naturedoi: 10.
1038/d41586-021-03383-9 The secret of the origin Electroacupuncture suppresses inflammation by activating neurons Toxic: A "stay away" history of nerve agents Copyright notice: This article is translated by Springer Nature Shanghai OfficeTrends Neurosci.
26, 222–227 (2003).
18.
Requarth, T.
& Sawtell, NB Curr.
Opin.
Neurobiol.
21, 602–608 (2011).
The original article was published in 2021 under the title Cerebellar neurons that curb food consumption On November 17, 2019 in the News and Views section of Nature © naturedoi: 10.
1038/d41586-021-03383-9 The secret of the origin Electroacupuncture suppresses inflammation by activating neurons Toxic: A "stay away" history of nerve agents Copyright notice: This article is translated by Springer Nature Shanghai Office
.

The Chinese content is for reference only, and the original English version shall prevail
.