Nat Neurosci He Yanlin/Xu Yong team discovered and revealed a new regulatory mechanism of anorexia nervosa

Editor-in-Chief | Anorexia Nervosa (AN) refers to an eating disorder in which individuals deliberately cause and maintain a significantly lower body weight through dieting and other means, and is one of the mental diseases with high fatality rate [1]
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Its main symptoms are extreme attention and cognitive confusion about one's own body, self-fasting, significant weight loss and high-intensity exercise, often accompanied by anxiety, metabolic and endocrine disorders [2], and severe physical and psychological morbidity.

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In recent years, with the development of globalization, changes in dietary habits and changes in women's social roles, the incidence of anorexia nervosa has increased significantly [2]
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At present, the pathogenesis of anorexia nervosa is not clear, and the treatment methods are limited [2,3]
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Previous studies have shown that dopamine (Dopamine) neurons located in the ventral tegmental area (VTA) of the midbrain and serotonin (5-HT) neurons located in the dorsal raphe nucleus (DRN) of the midbrain can participate in the regulation of food intake.
Motivated behaviors [4,5], they have also been found to be associated with the pathogenesis of anorexia nervosa [6]
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However, how these two types of neurons work through neural circuits is unclear
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On May 2, 2022, the research team of Professor Xu Yong from Baylor College of Medicine and Professor He Yanlin from the Pennington Biomedical Research Center of Louisiana State University jointly published a paper entitled A D2 to D1 shift in the journal Nature Neuroscience.
The research paper on dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice is the first to report the regulation of dopaminergic neurons → 5-HT neurons in the ventral tegmental area of ​​the midbrain-dorsal raphe nucleus (VTA→DRN).
Appetite and anorexia nervosa
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The research team first used a transgenic mouse model, neural circuit tracing and electrophysiological techniques to demonstrate that dopamine neurons in the VTA brain region can project to 5-HT neurons in the DRN brain region (DAVTA→5-HTDRN), and found that dopamine The receptors DRD1 and DRD2 are co-expressed on a subset of 5-HTDRN neurons
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At the same time, they found that low concentrations of dopamine inhibited 5-HTDRN neurons by binding to DRD2 receptors, while high concentrations of dopamine activated 5-HTDRN neurons by binding to DRD1 receptors
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The researchers injected the light-activated channel protein vector (AAV-DIO-ChR2) into the VTA brain region of DAT-CreER mice and made it specifically expressed on DAVTA neurons
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Combining patch-clamp and optogenetic techniques, they found that 5-HTDRN neurons could be modulated differently after 473nm blue light activated dopamine neuron fiber projections in the DRN brain region
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Low frequency (2Hz) blue light stimulation can inhibit the activity of 5-HTDRN neurons through DRD2 receptors, but high frequency (10-30Hz) blue light can activate 5-HTDRN neurons through DRD1 receptors
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More interestingly, the DAVTA→5-HTDRN neuronal circuit mediated by DRD2 or DRD1 receptors could increase or decrease feeding, respectively
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Next, the researchers used a fiber optic recording system to record calcium ion signals and dopaminergic neurons projected to the DRN during starvation and feeding in a mouse model of anorexia nervosa (Activity based anorexia, ABA) and control mice.
Dopamine signaling in DRN brain regions
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The results showed that the two signals in the control group were significantly increased after fasting and gradually decreased with the prolongation of feeding time
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Interestingly, both signals remained highly active in mice with anorexia nervosa relative to controls
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The research team then used chemogenetics to selectively inhibit the DAVTA→5-HTDRN neural circuit and found that it partially reversed symptoms of anorexia while improving survival in mice with anorexia nervosa model
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The research team also used transgenic mice to further knock out the DRD1 receptor on 5-HTDRN neurons.
They found that after knocking out the DRD1 receptor expressed by 5-HTDRN neurons, the anorexia nervosa mice had significantly reduced anorexia symptoms.
; If the DRD2 receptor on 5-HTDRN neurons is knocked out, the weight of the mice is significantly reduced and the food intake is reduced, which makes them more prone to anorexia
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In conclusion, this study revealed the bidirectional regulation mechanism of DAVTA neurons on 5-HTDRN neuronal activity using electrophysiology, molecular genetics, optogenetics, neural circuit tracing, and gene knockout
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Low concentrations of dopamine inhibit 5-HTDRN neuronal activity through DRD2 receptors; high concentrations of dopamine activate 5-HTDRN neuronal activity through DRD1 receptors
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DAVTA neurons will further increase or decrease feeding by inhibiting or activating 5-HTDRN neuronal activity
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Interestingly, the research team found through studies in anorexia nervosa model mice that when the regulation mode of DAVTA neurons on 5-HTDRN neurons is switched from DRD2 receptors to DRD1 receptors, this is the cause of anorexia nervosa.
underlying pathogenesis of symptoms
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The team's research results also showed that DRD1 receptor antagonists could partially alleviate anorexia symptoms in anorexia nervosa mouse model, thus confirming that the DRD1 receptor expressed on 5-HTDRN neurons can be used as a treatment for anorexia nervosa.
potential target
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This study deeply revealed the complex regulation mechanism of DAVTA→5-HTDRN neural circuit on appetite, and provided a new idea for the treatment of anorexia nervosa
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Dr.
Cai Xing (now an assistant researcher at the Kunming Institute of Zoology, Chinese Academy of Sciences) and Dr.
Liu Hailan at Baylor College of Medicine are the co-first authors of this article, and Professor He Yanlin of the Pennington Biomedical Research Center at Louisiana State University and the Baylor College of Medicine's co-first authors Professor Xu Yong is the co-corresponding author of this article.
Other participating researchers include Dr.
Feng Bing from Louisiana State University, Dr.
Wang Chunmei, Dr.
Wu Qi from Baylor College of Medicine, Dr.
Xu Pingping from the University of Illinois at Chicago, Texas State University Health Research Center Houston Campus ( UT Health Science Center at Houston) Dr.
Tong Qingchun,
etc.

Professor Xu Yong (yongx@bcm.
edu)'s research group welcomes postdoctoral fellows, visiting scholars and exchange students.
The website of the research group is as follows: https:// Dr.
Yanlin He (Yanlin .
He@pbrc.
edu) research group recruits postdoctoral fellows and visiting scholars.
The website of the research group is as follows: https:// Dr.
Cai Xing ( caixing@mail.
kiz.
ac.
cn), the research group of Kunming Institute of Zoology, Chinese Academy of Sciences recruits master and doctoral students.
The website of the research group is introduced as follows: http://sourcedb.
kiz.
cas.
cn/zw/zjrc/201907/t20190703_5332056.
html Original link: https://doi.
org/10.
1038/s41593-022-01062-0 Publisher: Eleven References 1.
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